Lifetime medication burden from current approaches to LDL-cholesterol (LDL-C) lowering is reliant on small molecules requiring daily dosing with the burden of responsibility placed upon patients. Patient-related factors (risk perception, health literacy) impact adherence and persistence. Adherence to statins and ezetimibe correlate with LDL-C reduction and risk, potentially accounting for approximately 12 000 avoidable cardiovascular events per 500 000 patients annually (1). Attempts to improve adherence have had mixed results with only textmessaging reminders, community health worker-based reinforcement and fixed-dose combination pills shown to be effective at improving adherence and clinical events (2). Patienttailored strategies combining multiple approaches including in-person consultations may yield better outcomes, but implementation is complex, consuming both time and resource. Obesity and smoking cessation have been tackled with monetary compensation. Technology offers scalable low-cost options for pill and refill reminders through the use of telephone calls, text-messages, and mobile apps. Finally, a crucial barrier to long-term adherence is the asymptomatic nature of cardiovascular risk factors which may impact medication adherence. This could be facilitated by simplifying access to prescriptions and refills, through electronic healthcare solutions that connect pharmacies to electronic patient records and enable automated prescriptions. Here we draw on population studies and therapeutic developments to potentially address the issue of adherence and lifetime exposure to LDL-C.

Background:The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood.Methods:In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories.Results:Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12–6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33–3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82–1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes.Conclusions:Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction.Clinical Trial Registration:https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Background:People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV–) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.Methods:We studied 1123 men (589 HIV+ and 534 HIV–) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1–quartile 3]: 78.3 [66.3–83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Results:Mean (SD) age was 60.1 (11.9) years among HIV– and 54.2 (11.2) years among HIV+ participants (P<0.001), 83% of whom had undetectable (<20 copies/mL) HIV-1 viral load (VL). In comparison with HIV– men, HIV+ men had higher QTVI (adjusted difference of +0.077 [95% CI, +0.032 to +0.123]). The magnitude of this association depended on the degree of viremia, such that in HIV+ men with undetectable VL, adjusted QTVI was +0.064 (95% CI, +0.017 to +0.111) higher than in HIV– men, whereas, in HIV+ men with detectable VL, adjusted QTVI was higher by +0.150 (95% CI, 0.072–0.228) than in HIV– referents. Analysis of QTVI subcomponents showed that HIV+ men had: (1) lower heart rate variability irrespective of VL status, and (2) higher QT variability if they had detectable, but not with undetectable, VL, in comparison with HIV– men. Higher levels of C-reactive protein, interleukin-6, intercellular adhesion molecule-1, soluble tumor necrosis factor receptor 2, and soluble cluster of differentiation-163 (borderline), were associated with higher QTVI and partially attenuated the association with HIV serostatus.Conclusions:HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV– men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

Background:Antiarrhythmic drugs have not proven to significantly improve overall survival after out-of-hospital cardiac arrest from shock-refractory ventricular fibrillation/pulseless ventricular tachycardia. How this might be influenced by the route of drug administration is not known.Methods:In this prespecified analysis of a randomized, placebo-controlled clinical trial, we compared the differences in survival to hospital discharge in adults with shock-refractory ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest who were randomly assigned by emergency medical services personnel to an antiarrhythmic drug versus placebo in the ALPS trial (Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study), when stratified by the intravenous versus intraosseous route of administration.Results:Of 3019 randomly assigned patients with a known vascular access site, 2358 received ALPS drugs intravenously and 661 patients by the intraosseous route. Intraosseous and intravenous groups differed in sex, time-to-emergency medical services arrival, and some cardiopulmonary resuscitation characteristics, but were similar in others, including time-to-intravenous/intrasosseous drug receipt. Overall hospital discharge survival was 23%. In comparison with placebo, discharge survival was significantly higher in recipients of intravenous amiodarone (adjusted risk ratio, 1.26 [95% CI, 1.06–1.50]; adjusted absolute survival difference, 5.5% [95% CI, 1.5–9.5]) and intravenous lidocaine (adjusted risk ratio, 1.21 [95% CI, 1.02–1.45]; adjusted absolute survival difference, 4.7% [95% CI, 0.7–8.8]); but not in recipients of intraosseous amiodarone (adjusted risk ratio, 0.94 [95% CI, 0.66–1.32]) or intraosseous lidocaine (adjusted risk ratio, 1.03 [95% CI, 0.74–1.44]). Survival to hospital admission also increased significantly when drugs were given intravenously but not intraosseously, and favored improved neurological outcome at discharge. There were no outcome differences between intravenous and intraosseous placebo, indicating that the access route itself did not demarcate patients with poor prognosis. The study was underpowered to assess intravenous/intraosseous drug interactions, which were not statistically significant.Conclusions:We found no significant effect modification by drug administration route for amiodarone or lidocaine in comparison with placebo during out-of-hospital cardiac arrest. However, point estimates for the effects of both drugs in comparison with placebo were significantly greater for the intravenous than for the intraosseous route across virtually all outcomes and beneficial only for the intravenous route. Given that the study was underpowered to statistically assess interactions, these findings signal the potential importance of the drug administration route during resuscitation that merits further investigation.

Background:Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.Methods:To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery.Results:Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca2+ signaling alterations (increased SOCE, decreased [Ca2+]i transients amplitude and decay rate, lower SR Ca2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.Conclusions:The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

Background:Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the roles of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction.Methods:We used isolated adult mouse cardiac myocytes and fibroblasts, as well as preclinical mouse models of hypertrophy and heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice were used.Results:We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. In vitro, PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated cardiac myocyte pathological hypertrophy induced by Angiotensin II, phenylephrine, and isoproterenol, but did not affect cardiac myocyte physiological hypertrophy induced by IGF-1 (insulin-like growth factor 1). TP-10 also reduced TGF-β (transforming growth factor-β)–stimulated cardiac fibroblast activation, proliferation, migration and extracellular matrix synthesis. TP-10 treatment elevated both cAMP and cGMP levels in cardiac myocytes and cardiac fibroblasts, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. In vivo, global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and dysfunction induced by chronic pressure overload via transverse aorta constriction or chronic neurohormonal stimulation via Angiotensin II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy.Conclusions:Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.

The elimination of specific dietary cholesterol target recommendations in recent guidelines has raised questions about its role with respect to cardiovascular disease. This advisory was developed after a review of human studies on the relationship of dietary cholesterol with blood lipids, lipoproteins, and cardiovascular disease risk to address questions about the relevance of dietary cholesterol guidance for heart health. Evidence from observational studies conducted in several countries generally does not indicate a significant association with cardiovascular disease risk. Although meta-analyses of intervention studies differ in their findings, most associate intakes of cholesterol that exceed current average levels with elevated total or low-density lipoprotein cholesterol concentrations. Dietary guidance should focus on healthy dietary patterns (eg, Mediterranean-style and DASH [Dietary Approaches to Stop Hypertension]–style diets) that are inherently relatively low in cholesterol with typical levels similar to the current US intake. These patterns emphasize fruits, vegetables, whole grains, low-fat or fat-free dairy products, lean protein sources, nuts, seeds, and liquid vegetable oils. A recommendation that gives a specific dietary cholesterol target within the context of food-based advice is challenging for clinicians and consumers to implement; hence, guidance focused on dietary patterns is more likely to improve diet quality and to promote cardiovascular health.

In the article by Brandenburg et al, “Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study,” which published in the May 23, 2017, issue of Circulation (Circulation. 2017;135:2081-2083. doi: 10.1161/CIRCULATIONAHA.116.027011), a correction is needed. There were 3 typos in the table, in which the unit ‘mL’ was used instead of ‘µL’. Row 2: “Calcification volume, mL” has been corrected to “Calcification volume, µL”. Row 6: “Delta calcification volume, mL” has been corrected to “Delta calcification volume, µL”. Row 7: “Delta calcification volume index, mL/m2 BSA” has been corrected to “Delta calcification volume index, µL/m2 BSA”. These corrections have been made to the current online version of the article, which is available at https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.116.027011.

Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis.Methods: Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression. In vitro findings were confirmed in vivo, using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing.Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective anti-fibrotic molecules both in vitro and in vivo leading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds.Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration.Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%).Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients.

Background: Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Methods: Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients.Results: Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes.Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or its downstream mediators (e.g. Nlrp3, IL-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in ACS patients.

Background: Individuals with carotid stenosis enter surveillance or are considered for surgery based upon disease severity assessed by ultrasound. However, there is variation in the ultrasound diagnostic thresholds used to determine disease severity. Our objective was to describe this variation and its potential impact on patients.Methods: To describe the variation in carotid ultrasound diagnostic thresholds, we examined testing protocols from 338 accredited vascular testing centers in the United States. To determine the potential impact of this variation, we applied the range of thresholds to carotid ultrasound parameters from two groups: a population-based sample age ≥65 years in the Cardiovascular Health Study (n=4,791), and a cohort of patients who underwent surgery for asymptomatic carotid stenosis in the Vascular Quality Initiative registry (n=28,483).Results: Internal carotid artery peak systolic velocity was used by all centers to assess disease severity, with 60 distinct thresholds in use. The peak systolic velocity threshold for moderate (≥50%) stenosis ranged from 110 to 245 centimeters per second (cm/s; median: 125; 5th and 95th percentile: 125 and 150), and the threshold for severe (≥70%) stenosis ranged from 175 to 340 cm/s (median: 230; 5th and 95th percentile: 230 and 275). In the population-based sample, the 5th percentile threshold would assign a diagnosis of moderate carotid stenosis to twice as many individuals as the 95th percentile threshold (7.9%, versus 3.9%; RR: 2.01, CI: 1.70-2.38). In the surgical cohort, one in ten (9.8%) patients had peak systolic velocity values that warranted the diagnosis of severe carotid stenosis at centers in the 5th percentile, but not in the 95th.Conclusions: The diagnostic threshold for carotid stenosis varies considerably. Whether or not a person is said to have moderate stenosis and enters surveillance - and whether or not they have severe stenosis and are candidates for surgery - can depend on which center performs their ultrasound.

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that HDL atheroprotective role lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been comprehensively investigated.Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial where participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to controls by sex, age, intervention group, body mass index, and follow-up time. We investigated its two individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between one standard deviation increments in HDL functional characteristics and clinical outcomes.Results: Low values of cholesterol efflux capacity (OR1SD: 0.58, 95% CI: 0.40-0.83), and levels of sphingosine-1-phosphate (OR1SD: 0.70, 95% CI: 0.52-0.92), and apolipoprotein A-I (OR1SD: 0.58, 95% CI: 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR1SD: 1.27, 95% CI: 0.99-1.63). Low values of cholesterol efflux capacity (OR1SD: 0.33, 95% CI: 0.18-0.61), sphingosine-1-phosphate (OR1SD: 0.60, 95% CI: 0.40-0.89) and apolipoprotein A-I (OR1SD: 0.59, 95% CI: 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR1SD: 1.53, 95% CI: 1.01-2.33) and low apolipoprotein A-I levels (OR1SD: 0.52, 95% CI: 0.31-0.88) were associated with unstable angina.Conclusions: Low cholesterol efflux capacity values, pro-oxidant/pro-inflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in high cardiovascular risk subjects.Clinical Trial Registration: URL: http://www.controlled-trials.com Unique identifier: ISRCTN35739639

Background: Brazil, Russia, India, China and South Africa (BRICS) are emerging economies making up almost half the global population. We analyzed trends in cardiovascular disease (CVD) mortality across the BRICS, and associations with age, period and birth cohort.Methods: Mortality estimates were derived from the Global Burden of Disease Study 2017. We used age-period-cohort modeling to estimate cohort and period effects in CVD between 1992- 2016. Period was defined as survey year, and period effects reflect population wide exposure at a circumscribed point in time. Cohort effects are defined as differences in risks across birth cohort. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated.Results: In 2016, there were 8.4 million CVD deaths across the BRICS. Between 1992 and 2016, the reduction in CVD age-standardized mortality rate (ASMR) in BRICS (-17%) was less than in North America (-39%). 88% of the increased number of all- cause deaths resulted from the increase in CVD deaths. ASMR from stroke and HHD declined by approximately one third across the BRICS, whereas IHD increased slightly (2%). Brazil had the largest ASMR reductions across all CVD categories, with both improvement over time and in recent birth cohorts. South Africa was the only country where CVD ASMR increased. Different age-related CVD mortality was seen in those aged ≥ 50 years in China, ≤ 40 years in Russia, 35-60 years in India, and ≥ 55 years in South Africa. Improving period and cohort risks for CVD mortality were generally found across countries, with the exception of worsening period effects in India and greater risks for IHD in Chinese cohorts born in the 1950s and 1960s.Conclusions: With the exception of Brazil, reductions of CVD mortality across the BRICS have been less than in North America, such that China, India and South Africa contribute an increasing proportion of global CVD deaths. Brazil's example suggests that prevention policies can both reduce the risks for younger birth cohorts and shift the risks for all age groups over time.

Background: Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified post-translationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium.Methods: Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from non-failing and HF hearts, and viscoelasticity was characterized following interventions targeting microtubules. Next, intact left-ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and post-treatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains.Results: Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared to non-failing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a two-fold reduction in energy dissipation upon microtubule depolymerization. Post-hoc sub-group analysis revealed that myocardium from patients with HF with reduced ejection fraction (HFrEF) were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction (HFpEF), which were relatively more viscous. Colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium.Conclusions: Failing cardiomyocytes exhibit elevated viscosity, and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix and/or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.

Background: G-protein-coupled receptors (GPCRs) are important regulators of contractility and differentiation in vascular smooth muscle cells (SMC), but the specific function of SMC-expressed orphan GPCR GPRC5B is unclear.Methods: We studied the role of GPRC5B in the regulation of contractility and dedifferentiation in human and murine SMC in vitro as well as in tamoxifen-inducible, SMC-specific knockout mice (iSM-Gprc5b-KO) under conditions of arterial hypertension and atherosclerosis in vivo.Results: Mesenteric arteries from SMC-specific Gprc5b-KOs showed ex vivo significantly enhanced prostacyclin receptor (IP)-dependent relaxation, whereas responses to other relaxant or contractile factors were normal. In vitro, knockdown of GPRC5B in human aortic SMC resulted in increased IP-dependent cAMP production and consecutive facilitation of SMC relaxation. In line with this facilitation of IP-mediated relaxation, iSM-Gprc5b-KO mice were protected from arterial hypertension, and this protective effect was abrogated by IP antagonists. Mechanistically, we show that knockdown of GPRC5B increased the membrane localization of IP both in vitro and in vivo, and that GPRC5B, but not other GPCRs, physically interact with IP. Finally, we show that enhanced IP signaling in GPRC5B-deficient smooth muscle cells does not only facilitate relaxation, but also prevents dedifferentiation during atherosclerosis development, resulting in reduced plaque load and increased differentiation of SMC in the fibrous cap.Conclusions: Taken together, our data show that GPRC5B regulates vascular SMC tone and differentiation by negatively regulating IP signaling.

Background: Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.Methods: To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Results: Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, the Il6 mRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although the Il6 mRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction of Il6 mRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.Conclusions: The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.

Background: A "malignant" subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk.Methods: Participants (n=15, 710) without prevalent cardiovascular disease were pooled from three population-based cohort studies, the Atherosclerosis Risk in Communities Study (ARIC), the Dallas Heart Study (DHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were classified into three groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT < 6 ng/L and NT-proBNP < 100 pg/mL), and those with ECGLVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF.Results: Over the 10 year follow up period, HF occurred in 512 (3.3%) participants, with rates 5.2% among black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women vs white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI 2.1 to 3.5) in those with malignant LVH and 0.9 (95% CI 0.6 to 1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction (PAF) of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding PAF, were intermediate and similar among black women and white men and lowest among white women.Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of heart failure among blacks vs whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower heart failure risk and mitigate racial disparities.

Background:Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium–glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ).Methods:KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months.Results:A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3–91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57–0.86]; hazard ratio, 0.77 [95% CI, 0.61–0.98]; hazard ratio, 0.62 [95% CI, 0.46–0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78–0.90]; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08–1.23]; odds ratio, 1.15 [95% CI, 1.08–1.22]; odds ratio, 1.14 [95% CI, 1.07–1.22]; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score).Conclusions:Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

Articles, see p 90 and 100 The serial development of treatments that improve morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) is one of the great success stories of cardiovascular therapeutics. Until recently, the combination of β-blockers, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF). These agents, each of which provides clear benefits on mortality and morbidity in patients with HFrEF, collectively came to be termed guideline-directed medical therapy (GDMT). This stable foundation of HF therapeutics was upended in 2014 by the stunning results of the PARADIGM-HF study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), demonstrating substantial improvements in outcomes with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan above and beyond the benefits provided by the angiotensin-converting enzyme inhibitor enalapril.1 Now, only a few years later, a remarkable data set has emerged with the sodium-glucose cotransporter-2 inhibitors (SGLT2is) in HF. Initially, the diabetes cardiovascular outcome trials provided evidence of the role of these agents in preventing incident HF in patients with type 2 diabetes mellitus. Last, the recent publication of the primary results of the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) demonstrated substantial benefits in outcomes on top of triple therapy for patients with chronic HFrEF, benefits that are remarkably similar in patients with and without diabetes mellitus.2 So is it now time for triple therapy to evolve to quadruple therapy in patients with HFrEF? The field of HF must now grapple with a number of questions in light of these new data in patients with established HFrEF. Is this a class effect of SGLT2is in general or specific to dapagliflozin? What about other benefits beyond morbidity and mortality? What are the specific mechanisms underlying the observed effects? And last, how should this new class of drugs be implemented, especially in groups of patients (eg, the elderly) where aggressive uptitration of triple therapy has often been a challenge? In that context, the articles by Kosiborod et al3 and Martinez et al4 in this issue of Circulation expand the dapagliflozin in HF story and provide greater insights into some of these critical questions. First, Kosiborod et al3 present a detailed analysis of the effects of dapagliflozin on health-related quality of life in the DAPA-HF study. These data are of critical importance, because improving patient-reported outcomes in HF, especially in highly symptomatic patients, is an important goal in drug development. The reported analysis from DAPA-HF shows a clinically important benefit on health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo that was sustained >8 months. In a responder analysis, patients randomly assigned to dapagliflozin were more likely to experience a 5-, 10-, or ≥15-point improvement in Kansas City Cardiomyopathy Questionnaire score (consistent with small, medium, and large improvements in health-related quality of life) than were patients on placebo. Although the mean improvement (a 2.8 change in Kansas City Cardiomyopathy Questionnaire total symptom score over placebo at 8 months) may appear modest, it should be noted that this is a similar or greater magnitude of improvement in comparison with Kansas City Cardiomyopathy Questionnaire changes with other effective HF therapies, including sacubitril-valsartan, ivabradine, and cardiac resynchronization therapy. These results confirm and extend the prior results from the DEFINE-HF study (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) in a larger population with longer follow-up.5 Dapagliflozin therefore joins a select group of HF interventions that improve mortality, reduce hospitalizations, and improve health-related quality of life in patients with HFrEF: the 3 critical goals of HF treatment. Another highly relevant question about the potential role of dapagliflozin in HF is how well it works across the spectrum of patients with HFrEF, in particular, groups of patients in whom it is often challenging to optimize GDMT, such as the elderly. Older patients are underrepresented in clinical trials in HF, and aggressive uptitration of GDMT in older patients is often limited by comorbidities, frailty, and polypharmacy. The article by Martinez et al4 reports the efficacy and tolerability of dapagliflozin stratified by age group. As expected, the event rate for the primary end point (cardiovascular death or HF event) increased with age, driven primarily by a greater risk of HF events. It is reassuring that, in DAPA-HF, the treatment effect of dapagliflozin was similar across all age groups, including patients >75 years of age. Indeed, the point estimate for the treatment effect of dapagliflozin in the 1149 patients >75 years of age was numerically greatest of all age categories (hazard ratio, 0.68), and the absolute risk reduction in older patients was higher (because of a higher baseline risk than younger patients). In DAPA-HF, older patients were less likely to be aggressively treated with GDMT, consistent with other studies. As anticipated, older patients were more likely to have adverse events and drug intolerance, but this was similar in both the dapagliflozin and placebo groups. These data emphasize another potentially attractive feature of SGLT2is as HF therapy: in general, these agents play well with others when it comes to overlapping intolerances that often limit (either in reality or in perception) the optimization of GDMT. Although SGLT2i therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2is generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive uptitration of GDMT problematic, in particular, in older patients or those with more advanced disease. Where do we go from here? It is important to acknowledge that, although well-conducted and convincing, DAPA-HF is only a single trial. Multiple ongoing studies will continue to fill out the picture of the role of SGLT2is as a class in the treatment of HF, including studies with other SGLT2s, and trials in patients with HF and preserved ejection fraction and those hospitalized with HF, as well. Although the accumulated data on this class to date certainly seem hopeful, definitive answers to some of these questions await the results of ongoing studies. Assuming that future data confirm the benefits of SGLT2is in HF, the next critical step is implementation, a challenge that has been well documented in other aspects of GDMT despite most therapies being available as low-cost generic drugs.6 On the basis of the recent experience with sacubitril-valsartan, it is clear that evidence generation alone is insufficient to move the needle for the uptake of new efficacious treatments.7 Gaps in implementation can result from a combination of knowledge deficits, clinical inertia, patient reluctance to take additional medications, and barriers to access from payers. As we stand at the beginning of a new era of quadruple therapy for HFrEF with β-blockers, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2is, it is incumbent on the field to realize that the real work of getting the right drug to the right patient at the right time has only just begun. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Windtree Therapeutics, Rocket Pharma, and SC Pharma. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circ

Background:Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF.Methods:Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion.Results:There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure – right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028).Conclusions:LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

Background:Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.Methods:We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala.Results:We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04–1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21–2.09], P<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29–0.73], P<0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89–1.01], P=0.08; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036).Conclusions:CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.

Background:Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known.Methods:We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1C1039G/+), gene-edited MFS pigs (FBN1Glu433AsnfsX98/+), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)–tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1C1039G/+;Ccr2RFP/RFP) were generated to determine the requirements of recruited macrophages to MVD progression.Results:MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2–), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity.Conclusions:All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.

Longevity is increasing, and more adults are living to the stage of life when age-related biological factors determine a higher likelihood of cardiovascular disease in a distinctive context of concurrent geriatric conditions. Older adults with cardiovascular disease are frequently admitted to cardiac intensive care units (CICUs), where care is commensurate with high age-related cardiovascular disease risks but where the associated geriatric conditions (including multimorbidity, polypharmacy, cognitive decline and delirium, and frailty) may be inadvertently exacerbated and destabilized. The CICU environment of procedures, new medications, sensory overload, sleep deprivation, prolonged bed rest, malnourishment, and sleep is usually inherently disruptive to older patients regardless of the excellence of cardiovascular disease care. Given these fundamental and broad challenges of patient aging, CICU management priorities and associated decision-making are particularly complex and in need of enhancements. In this American Heart Association statement, we examine age-related risks and describe some of the distinctive dynamics pertinent to older adults and emerging opportunities to enhance CICU care. Relevant assessment tools are discussed, as well as the need for additional clinical research to best advance CICU care for the already dominating and still expanding population of older adults.

In the article by Benjamin et al, “Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association,” which published ahead of print January 31, 2019, and appeared in the March 5, 2019, issue of the journal (Circulation. 2019;139:e56–e528. DOI: 10.1161/CIR.0000000000000659), a correction was needed. On page e352, in the left column, the text under the heading “Mortality (See Chart 16-7) 2016 ICD-9 427.3; ICD-10 I48” read, “In 2016, AF was the underlying cause of death in 24 855 people and was listed on 15 816 US death certificates (any-mention mortality).” The text has been updated to read, “In 2016, AF was the underlying cause of death in 24 855 people and was listed on 154 816 US death certificates (any-mention mortality).” This correction has been made to the current online version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIR.0000000000000659.

In the article by Levine et al, “Recent Innovations, Modifications, and Evolution of ACC/AHA Clinical Practice Guidelines: An Update for Our Constituencies: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines,” which published ahead of print on March 20, 2019, and appeared in the April 23, 2019, issue of the journal (Circulation. 2019;139:e879–e886. DOI: 10.1161/CIR.0000000000000651), a correction was needed. On page e886, in “Appendix 1. Author Relationships With Industry and Other Entities (Relevant),” in the row for Zachary D. Goldberger, the entry in the “Employment” column read, “University of Washington School of Medicine—Assistant Professor of Medicine; Division of Cardiology, Harborview Medical Center.” It has been updated to read, “University of Wisconsin School of Medicine and Public Health—Associate Professor of Medicine; Division of Cardiovascular Medicine/Electrophysiology.” This correction has been made to the current online version of the article, which is available at https://www.ahajournals.org/doi/10.1161/CIR.0000000000000651.

Background: Coconut oil is high in saturated fat and may, therefore, raise serum cholesterol concentrations, but beneficial effects on other cardiovascular risk factors have also been suggested. Therefore, we conducted a systematic review of the effect of coconut oil consumption on blood lipids and other cardiovascular risk factors compared with other cooking oils using data from clinical trials.Methods: We searched PubMed, SCOPUS, Cochrane Registry, and Web of Science through June 2019. We selected trials that compared the effects of coconut oil consumption with other fats that lasted at least 2 weeks. Two reviewers independently screened articles, extracted data, and assessed the study quality according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The main outcomes included low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), total cholesterol, triglycerides, measures of body fatness, markers of inflammation, and glycemia. Data were pooled using random-effects meta-analysis.Results: 16 articles were included in the meta-analysis. Results were available from all trials on blood lipids, 8 trials on body weight, 5 trials on percentage body fat, 4 trials on waist circumference, 4 trials on fasting plasma glucose, and 5 trials on C-reactive protein. Coconut oil consumption significantly increased LDL-cholesterol by 10.47 mg/dL (95% CI: 3.01, 17.94; I2 = 84%, N=16) and HDL-cholesterol by 4.00 mg/dL (95% CI: 2.26, 5.73; I2 = 72%, N=16) as compared with nontropical vegetable oils. These effects remained significant after excluding nonrandomized trials, or trials of poor quality (Jadad score <3). Coconut oil consumption did not significantly affect markers of glycemia, inflammation, and adiposity as compared with nontropical vegetable oils.Conclusions: Coconut oil consumption results in significantly higher LDL-cholesterol than nontropical vegetable oils. This should inform choices about coconut oil consumption.

Background: Diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury.Methods: Adult male mice were fed a normal or a high fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid (HG/HL)-challenged non-diabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection.Results: Intramyocardial injection of diabetic serum sEV in the non-diabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or HG/HL-challenged non-diabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in non-diabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. Mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and HG/HL-challenged non-diabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and non-diabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in non-diabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced pro-apoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from type 2 diabetic patients. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor.Conclusions: We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple anti-apoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.

Background: Loop diuretics have well described toxicities and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Non-renal removal of sodium directly across the peritoneal membrane (direct sodium removal, DSR) using a sodium free osmotic solution should result in extraction of large quantities of sodium with limited off target solute removal.Methods: This report describes the pre-clinical development and first-in-human proof of concept for DSR. Sodium free 10% dextrose was utilized as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, scalability, and to determine the effect of experimental HF. In the human study, participants with end stage renal disease (ESRD) on peritoneal dialysis (PD) underwent randomization and crossover to either a two-hour dwell with one liter of DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary endpoint was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary endpoint was difference in sodium removal between DSR and standard PD solution.Results: Porcine experiments revealed that one liter of DSR solution removed 4.1±0.4 grams of sodium in 2 hours with negligible off target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (p=0.005). In the setting of experimental HF with elevated right atrial pressure, sodium removal was ~4 times greater than in healthy animals (p<0.001). In the human proof of concept study, DSR solution was well-tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable and off target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 grams) compared to standard PD solution (1.0±0.3 grams, p<0.0001).Conclusions: DSR was well-tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in HF is warranted.Clinical Trial Registration: URL: https://clinicaltrials.gov Unique identifier: NCT03801226

Background: Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF), however there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Hypothesis: Routine use of CMR will yield more specific diagnoses in non-ischemic HF. Secondary hypothesis: Routine use of CMR will improve patient outcomes.Methods: Patients with non-ischemic HF were randomized to Routine versus Selective CMR. Patients in the Routine strategy underwent echo and CMR whereas those assigned to Selective use underwent echo with or without CMR according to the clinical presentation. HF etiology was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months.Results: 500 patients (344 male), mean age 59±13, were randomized. The Routine and Selective CMR strategies had similar rates of specific HF etiologies at 3 months clinical follow-up, 44% vs. 50% respectively, p=0.22. At image interpretation, rates of specific HF etiology were also not different between Routine and Selective CMR, 34% vs. 30% respectively, p=0.34. However, 24% of patients in the Selective group underwent a non-protocol CMR. Patients with specific HF etiologies had more clinical events than those with non-specific etiologies based on imaging classification, 19% vs. 12% respectively, p=0.02, but not on clinical assessment, 15% vs. 14%, p=0.49.Conclusions: In patients with non-ischemic HF, Routine CMR does not yield more specific HF etiologies on clinical assessment. Patients with specific HF etiologies from imaging had worse outcomes whereas HF etiologies defined clinically did not.Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT01281384

Background: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Methods: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.Results: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Conclusions: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.

Background: Hypertension is the leading risk factor for death worldwide and high levels of physical activity is associated with lower incidence of hypertension. The associations of excessive levels of exercise and incidence of hypertension is less known. We aim to compare the incidence of hypertension among 206,889 participants in a long-distance cross-country skiing event and 505,542 persons randomly sampled from the general population (matched to the skiers on age sex and place of residence).Methods: Skiers best performance (in per cent of winning time) and number of completed races during the study period were associated to incidence of hypertension after participation in Vasaloppet. Hypertension was defined as prescription of blood pressure-lowering drugs as obtained from the national drug registry. Models were adjusted for sex, age, education and income (total effect).Results: During a median time-of-risk of 8.3 years skiers had lower incidence of hypertension compared to non-skiers (HR 0.59; 95% confidence interval [CI] 0.58-0.60). Among the skiers, better performance (in % of winning time) in Vasaloppet was strongly associated with lower incidence of hypertension (Fastest fifth: HR 0.41; 95% CI 0.39-0.42. Slowest fifth: 0.78 CI 0.75-0.81). The association was near linear and did not differ between sexes. Among the skiers, a weaker association of number of completed races during the study period with incidence of hypertension (1 race: HR 0.63; 95% CI 0.62-0.65.>5 races: HR 0.51; 95% CI 0.50-0.53). A sub-analysis of 10,804 participants including adjustment for lifestyle factors showed similar results.Conclusions: Participation in a long-distance skiing event was associated with 41% lower incidence of hypertension over the next 8 years, compared to non-participation; and the better the performance, the lower the incidence of hypertension. This adds to the list of beneficial effects of intensive training, as hypertension is the leading risk factor of premature death globally.

Background: Type 2 myocardial infarction (T2MI) occurs due to an acute imbalance in myocardial oxygen supply and demand in the absence of athero-thrombosis. Despite being frequently encountered in clinical practice, the population-based incidence and trends remain unknown and the long-term outcomes incompletely characterized.Methods: We prospectively recruited residents of Olmsted County, Minnesota who experienced an event associated with a cardiac troponin T (cTnT) >99th percentile of a normal reference population (≥0.01 ng/mL) between 1/1/2003 and 12/31/2012. Events were retrospectively classified into type 1 MI (T1MI, atherothombotic event), T2MI or myocardial injury (troponin rise not meeting criteria for MI) using the universal definition. Outcomes were long term all-cause and cardiovascular mortality and recurrent MI. T2MI was further subclassified by inciting event for supply/demand mismatch.Results: A total of 5460 patients had at least one cTnT ≥0.01 ng/mL, of whom 1365 were classified as index T1MI (age 68.5±14.8 years, 63% male) and 1054 T2MI (age 73.7±15.8 years, 46% male). The annual incidence of T1MI decreased markedly from 202 to 84 per 100,000 persons between 2003 and 2012 (p<0.001), while the incidence of T2MI declined from 130 to 78 per 100,000 persons (p=0.02). Compared to T1MI, patients with T2MI had higher long-term all-cause mortality after adjustment for age and sex, driven by early and non-cardiovascular death. Rates of cardiovascular death were similar after either type of MI (HR 0.8, 95% CI 0.7-1.0, p=0.11). Sub-classification of T2MI by etiology demonstrated a more favorable prognosis when the principal provoking mechanism was arrhythmia, compared with post-operative status, hypotension, anemia and hypoxia. After index T2MI, the most common MI during follow-up was a recurrent T2MI while the occurrence of a new T1MI was relatively rare (estimated rates 9.7% and 1.7% at 5 years).Conclusions: There has been an evolution in type of MI occurring in the community over a decade, with the incidence of T2MI now being similar to T1MI. Mortality after T2MI is higher and driven by early and non-cardiovascular death. The provoking mechanism of supply/demand mismatch affects long-term survival. These findings underscore the healthcare burden of T2MI and provide benchmarks for clinical trial design.

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.

Background: Likelihood of neurologically favorable survival declines with prolonged resuscitation. However, the ability of extracorporeal cardiopulmonary resuscitation (ECPR) to modulate this decline is unknown. We aimed to examine the effects of resuscitation duration on survival and metabolic profile in patients who undergo ECPR for refractory ventricular fibrillation/ventricular tachycardia out-of-hospital cardiac arrest (VF/VT OHCA).Methods: We retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT OHCA treated with the UMN-ECPR protocol (transport with ongoing CPR to the cardiac catheterization laboratory for ECPR) compared with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. We evaluated the metabolic changes and rate of survival in relation to duration of CPR in UMN-ECPR patients.Results: Neurologically favorable survival was significantly higher in UMN-ECPR patients vs. ALPS patients (33% vs. 23%; p = 0.01) overall. The mean duration of CPR was also significantly longer for UMN-ECPR patients vs. ALPS patients (60 vs. 35 min; p < 0.001). Analysis of the effect of CPR duration on neurologically favorable survival demonstrated significantly higher neurologically favorable survival for UMN-ECPR patients compared to ALPS patients at each CPR duration interval less than 60 minutes; however, longer CPR duration was associated with progressive decline in neurologically favorable survival in both groups. All UMN-ECPR patients with 20-29 minutes of CPR (8/8) survived with neurologically favorable status compared to 24% (24/102) for ALPS patients with the same duration of CPR. There were no neurologically favorable survivors in the ALPS cohort with CPR {greater than or equal to}40 minutes, whereas neurologically favorable survival was 25% (9/36) for UMN-ECPR patients with 50-59 minutes of CPR and 19% with {greater than or equal to}60 minutes. Relative risk of mortality or poor neurologic function was significantly reduced in UMN-ECPR patients with CPR duration {greater than or equal to} 60 minutes, Significant metabolic changes included decline in pH, increased lactic acid and paCO2, and thickened left ventricular wall with prolonged professional CPR.Conclusions: ECPR was associated with improved neurologically favorable survival at all CPR durations less than 60 minutes despite severe progressive metabolic derangement. However, CPR duration remains a critical determinate of survival.

Background: Pulmonary endarterectomy (PEA) is the gold standard treatment for patients with operable chronic thromboembolic pulmonary hypertension (CTEPH). However, persistent pulmonary hypertension (PH) after PEA remains a major determinant of poor prognosis. A concomitant small-vessel arteriopathy in addition to major pulmonary artery obstruction has been suggested to play an important role in the development of persistent PH and survival after PEA. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence and severity of small-vessel arteriopathy. Using the pulmonary artery occlusion technique, we sought to assess the presence and degree of smallvessel disease in CTEPH patients undergoing PEA in order to predict postoperative outcome before surgery.Methods: Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure (Pc'), we partitioned pulmonary vascular resistance in larger arterial (Rup, upstream resistance) and small arterial plus venous components (Rds, downstream resistance) in 90 patients prior to PEA. For validation, lung wedge biopsies were taken from non-obstructed and obstructed lung territories during PEA in 49 cases. Biopsy sites were chosen according to the pulmonary angiogram still frames that were mounted in the operating room. All vessels per specimen were measured, in each patient. Percent media (%MT) (arteries) and intima thickness (%IT) (arteries, veins, and indeterminate vessels) were calculated relative to external vessel diameter.Results: Decreased Rup was an independent predictor of persistent PH (OR per 10%: 0.40 [0.23-0.69]; p=0.001) and survival (HR per 10%: 0.03 [0.00-0.33]; p=0.004). Arterial %MT and %IT of non-obstructed lung territories and venous %IT of obstructed lung territories were significantly increased in patients with persistent PH and non-survivors. Rup correlated inversely with %MT (r=-0.72, p<0.001) and %IT (r=-0.62, p<0.001) of arteries from nonobstructed lung territories and with %IT (r=-0.44, p=0.024) of veins from obstructed lung territories. Receiver operating characteristic analysis disclosed that Rup <66% predicted persistent PH after PEA, while Rup <60% identified patients with poor prognosis after PEA.Conclusions: Pulmonary artery occlusion waveform analysis with estimation of Rup seems to be a valuable technique for assessing the degree of small-vessel disease and postoperative outcome after PEA in CTEPH.

Background: Blood pressure (BP) often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of pro-inflammatory cytokines increases in T lymphocyte. Prostaglandin (PG) D2, a pro-resolution mediator, suppresses Th1 cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of PGD2/DP1 axis in T cells on age-related hypertension.Methods: To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants and CD4+ T cells were sorted for gene expression, PG production and western bot assays. Mice BP was quantified by invasive telemetric monitor.Results: PGD2/DP1 axis was down-regulated in CD4+ T cells from older humans and aged mice, DP1 deletion in CD4+ T cells (TDP1KO) augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling and CD4+ T cells infiltration, superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. TNFα neutralization or IFNγ deletion ameliorated the age-related hypertension in TDP1KO mice. Mechanistically, DP1 inhibited Th1 activity via the Gαs/PKA/p-Sp1/NEDD4L pathway-mediated T-bet ubiquitination. T-bet deletion or forced NEDD4L expression in CD4+ T cell attenuated age-related hypertension in TDP1KO mice. DP1 receptor activation by BW245C prevented age-associated BP elevation and reduced vascular/renal superoxide production in male mice.Conclusions: PGD2/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension in males.

Background:The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin.Methods:The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models.Results:Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11–2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16–2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome.Conclusions:A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Background:Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes.Methods:Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women’s Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e’) and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses.Results:Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min−1·1.73 m−2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR.Conclusions:Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

Background:Bystander cardiopulmonary resuscitation (B-CPR) delivery and survival after out-of-hospital cardiac arrest vary at the neighborhood level, with lower survival seen in predominantly black neighborhoods. Although the Hispanic population is the fastest-growing minority population in the United States, few studies have assessed whether the proportion of Hispanic residents in a neighborhood is associated with B-CPR delivery and survival from out-of-hospital cardiac arrest. We assessed whether B-CPR rates and survival vary by neighborhood-level ethnicity. We hypothesized that neighborhoods with a higher proportion of Hispanic residents have lower B-CPR rates and lower survival.Methods:We conducted a retrospective cohort study using data from the Resuscitation Outcomes Consortium Epistry at US sites. Neighborhoods were classified by census tract based on percentage of Hispanic residents: <25%, 25% to 50%, 51% to 75%, or >75%. We independently modeled the likelihood of receipt of B-CPR and survival by neighborhood-level ethnicity controlling for site and patient-level confounding characteristics.Results:From 2011 to 2015, the Resuscitation Outcomes Consortium collected 27 481 US arrest events; after excluding pediatric arrests, emergency medical services–witnessed arrests, or arrests occurring in a healthcare or institutional facility, 18 927 were included. B-CPR was administered in 37% of events. In neighborhoods with <25% Hispanic residents, B-CPR was administered in 39% of events, whereas it was administered in 27% of events in neighborhoods with >75% Hispanic residents. Compared with <25% Hispanic neighborhoods in a multivariable analysis, out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods had lower B-CPR rates (51% to 75% Hispanic: odds ratio, 0.79 [CI, 0.65–0.95], P=0.014; >75% Hispanic: odds ratio, 0.72 [CI, 0.55–0.96], P=0.025) and lower survival rates (global P value 0.029; >75% Hispanic: odds ratio, 0.56 [CI, 0.34–0.93], P=0.023).Conclusions:Individuals with out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods were less likely to receive B-CPR and had lower likelihood of survival. These findings suggest a need to understand the underlying disparities in cardiopulmonary resuscitationdelivery and an unmet cardiopulmonary resuscitationtraining need in Hispanic communities.

Background:Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.Methods:The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.Results:In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.Conclusions:Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

Background:Mutations in low-density lipoprotein (LDL) receptor (LDLR) are one of the main causes of familial hypercholesterolemia, which induces atherosclerosis and has a high lifetime risk of cardiovascular disease. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is an effective tool for gene editing to correct gene mutations and thus to ameliorate disease.Methods:The goal of this work was to determine whether in vivo somatic cell gene editing through the CRISPR/Cas9 system delivered by adeno-associated virus (AAV) could treat familial hypercholesterolemia caused by the Ldlr mutant in a mouse model. We generated a nonsense point mutation mouse line, LdlrE208X, based on a relevant familial hypercholesterolemia–related gene mutation. The AAV-CRISPR/Cas9 was designed to correct the point mutation in the Ldlr gene in hepatocytes and was delivered subcutaneously into LdlrE208X mice.Results:We found that homogeneous LdlrE208X mice (n=6) exhibited severe atherosclerotic phenotypes after a high-fat diet regimen and that the Ldlr mutation was corrected in a subset of hepatocytes after AAV-CRISPR/Cas9 treatment, with LDLR protein expression partially restored (n=6). Compared with the control groups (n=6 each group), the AAV-CRISPR/Cas9 with targeted single guide RNA group (n=6) had significant reductions in total cholesterol, total triglycerides, and LDL cholesterol in the serum, whereas the aorta had smaller atherosclerotic plaques and a lower degree of macrophage infiltration.Conclusions:Our work shows that in vivo AAV-CRISPR/Cas9–mediated Ldlr gene correction can partially rescue LDLR expression and effectively ameliorate atherosclerosis phenotypes in Ldlr mutants, providing a potential therapeutic approach for the treatment of patients with familial hypercholesterolemia.

An 85-year-old woman with history of hypertension, atrial fibrillation, and right subdural and bilateral subarachnoid hemorrhage 1 month ago after an accidental fall, presented to the emergency department with altered mental status. There was a history of multiple falls 2 days before this presentation. She had a CHADS2VaSc score of 4 and was initially on Coumadin, which was discontinued after the intracranial bleed. ECG at baseline is shown in Figure 1. On admission, a computerized tomography scan of the head showed hydrocephalus with no change in size of the subdural hematoma and an external ventricular drain was placed. Urine cultures grew Klebsiella pneumonia, and she was treated with levofloxacin. A lower limb compression device was used to prevent deep venous thrombosis. Transthoracic echocardiogram obtained at admission showed normal left ventricular function and wall motion; there were no valvular abnormalities and no thrombi. Subsequently, her neurologic status improved, external ventricular drain was removed and she was ambulatory and was planned for discharge when she had sudden onset of hypotension and loss of consciousness. An ECG obtained in association with this collapse event is shown in Figure 2. Figure 1. Baseline 12-lead ECG. Figure 2. ECG obtained during sudden onset hypotension and loss of consciousness. Please turn the page to read the diagnosis. The baseline 12-lead ECG shows atrial fibrillation with left ventricular hypertrophy and secondary ST-segment depression. ECG obtained in conjunction with the hypotensive event (Figure 2) showed atrial fibrillation with new right bundle branch block morphology and a prominent ST elevation in leads II, III, aVF, and V1–V3, and ST depression in I, aVL, and V5–V6. The coved ST segments in V1–V3 were deemed consistent with a Brugada pattern. The new ECG changes combined with the sudden onset of hypotension and loss of consciousness was concerning for an acute coronary syndrome. However, a coronary angiogram showed only nonobstructive coronary artery disease. Thereafter, she continued to exhibit persistent hypotension and an intra-aortic balloon pump was placed. A repeat transthoracic echocardiogram (Figure 3) showed massive dilatation of the right ventricle (RV) with significant reduction in RV function raising concern for pulmonary embolism. Unfortunately, her clinical condition worsened with recurrent episodes of ventricular fibrillation and cardiac arrest. Ultimately, she could not be resuscitated. Figure 3. Apical 4-chamber view on transthoracic echocardiography showing new onset massive RA and RV dilatation. The ST elevation in V1–V3 are suggestive of a Type I Class B Brugada phenocopy (BrP). Brugada phenocopies are Brugada-like ECG patterns from reversible conditions such as metabolic imbalances, ischemia, and pulmonary embolism.1 Criteria used for a diagnosis of Class A BrP include: a typical Type I or Type 2 Brugada pattern on ECG in a patient with a low probability of Brugada syndrome based on age, family history of sudden death, and absence of symptoms such as unexplained syncope or palpitations with a negative provocation test with ajmaline, flecainide, or procainamide and resolution of BrP with resolution of underlying cause.1 A diagnosis of Class B BrP is made in the absence of provocative testing. Pulmonary embolism has been recognized as one of the causes of BrP.2 Massive pulmonary embolism results in an increase in RV afterload, leading to increased RV metabolic demands and RV ischemia. This ischemia may lead to an RV strain pattern on the ECG, or if very severe may result in a current of injury leading to ST-segment elevation in V1–V3 or aVR and inferior leads giving rise to a BrP pattern.3 Our patient had several risk factors for pulmonary embolism: a high CHADS2VaSc score, discontinuation of therapeutic anticoagulation, and prolonged immobilization, which likely led to the development of deep venous thrombosis with subsequent massive pulmonary embolism leading to RV strain and RV ischemia. Although a CT scan was not done to prove the presence of pulmonary embolism, it was the most likely cause in the setting of the clinical findings mentioned above. The main learning point of this case is that pulmonary embolism may present with Brugada pattern ECG changes in the right precordial leads as was the case in which there was a >2-mm ST-segment elevation followed by a down-sloping concave ST-segment with a negative T wave. Dr Benditt is a recipient of a grant from the Dr Earl E. Bakken family in support of Heart-Brain research. None. https://www.ahajournals.org/journal/circ

The latest generation of high-sensitivity cardiac troponin assays are able to quantify very low concentrations of troponin in the majority of people. Indeed, international guidelines now recommend the use of low concentrations of troponin to risk-stratify patients with suspected acute coronary syndrome.1 Furthermore, troponin is an independent predictor of cardiovascular events in apparently healthy populations, and therefore, concentrations within the reference range may have a wider role in guiding the use of preventative therapies.2 However, troponin can become significantly elevated after physical exercise. Interpreting troponin concentrations in this context is challenging because the kinetics of troponin release after physical exercise are not well understood. Most previous research has used assays that are not able to quantify troponin within the reference range, or has involved endurance athletes and evaluated a single time point rather than serial sampling.3 In this study, we evaluated the effect of intensity and duration of physical exercise on troponin concentration in 10 physically active healthy volunteers (7 men and 3 women; age, mean±SD, 34±7 y). The study was approved by the Research Ethics Committee and was conducted with written informed consent. Eligibility was assessed using the Physical Activity Readiness Questionnaire, the American Heart Association Pre-Participation Screening Questionnaire, and a 12-lead electrocardiogram. All participants underwent an initial fitness test using a maximal graded exercise test on a cycle ergometer to exhaustion to quantify their lactate threshold. They subsequently attended 3 study visits, at least 7 days apart, during which they underwent exercise on a cycle ergometer. The first visit involved low-intensity cycling (50%–60% of the participant’s lactate threshold) for 60 minutes. During the second visit, participants cycled at high intensity (80%–90% lactate threshold) for 60 minutes, and during the third study visit, participants cycled at moderate intensity (60%–70% lactate threshold) for 4 hours. Troponin concentrations were measured at the start of exercise and then hourly for up to 6 hours during each study visit, followed by measurements at 1, 2, and 7 days thereafter using the ARCHITECTSTAT high-sensitive troponin I assay (Abbott Laboratories). This assay has a limit of detection of 1.2 ng/L and an upper reference limit (99th percentile) of 34 ng/L in men and 16 ng/L in women. Change in troponin concentration within each study visit was evaluated by a 1-way repeated-measures ANOVA and paired t tests. We compared troponin concentrations between visits by a 2-way repeated-measures ANOVA. Study participants had a median troponin concentration of 1.8 ng/L (interquartile range, 0.8–5.7) at baseline. Troponin was elevated after moderate- and high-intensity exercise (1-way ANOVA, P<0.001 for both), but was unchanged after low-intensity exercise (P=0.055). Troponin concentrations were significantly higher after the shorter duration of high-intensity exercise (peak, 13.0 ng/L [6.5–27.1]) compared with the longer duration of moderate-intensity exercise (6.9 ng/L [2.9–7.9]; 2-way ANOVA, P=0.028). After moderate- and high-intensity exercise, troponin concentration returned to baseline within 48 hours (Figure). The median heart rate and peak power output were 112 bpm (interquartile range, 99–142) and 113 W (88–135), respectively, during low-intensity exercise, 151 bpm (135–162) and 139 W (127–159) during moderate-intensity exercise, and 155 bpm (139–165) and 178 W (161–205) during high-intensity exercise. Figure. The effect of exercise intensity and duration on cardiac troponin release. A, Median high-sensitivity cardiac troponin I concentrations after low-, moderate-, and high-intensity exercise. Values are median (interquartile range) in ng/L; n = 10 participants. Statistical tests performed on log-transformed troponin ratio relative to baseline concentration at each time point. B, Individual participant time-activity curves illustrating fold-changes in cardiac troponin I concentration from baseline. *One-way repeated-measures ANOVA comparing troponin concentration across time points. †Significant difference from baseline concentration using paired t tests (P value <0.05). NA indicates not assessed. Our findings suggest that the magnitude of troponin release is more significantly associated with intensity than duration of physical exercise. The underlying mechanisms of release after exercise are still incompletely understood. It is thought that a small pool of troponin exists unbound within the cytosol of cardiomyocytes. Mechanical shear stress as a result of the hemodynamic response to strenuous physical activity may transiently increase cell membrane permeability, leading to the release of troponin from this cytosolic pool. Differences in the cellular mechanisms of release are likely to explain why the duration of exercise-induced troponin release is significantly shorter than in acute myocardial infarction, where troponin concentrations remain elevated for >1 week. We observed significant heterogeneity in the magnitude of troponin release across individual participants, with the ratio of peak troponin concentration compared with baseline ranging from 2 to 600 across individual participants. Although only 3 participants had troponin concentrations above the 99th percentile after moderate or high-intensity exercise, 9 of 10 had concentrations above the threshold of 5 ng/L used to risk-stratify patients with suspected acute coronary syndrome.4 This has important clinical implications given the increasing use of early rule-out pathways, which use low concentrations of troponin to make clinical decisions. Our data would suggest that the intensity, duration, and elapsed time since physical exercise should be considered when interpreting troponin concentrations. Furthermore, recent reports suggest that greater exercise-induced troponin release may be associated with higher risk of future adverse cardiovascular events.5 Further research is required to understand the determinants of heterogeneity in this response to exercise and the clinical significance of these exercise-induced troponin elevations, particularly in individuals with lower cardiorespiratory fitness. We thank Marina Mocognie, Russell Wilson, and Neil Guthrie, laboratory technicians at Napier University, for their assistance in the study. This study was funded by the British Heart Foundation through a Clinical Research Training Fellowship (FS/18/25/33454), a Senior Clinical Research Fellowship (FS/16/14/32023), and a Research Excellence Award (RE/18/5/34216). Drs Lee, Chapman, Anand, and Shah have received honoraria from Abbott Diagnostics. Dr Mills reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Diagnostics outside the submitted work, and honoraria from Abbott Diagnostics, Siemens Diagnostics, Roche Diagnostics and Singulex. The other authors report no conflicts. *L. Marshall and Dr Lee contributed equally. Data sharing: The data that supports the findings of this study are available from the corresponding author upon reasonable request. https://www.ahajournals.org/journal/circ

Over the past 4 decades, trends in cardiovascular disease (CVD) have declined, with the most notable improvements observed for CVD-related mortality.1 Nonetheless, these trends have not been consistent across all subgroups of the population. In young women, the incidence of acute myocardial infarction continues to rise largely because of the increased prevalence of comorbidities (eg, diabetes mellitus) and traditional risk factors for CVD (eg, hypertension and obesity). In addition, these women are more likely to report a history of hypertensive disorders of pregnancy than the general population of women.2 Studies have consistently shown an association between a history of pregnancy complications, including hypertensive disorders of pregnancy, gestational diabetes, stillbirth, preterm birth, placental abruption, and intrauterine growth restriction, and subsequent CVD in women.2 The potential importance of these complications for the early identification of women at risk of future CVD has been acknowledged by professional societies, including the American Heart Association, the American College of Obstetricians and Gynecologists, and the Society of Obstetricians and Gynaecologists of Canada. A more recent presidential advisory from the American Heart Association/American College of Obstetricians and Gynecologists and the American College of Obstetricians and Gynecologists Task Force, and a perspective piece have highlighted the need for targeted screening and long-term follow-up in these women as part of routine practice across all levels of care (eg, general practitioners to specialists). This call for early risk stratification in women of reproductive age highlights the need for high-quality research to develop prediction models that incorporate relevant information in a relevant population. Despite these recommendations, and the evidence that women with these complications are at increased risk, currently available tools to predict the risk of CVD lack the accuracy to identify high-risk women <40 years of age, because these tools were developed and validated in older populations (>50 years of age). Three studies to date have examined the incremental value of hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and low birth weight above well-established risk factors for the prediction of CVD in women and found no added value.3–5 These studies used population-based registries and cohorts from Norway, Sweden, and the United States to create sample populations of parous women ≥40 years of age with no prior history of CVD. The risk prediction models in these studies varied slightly, including risk factors such as age, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, use of antihypertensive medications, and family history of myocardial infarction. The proportion of women experiencing a CVD event across these studies ranged from 1% to 8%. Although these studies used population-based cohorts, the primacy of women beyond their reproductive years in the sample populations may in part explain the lack of positive findings. Guidance documents for the development of prognostic models emphasize the importance of choosing sample populations that reflect the target population intended for screening. Therefore, if the objective is early detection and management of risk factors for CVD soon after a pregnancy affected by a complication, women would ideally be screened in the postpartum period with a target population for development of prognostic models that includes women of reproductive age (ie, 15–45 years). Moreover, the sample population used to develop these models should consist of nulliparous and parous women to increase the generalizability of the model to the target population intended for screening. In addition, the prevalence of predictors in the sample population is an important determinant of the relative contribution and subsequent inclusion of predictors in prognostic models. There are notable differences in the prevalence of traditional risk factors for CVD in women above the age of 50 years relative to younger women. For example, hypertension is present in 29.4% of women aged 40 to 59 years versus only 5.6% in women under the age of 40 years. A similar trend occurs with other comorbidities, such as diabetes mellitus, obesity, and dyslipidemia, because their prevalence increases with advanced maternal age. Sampling older women may have contributed to the limited incremental value of hypertensive disorders of pregnancy or low birth weight seen in these previous studies, and led to the underestimation of the importance of pregnancy complications to the early detection of women at long-term risk for CVD. This variation in prevalence of predictors also affects the generalizability of prediction models such that models developed in older women may not be applicable to younger women and vice versa. In contrast to causal models, the choice of variables for inclusion in prediction models should favor risk factors that are known to be associated with or highly predictive of the outcome. Because the etiology of several pregnancy complications, in particular, preeclampsia, intrauterine growth restriction, and stillbirth, is unknown, it may be difficult to disentangle the relative contribution of these individual factors to the development of CVD. Moreover, previous studies have hypothesized that these complications may not be causal of CVD but rather markers of an underlying etiology that itself is associated with the development of CVD. Many of these complications may also not be independent of each other and may act as intermediates on the causal pathway to CVD. However, if the goal is to stratify women at risk of CVD, then the objective should be to include risk factors that are highly predictive of CVD independent of their causal relationship with CVD. Therefore, if the estimates from previous studies are accurate with respect to the association of pregnancy- and female-specific risk factors (eg, preeclampsia, depression, infertility, rheumatoid arthritis) and CVD, then these factors have the potential to contribute to the early identification of women who would benefit from management and treatment of cardiovascular risk factors. Researchers developing prognostic models also need to be mindful of the candidate predictors considered for inclusion in the models and the complexity of models. To facilitate the integration of prediction models in clinical practice, it is essential that researchers only consider predictors readily available to clinicians at the time of screening. Although researchers may be inclined to include well-established risk factors for CVD (eg, dyslipidemia, atrial fibrillation) when building prognostic models, the low prevalence, in general, and the high probability of missingness of these predictors in women of reproductive age hinder the utility of such a model and raise concerns regarding the representativeness of the sample of measured values. In addition, complex models may restrict the utility of prognostic models in clinical practice despite the potential gains in the predictive accuracy of these models. Therefore, careful consideration should be taken when developing prognostic models for implementation in clinical practice to improve the transportability to a wide range of clinical settings. To realize the recommendations from professional societies for early screening and management of risk factors for CVD in women with a history of pregnancy complications, clinicians need a tool that is able to provide accurate risk stratification in this patient population. Although assessing the incremental value of pregnancy complications above traditional risk factors seems like the logical starting point to develop prognostic models in this patient population, the above-mentioned limitations mask the relative contribution of these predictors for risk prediction. This therefore highlights the need to develop a prognostic model in a sample of women of reproductive age to facilitate the early identification of women who would benefit from targeted treatment and continual follow-up. Drs Smith and Platt and S.M. Grandi report a grant from the Canadian Institutes of Health Research as part of the submitted work. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circ

Timely reperfusion is critical for salvaging ischemic tissue in myocardial infarction, in stroke, and during resuscitation. Paradoxically, the reperfusion of blood into the ischemic organ is damaging in itself, leading to ischemia/reperfusion (IR) injury. Best clinical practice is to reperfuse rapidly to limit ischemic time. Despite this, extensive IR injury still occurs, which is a major driver of pathology, making the prevention of this damage a clear unmet clinical need.1 Recent work has shown a role for mitochondrial succinate metabolism in IR injury that opens up exciting new therapeutic approaches. IR injury was long thought of as a random and chaotic series of damaging events resulting in reactive oxygen species production from reperfusing ischemic tissue. A different picture is now emerging, suggesting that metabolic mechanisms within mitochondria are central to IR injury, providing a rational basis for therapies. During ischemia, the citric acid cycle metabolite succinate builds up.2 Upon reperfusion, this succinate is oxidized rapidly by succinate dehydrogenase (SDH), driving a burst of reactive oxygen species production by mitochondrial complex I.2 This reactive oxygen species pulse, together with calcium dysregulation and ATP depletion, initiates a cascade of damaging events that culminate in cardiomyocyte death, termed reperfusion injury.1 Whereas cell death from ischemia contributes to the infarct, reperfusion leads to damage additional to that from ischemia alone, thus reperfusion injury provides a therapeutic window to reduce organ damage. Many clinical trials have targeted different facets of IR injury after heart attack but translation to the clinic has been unsuccessful. We highlight the emerging therapeutic strategy of targeting succinate metabolism. SDH is a key enzyme in succinate formation during ischemia and its oxidation upon reperfusion.1 Malonate, a competitive inhibitor of SDH, has emerged as a candidate therapy for selective SDH inhibition to diminish reperfusion injury. This was first shown using the malonate prodrug dimethyl malonate, where it was protective when administered before and throughout ischemia.2 Disodium malonate also had a cardioprotective effect when administered intracoronary at reperfusion in a pig model of IR injury.3 Both approaches alter succinate metabolism, either preventing its accumulation during ischemia (thus less succinate is available to be oxidized during reperfusion) or directly blocking its oxidation during reperfusion. Not all the succinate that accumulates in the heart during ischemia is oxidized by mitochondria upon reperfusion. A significant proportion is released selectively into the circulation, as has been demonstrated in patients with an ST-segment–elevation myocardial infarction. In this situation, succinate was released into the bloodstream after reperfusion by primary percutaneous coronary intervention.4 The mechanism of succinate release from the cardiomyocytes is unclear, but once released it may be detected by the succinate receptor (SUCNR1), which is involved in inflammation. Thus by targeting succinate accumulation during ischemia, subsequent release, and action in the circulation, malonate may provide additional therapeutic strategies for the heart damage underlying chronic heart failure (Figure). In addition to heart attack, ischemic stroke and kidney IR injury may benefit from malonate therapy.2 Furthermore, disrupting succinate metabolism during predictable periods of ischemia, such as that occurring in elective surgery or organ transplantation, is another potential therapeutic target. Cessation of circulation in these scenarios leads to ischemia and a rise in succinate. Upon reperfusion, the succinate will be oxidized rapidly, driving IR injury, tissue damage, and inflammation. Treatment with malonate to blunt succinate accumulation before elective surgery or transplantation thus provides a promising therapeutic opportunity. Dimethyl malonate has also been shown to decrease the brain damage associated with resuscitation after cardiac arrest in rats.5 Infusing dimethyl malonate intravenously before cardiopulmonary resuscitation improved neurologic performance after cardiac arrest, suggesting SDH inhibition by malonate in the brain decreased the production of mitochondrial reactive oxygen species and downstream damage, although whether the action of dimethyl malonate is during ischemia or at reperfusion is unclear. IR injury to the brain, either during cardiopulmonary resuscitation or stroke, is clinically important and there are no pharmacologic interventions available. Thus therapies modulating SDH may help address this unmet clinical need. Despite clear in vitro and animal model efficacy of many compounds in preventing IR injury, translation has proved difficult.1 High failure rates in human trials are often caused by low drug exposure at the target site or clinical safety problems. Translation failure in IR injury is likely caused by delivery difficulties or insufficient knowledge of the pathologic mechanisms, leading to inappropriate drug targets, such as the broad use of antioxidants. In addition, target-specific drugs such as cyclosporine A may be too far downstream of the damage-initiating mechanism. Furthermore, inappropriate trial design ranging from poor inclusion criteria to insufficient powering has led to disappointing outcomes. Malonate use nullifies a number of barriers to clinical translation. Malonate can enter mitochondria by endogenous transport mechanisms, thus allowing the compound to reach the target site in a timely manner. Furthermore, malonate has limited toxicity, a well-established metabolism, and has been used as an excipient in pharmaceutical development. For the successful translation of malonate therapy, some hurdles remain. First, because malonate is a competitive inhibitor, high concentrations are required for protection. Strategies to improve the cellular delivery of malonate may therefore enable a dose reduction to overcome this issue. Second, the correct timing of malonate administration is critical. For clinical use to reduce reperfusion injury, the drug must be at the correct concentration in the affected tissue at the time of reperfusion. Therefore, understanding the pharmacokinetics of malonate during administration will be important to know the timing of malonate delivery. Third, selectivity to the ischemic tissue by malonate is unlikely. However, strategies to limit off-target malonate delivery are possible and may enable rapid cardioselective malonate delivery to prevent IR injury. Overcoming each hurdle presented here may lead to successful translation of malonate-based therapeutics from bench to bedside in the coming years. Figure. Targeting succinate metabolism to protect against ischemia/reperfusion injury. During ischemia, succinate is accumulated extensively via reversal of succinate dehydrogenase (SDH) to reduce fumarate (left). Fumarate supply is maintained by either (1) the degradation of purine nucleotides by the purine nucleotide cycle or (2) arising from upstream aspartate transamination and translocating to the mitochondria via the dicarboxylate carrier (DIC). With the depletion of the GTP and coenzyme A (CoA) pool in mitochondria, succinate activation to succinyl-CoA is inhibited, thus succinate is a terminal metabolite during ischemia. The canonical tricarboxylic acid (TCA) cycle may also contribute to succinate accumulation through glutaminolysis to α-ketoglutarate (α-KG). Because of the extent of succinate accumulation during ischemia, succinate is exchanged from mitochondria into the cytosol, where it can act to inhibit prolyl hydroxylases (PHD) involved in the degradation of hypoxia-inducible factor 1α (HIF-1α). As HIF escapes degradation, it can translocate to the nucleus and promote the transcription of a number of genes involved in the hypoxic response. Inhibiting SDH with dimethyl malonate prevents the accumulation of succinate during ischemia. (Right) During reperfusion, the accumulated succinate has 2 fates: oxidation by SDH or efflux from the cell. Succinate is rapidly oxidized by SDH, generating a highly reduced coenzyme Q pool and large mitochondrial membrane potential. These conditions drive reverse electron transport through complex I (CxI), generating superoxide, the proximal reactive oxygen species (ROS). Together with calcium dyshomeostasis, these events support the opening of the mitochondrial permeability transition pore (MPTP) and subsequent cell death associated with ischemia/reperfusion injury. By inhibiting SDH with malonate during reperfusion, succinate oxidation is slowed, reducing ROS production. In addition to oxidation, succinate is exported from the cell and able to enter the systemic circulation, and thus has the potential to carry out a signaling role by interacting with the succinate receptor, SUCNR1. ADSL indicates adenylosuccinate lyase; AST, aspartate transaminase; FH, fumarate hydratase; HRE, hypoxia response element; IMP, inosine monophosphate; and MDH, malate dehydrogenase. Dr Krieg is supported by grants from the Medical Research Council UK (MR/P000320/1) and the British Heart Foundation (PG/15/84/31670). Drs Prag and Kula-Alwar are supported by the Medical Research Council UK. Dr Krieg is named inventor on pending patents held by the University of Cambridge relating to inhibiting succinate metabolism and has received research funding from Takeda. *Drs Kula-Alwar and Prag contributed equally. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circ

Background:Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina).Methods:One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling.Results:At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (Pinteraction=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (Pinteraction=0.116), physical limitation (Pinteraction=0.461), quality of life (Pinteraction=0.689), EuroQOL 5 quality-of-life score (Pinteraction=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (Pinteraction=0.693), and treadmill exercise time (Pinteraction=0.426).Conclusions:The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Article, see p 1971 For the patient with stable coronary artery disease, demonstrating provocative ischemia, either with stress testing or invasive measures of lesion-specific ischemia (eg, fractional flow reserve [FFR]), is central in the decision to perform coronary revascularization.1–4 Yet, current randomized trial evidence is unclear as to the role of stress-induced ischemia in discerning a clinical outcome benefit of interventional versus conservative strategies of care; with reports of similar rates of major adverse events, such as death or myocardial infarction.5,6 Moreover, the only sham-controlled randomized trial of percutaneous coronary intervention (PCI), the ORBITA trial (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty), reported no effect of PCI on exercise time or angina frequency among patients with single-vessel coronary artery disease.7 In this issue of Circulation, a secondary analysis from the ORBITA trial examined the relation between baseline dobutamine stress echocardiographic ischemia and randomized treatment on patient-reported symptoms.8 Several findings from this ORBITA trial analysis are worthy of discussion. At baseline, patients enrolled in the ORBITA trial had a stress wall motion score averaging ≈1.6 in both the PCI and placebo arms. As described by the authors, the stress echocardiographic wall motion score used in this study varies from the conventional wall motion score index because it is a sum of wall motion abnormalities within the 17 segments of the left ventricle, without indexing to the number of segments assessed. Despite this, there was a significant interaction between the prerandomization stress echocardiographic score and the effect of PCI on angina frequency (interaction P=0.031; Figure 2 in article).8 PCI-treated patients with an echocardiographic score ≥1.0 (consistent with a stress-induced wall motion abnormality in at least 1 segment) had a reduced frequency of angina at 6 weeks of follow-up (P=0.007). The ORBITA trial findings are consistent with prior stable ischemic heart disease trials whereby PCI was associated with a prompt improvement in angina symptoms moreso than with medical therapy alone.1,5,9 From the Veterans Affairs–sponsored COURAGE trial (Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation), PCI with optimal medical therapy as compared to optimal medical therapy alone was more often associated with freedom from angina through 3 years of follow-up.5 As well, from the FAME 2 trial (FFR Versus Angiography for Multivessel Evaluation), there was a marked reduction (hazard ratio: 0.13, P<0.001) in unstable symptoms necessitating hospitalization and prompt revascularization.4 This improvement in patient-reported outcomes with PCI among those with evidence of ischemia is a theme within the published literature. Even more intriguing from this ORBITA trial secondary analysis was that the greater the ischemia on the stress echocardiogram, the greater the symptom improvement. Specifically, there was a greater reduction in angina frequency when the echocardiographic wall motion score exceeded ~1.5 to 2.0 (interaction P=0.031). Because of how the stress echocardiographic score is calculated, higher scores can represent either a greater extent of stress-induced wall motion abnormalities (ischemia) or a greater severity of the wall motion abnormality in a smaller region; however, either of these represent higher degrees of ischemia. The ≈50% of patients who had a baseline stress wall motion score ≥1 were nearly 5 times more likely to be angina free with PCI as compared with placebo (P=0.003, Table A3 in the article).8 These findings suggest that the severity of stress-induced myocardial ischemia plays a role in discerning a symptom benefit with PCI. The magnitude of the symptom improvement with PCI reported in the ORBITA trial analysis was likely affected by the use of a sham control as a comparator. The findings align with several stress imaging studies focusing on the relation between inducible ischemia and revascularization.1,9 For example, in the COURAGE trial nuclear substudy, in which reductions in stress ischemia at 1 year of follow-up more often occurred among PCI-treated patients than among patients treated with medical therapy alone when there was moderate or severe ischemia at baseline (P=0.007).9 It is unclear from the ORBITA trial and other randomized trials whether symptom improvement may only be realized above a threshold severity of ischemic myocardium. Prior stable ischemic heart disease trials did not require a given severity of stress-induced ischemia. The result was that a large proportion of patients enrolled in prior stable ischemic heart disease trials had minimal ischemia and were sufficiently low risk. Varying results may be realized among higher risk patients with moderate-severe ischemia or patients with myocardial ischemia in specific coronary territories. The US National Institutes of Health’s National Heart, Lung, and Blood Institute–sponsored ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) will provide more definitive information about the relation between ischemia severity at baseline and the effects of revascularization on symptoms, albeit without a sham control as in the ORBITA trial. The ISCHEMIA trial will also provide data on outcome comparisons, as >5000 patients with moderate-severe ischemia by stress imaging (nuclear, echocardiography, or magnetic resonance) or exercise electrocardiography have been randomized to an invasive strategy as compared with medical therapy alone. The authors of the ORBITA trial present a useful illustration (Figure 6 in the article by Al-Lamee et al)8 of the concept of myocardial ischemia-guided PCI proposing that key ingredients be linked to elicit improvement in symptoms; namely ischemia within a given subtended myocardium of a focal stenosis. Although this link is intuitive, stress ischemia used as a means to target PCI of a given stenosis does not have the same level of evidence as that of FFR-guided PCI. Moreover, for most of the stress testing literature, including this secondary analysis from the ORBITA trial, ischemia is largely employed as a criterion for referral to coronary angiography but not to target a specific lesion for PCI, akin to invasive FFR or instantaneous wave free ratio. This important evidence as to how stress ischemia in each vascular territory affects outcomes following PCI largely remains largely unknown. The ORBITA trial’s evidence does report a fair degree of concordance between stress echocardiographic abnormalities and invasive measures of lesion-specific ischemia (ie, FFR and instantaneous wave free ratio). In addition, the authors present some data in Table A1, in their online-only Data Supplement, on ischemia in each vascular territory of a coronary artery, noting a majority of ischemia in anterior segments on stress echocardiography.8 Given that a majority of patients in the ORBITA trial had targeted PCI in the left anterior descending coronary artery, it remains possible that the overall trial results are applicable to ischemia-stenosis colocalization. An important take-home message from the ORBITA trial is that ischemia is an important mediator of improved patient symptoms after PCI, but ischemia is likely not the only variable of importance. A knowledge gap remains as to how effective noninvasive ischemia testing is in revascularization decision making. Moreover, the small sample size of patients in the ORBITA trial limits exploration of heterogeneity of patient risk or, in this case, how improvements in patient symptoms may vary with the severity of ischemia (including more remote to the intervened stenosis) or how left ventricular scarring modulates the effects of revascularization, as is suggested by observational findings.2 These and other questions may be answered in the ISCHEMIA trial and represent fundamental next steps for noninvasive ischemia research to more clearly define the role of stress ischemia in the selection of management strategies for stable ischemic heart disease patients. Drs Shaw, Reynolds, and Picard have received funding from the US National Institutes of Health’s National Heart, Lung, and Blood Institute for the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). The authors have no other disclosures to report. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. https://www.ahajournals.org/journal/circ

Background:Prosthetic valve endocarditis (PVE) is a rare but critical mechanism of valve failure and death after transcatheter and surgical aortic valve replacement (TAVR, SAVR) warranting further analysis in modern aortic valve replacement experience. We characterize the incidence, risk factors, microbiological profile and outcomes of PVE from the PARTNER trials and registries (Placement of Aortic Transcatheter Valve).Methods:We analyzed a pooled cohort of all patients in PARTNER 1 and PARTNER 2 trials and registries. Patients had severe aortic stenosis, were treated with TAVR or SAVR, and were analyzed with respect to development of PVE. PVE adjudication by a clinical events committee was based on modified Duke Criteria. The incidence, infection timing, organism, and association between PVE and all-cause mortality were analyzed.Results:8530 patients were included. PVE occurred in 107 cases (5.06 PVE events per 1000 person-years over a mean follow-up of 2.69±1.55 years [95% CI, 4.19–6.12]). The incidence of TAVR-PVE (5.21 PVE per 1000 person-years [95% CI, 4.26–6.38]) was not significantly different from SAVR-PVE (4.10 per 1000 person-years [95% CI, 2.33–7.22]; incident rate ratio, 1.27 [95% CI, 0.70–2.32]; P=0.44). Temporal risk of PVE was similar for TAVR and SAVR, even after adjusting for competing risk of death (hazard ratio, 1.15 [95% CI, 0.58–2.28]; P=0.69). Through multivariable analysis, PVE was associated with baseline cirrhosis (incident rate ratio, 2.86 [95% CI, 1.33–6.16]; P=0.007), pulmonary disease (incident rate ratio, 1.70 [95% CI, 1.16–2.48]; P=0.006), and renal insufficiency (incident rate ratio, 1.71 [95% CI, 1.03–2.83]; P=0.04). Timing of PVE was similar between TAVR and SAVR (<30 days: 4.2% vs 8.3%; 31 days to 1 year: 52.6% vs 66.7%; >1 year: 43.2% vs 25.0%; P=0.28). Staphylococcus occurred more commonly after SAVR (58.3% vs 28.4% in TAVR; P=0.04). PVE was strongly associated with all-cause mortality after endocarditis diagnosis (hazard ratio, 4.4 [95% CI, 3.42–5.72]; P<0.0001).Conclusions:The widespread adoption of TAVR and application to lower-risk patients makes understanding mechanisms of valve failure increasingly important. PVE is an established mechanism of prosthetic valve failure post-SAVR and TAVR with unclear differences between approaches. We herein demonstrate in the largest trials and registries of TAVR that PVE remains rare, but often fatal, in modern AVR experience and that there is no difference in incidence, predictors, or risk of PVE between TAVR and SAVR.Clinical Trial Registration:https://www.clinicaltrials.gov. Unique identifiers: NCT00530894 (PARTNER 1), NCT01314313 (PARTNER 1IA), NCT02184442 (PARTNER 1IB), NCT03222141 (PII S3HR), NCT03222128 (PII S3i).

Background:Exposure to air pollution increases cardiovascular morbidity and mortality. Preventing chronic cardiovascular diseases caused by air pollution relies on detecting the early effects of pollutants on the risk of cardiovascular disease development, which is limited by the lack of sensitive biomarkers. We have previously identified promising biomarkers in experimental animals but comparable evidence in humans is lacking.Methods:Air pollution is substantially worse in Beijing than in Los Angeles. We collected urine and blood samples from 26 nonsmoking, healthy adult residents of Los Angeles (mean age, 23.8 years; 14 women) before, during, and after spending 10 weeks in Beijing during the summers of 2014 and 2015. We assessed a panel of circulating biomarkers indicative of lipid peroxidation and inflammation. Personal exposure to polycyclic aromatic hydrocarbons (PAHs), a group of combustion-originated air pollutants, was assessed by urinary PAH metabolite levels.Results:Urinary concentrations of 4 PAH metabolites were 176% (95% CI, 103% to 276%) to 800% (95% CI, 509% to 1780%) greater in Beijing than in Los Angeles. Concentrations of 6 lipid peroxidation biomarkers were also increased in Beijing, among which 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid levels reached statistical significance (false discovery rate <5%), but not 8-isoprostane (20.8%; 95% CI, −5.0% to 53.6%). The antioxidative activities of paraoxonase (−9.8%; 95% CI, −14.0% to −5.3%) and arylesterase (−14.5%; 95% CI, −22.3% to −5.8%) were lower and proinflammatory C-reactive protein (101%; 95% CI, 3.3% to 291%) and fibrinogen (48.3%; 95% CI, 4.9% to 110%) concentrations were higher in Beijing. Changes in all these biomarkers were reversed, at least partially, after study participants returned to Los Angeles. Changes in most outcomes were associated with urinary PAH metabolites (P<0.05).Conclusions:Traveling from a less-polluted to a more-polluted city induces systemic pro-oxidative and proinflammatory effects. Changes in the levels of 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid as well as paraoxonase and arylesterase activities in the blood, in association with exposures to PAH metabolites, might have important implications in preventive medicine as indicators of increased cardiovascular risk caused by air pollution exposure.

Background:Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension.Methods:Involvement of IgG was studied using IgG μ heavy chain–null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell–specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc).Results:Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow–fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension.Conclusions:Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

Extracorporeal membrane oxygenation has evolved, from a therapy that was selectively applied in the pediatric population in tertiary centers, to more widespread use in diverse forms of cardiopulmonary failure in all ages. We provide a practical review for cardiovascular clinicians on the application of veno-arterial extracorporeal membrane oxygenation in adult patients with cardiogenic shock, including epidemiology of cardiogenic shock, indications, contraindications, and the extracorporeal membrane oxygenation circuit. We also summarize cannulation techniques, practical management and troubleshooting, prognosis, and weaning and exit strategies, with attention to end of life and ethical considerations.

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy, which arises when the left ventricle is enlarged, dilated, and weak. Sudden cardiac death may be the first manifestation of LMNA-related dilated cardiomyopathy, because of abnormal heart rhythms. New research reveals a possible drug target for dilated cardiomyopathy. To uncover the mechanisms that link mutations in LMNA to cardiac arrhythmias, a team led by investigators at the Stanford University School of Medicine conducted experiments with patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). In the study, which is published in Nature, cells with a lamin mutation failed to beat properly, as seen in patients with the disease. Cells with a mutation in lamin, which forms part of the nuclear envelope, also had fewer regions of tightly packed DNA, or heterochromatin, which could affect gene expression. Additional experiments revealed that nearly 250 genes were more highly expressed in mutated cells than in normal cells. Many of the genes were part of the platelet-derived growth factor, or PDGF, signaling pathway. This pathway is important in the formation of blood vessels and normally is active only during development or stress. Inhibiting the PDGF signaling pathway restored regular, rhythmic beating in the mutant iPSC-CMs in vitro. The findings suggest that several inhibitors of the PDGF pathway that are currently approved as therapies for patients with cancer, such as sunitinib, sorafinib, and axitinib, may be repurposed for treating LMNA-related dilated cardiomyopathy. Additional studies are needed, however, because these drugs may be associated with cardiac toxicity. “By combining several new technologies, including creation of patient-specific heart cells, our study provides an unprecedented understanding of the relationship between LMNA gene errors and development of heart disease,” said senior author Dr Joseph Wu. “These findings pave the way for disease-specific therapeutics—or precision medicine—in the future.” Lee J et al. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature. 2019;572:335–340. doi: 10.1038/s41586-019-1406-x A newly discovered sex-specific molecular pathway promotes metabolic flexibility in female mice and allows their skeletal muscle to adapt to fasting conditions. Skeletal muscle regulates fat storage, glucose uptake, and other processes involved in metabolism, and during times of low nutrient availability or exercise, skeletal muscle switches from using glucose to oxidizing fatty acids as a source of fuel. “Defective handling of fuels like glucose and fatty acids is found in diseases including obesity and diabetes, and even in aging. Surprisingly, the regulatory mechanisms involved are still not clear,” said Dr Chi Bun Chan, of The University of Hong Kong. In their Science Signalingstudy designed to understand the pathways involved in switching metabolic fuel sources, Dr Chan and his colleagues found that fasting in female mice led to production of brain-derived neurotrophic factor (BDNF) in the gastrocnemius muscle of the calf. This in turn led to increased activity of AMP-activated protein kinase and enzymes involved in fatty acid oxidation, causing the gastrocnemius in fasted female mice to switch from using glucose to fatty acids. When the investigators bred mice lacking BDNF exclusively in skeletal muscle, they observed that female rodents could not switch fuel sources during fasting, leading to weaker muscles and insulin resistance. These effects were not seen in male BDNF-deficient mice. Although BDNF, which is best known for promoting the development and survival of neurons, may not have the same effects in human muscle, the findings suggest that the factor may help regulate metabolism in addition to its role in the nervous system. “Reinforcing BDNF signaling in muscle may be beneficial to pathological conditions with poor metabolic regulation, like obesity and diabetes,” said Dr Chan. The team’s previous work revealed that adding orally active BDNF mimetics to the drinking water of obese mice reduced their body weight and lipid levels, and improved their insulin sensitivity. Yang X et al. Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility. Sci Signal. 2019;12:eaau1468. doi: 10.1126/scisignal.aau1468 Immune cells engineered to recognize and destroy malignant cells have been used successfully to treat cancer, and now investigators have used a similar approach against cardiac fibrosis. Cardiac fibrosis is seen in most forms of heart disease, but few treatments improve symptoms and no therapies directly target the processes involved. In cancer therapy, cytotoxic T cells are redirected to recognize specific antigens on cancer cells using either a modified T-cell receptor or a chimeric antigen receptor (CAR). With this strategy in mind, researchers from the University of Pennsylvania identified a candidate target protein on activated cardiac fibroblasts from diseased human hearts. As described in a Naturestudy, modified T cells designed to recognize this protein, called fibroblast activation protein, reduced cardiac fibrosis and improved heart function when administered to mice with heart injury and developing fibrosis. CAR T immunotherapy has been approved by the US Food and Drug Administration for some forms of cancer, but more work is needed to assess the safety of its use in human heart disease and to determine whether fibroblast activation protein is the best target. The results of this study, however, provide proof-of-concept for the possibility of targeting cardiac fibrosis with engineered T cells and immunotherapy. “While much more research is needed before we can introduce this approach into the clinical setting, this marks a significant step forward in our efforts to treat—and potentially reverse—a condition that accelerates the progression of heart failure,” said senior author Dr Jonathan Epstein. Aghajanian H et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430–433. doi: 10.1038/s41586-019-1546-z

A 40-year-old man was referred to a tertiary center for consideration of ablation of a symptomatic supraventricular tachycardia resistant to oral bisoprolol (Figure 1). What is the underlying mechanism of arrhythmia, and what are the differential diagnostic considerations? Figure 1. Twelve-lead ECG. Please turn the page to read the diagnosis. The ECG reveals a narrow complex tachycardia with a ventricular rate of 108 beats/min and nonspecific ST-T wave changes. P waves are upright in lead V1 and inverted in leads II, III, and aVF, suggesting retrograde atrial activation. There is a short R-P interval (85 ms), and the P waves are mainly conducted with a 2:1 ratio (Figure 2). Figure 2. Annotated 12-lead ECG. The ECG reveals a narrow complex tachycardia with a ventricular rate of 108 beats/min and nonspecific ST-T wave changes. P waves consistent with retrograde atrial activation are seen (labeled with arrow), along with a short R-P interval (85 ms) and intermittent 2:1 ventriculoatrial conduction. The differential diagnosis for a narrow complex tachycardia with ventriculoatrial dissociation includes (1) atrioventricular nodal reentrant tachycardia with retrograde block in the upper common pathway, (2) junctional tachycardia with retrograde block to the atrium, and (3) orthodromic reciprocating nodofascicular or nodoventricular tachycardia with block to the atrium (Figure 3). The presence of atrioventricular dissociation rules out the possibility of conventional orthodromic atrioventricular reentrant tachycardia because the atrium is a required part of this circuit. Figure 3. Differential diagnosis of supraventricular tachycardia with ventriculoatrial block. Schematic of mechanisms of supraventricular tachycardia with ventriculoatrial dissociation. The main differential includes: atrioventricular nodal reentrant tachycardia with retrograde block in the upper common pathway (A), junctional tachycardia with retrograde block to the atrium (B), orthodromic reciprocating nodofascicular tachycardia with block to the atrium (C), and orthodromic reciprocating nodoventricular tachycardia with block to the atrium (D). AVN indicates atrioventricular node; FP, fast pathway; NF, nodofascicular; NV, nodoventricular; and SP, slow pathway. He underwent an electrophysiology study, which was consistent with a diagnosis of junctional tachycardia: premature atrial beats timed to septal refractoriness had no effect on the tachycardia cycle length; scanning premature atrial beats early in the diastolic interval would advance the immediate His potential with subsequent continuation of tachycardia; and ventricular extrastimuli timed to His refractoriness did not affect the timing of the next His activation.1 It is interesting to note that during the study, there were periods of marked sinus bradycardia with complete atrioventricular dissociation and a narrow complex tachycardia (Figure 4). Figure 4. Twelve-lead ECG on day of electrophysiology study. The ECG reveals sinus bradycardia with atrioventricular dissociation and a narrow complex tachycardia at a rate of 118 beats/min. Given that the junctional tachycardia focus typically lies in close anatomic proximity to the compact atrioventricular node, radiofrequency ablation was not attempted during the procedure because of the high risk of iatrogenic atrioventricular block. He was started on sotalol 120 mg twice daily with good response and maintained normal sinus rhythm on a follow-up 48-hour Holter monitor. Junctional tachycardia is an arrhythmia, well-described in pediatric patients, that can occur spontaneously or as a postoperative sequela of congenital heart surgery. In adults, junctional tachycardia is uncommon but may occur transiently after slow pathway modification in the electrophysiology laboratory or after cardiopulmonary bypass as a result of ischemic injury to the conduction system and postoperative inotropic agents. In addition, junctional tachycardia may be observed in the setting of myocardial ischemia or digoxin toxicity.2 In some patients, junctional tachycardia presents nearly continuously (also known as incessant junctional tachycardia). The mechanism of arrhythmia is likely enhanced automaticity, although triggered activity may contribute in some patients.3 Differentiation of junctional tachycardia from atrioventricular nodal reentrant tachycardia is clinically important, because ablation of junctional tachycardia is associated with a higher risk of atrioventricular block and reserved for cases where medical therapy is ineffective or contraindicated.2 Features that increase the likelihood of a diagnosis of junctional tachycardia include incessant tachycardia and the presence of atrioventricular dissociation. The onset of tachycardia is spontaneous, does not require initiation with a premature atrial or ventricular beat (unlike atrioventricular nodal reentrant tachycardia), and has a gradual onset (ie, warm-up phenomenon). During tachycardia, this arrhythmia may have varying degrees of cycle length irregularity or variation in heart rate. Last, overdrive pacing or electrical cardioversion does not reliably terminate the tachycardia.2 Confirmation of a diagnosis can be made during an invasive electrophysiology study.1 Dr Chew is supported by a Canadian Institutes of Health Research Banting Fellowship and an Arthur JE Child Cardiology Fellowship. None. https://www.ahajournals.org/journal/circ

Increased concentrations of high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) reflect subclinical myocardial injury and are strong predictors of incident heart failure and cardiovascular death.1–3 Although hs-cTnI and hs-cTnT commonly are considered to provide similar diagnostic and prognostic information, recent data have demonstrated important physiological differences.4 Recently, we reported that tobacco smoking is associated with lower circulating hs-cTnI in a general population cohort and that the prognostic merit of hs-cTnI is significantly lower in smokers than in nonsmokers.5 The observations were unexpected and raise the question whether the association with tobacco smoking can be generalized to populations with established cardiovascular disease. We therefore tested the hypotheses that current smoking is associated with lower concentrations and prognostic value of hs-cTnI and hs-cTnT in patients with stable coronary artery disease (CAD). We measured hs-cTnT and hs-cTnI concentrations at baseline in 3126 nonsmokers and 550 current smokers with stable CAD enrolled in the PEACE trial (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy). hs-cTnT and hs-cTnI were measured using high-sensitivity assays as described previously.2,3 Cigarette smoking status was self-reported as current smoker (≥1 cigarettes/day), former smoker, and never smoker. During a median follow-up of 5.2 years, 204 patients experienced the composite outcome of cardiovascular death or hospitalization for heart failure. All participants provided written informed consent, and the study was conducted after approval of ethics committees from all participating sites. The associations between log 2–transformed cardiac troponin concentrations and (1) smoking and (2) outcomes were assessed by multivariable linear regression and Cox regression, respectively. We generated both unadjusted models and models adjusting for covariates associated with troponin concentrations by linear regression analysis, ie, age, sex, N-terminal pro-B-type natriuretic peptide, body mass index, previous hypertension, estimated glomerular filtration rate, and use of β-blockers, diuretics, and insulin. Current smokers had lower concentrations of hs-cTnT (median, 4.9 ng/L [interquartile range, 2.9–7.5 ng/L] versus 6.1 [interquartile range, 4.1–9.4 ng/L], P<0.001), but not hs-cTnI (median, 4.1 ng/L [interquartile range, 2.8–6.9 ng/L] versus 4.4 [interquartile range, 2.9–7.2 ng/L], P=0.09) than noncurrent smokers. In adjusted models, current smoking was associated with 12% (95% CI, 4%–20%) lower hs-cTnT and a nonsignificant 0% (95% CI, –9% to +7%) lower hs-cTnI level in comparison with never-smokers, whereas former smoking was associated with a nonsignificant 1% (95% CI, –7% to +6%) lower hs-cTnT and a nonsignificant 0% (95% CI, –6% to +6%) lower hs-cTnI level in comparison with never-smokers. The percentage of smokers as a function of cardiac troponin T concentrations is shown in Figure A. Figure. Relation between cardiac troponin T (cTnT) and current smoking, and between cTnT and outcome according to smoking status. A, Proportion of current smokers as a function of high-sensitivity cTnT concentrations in patients with stable coronary artery disease. B, Association between high-sensitivity cTnT concentrations and the incidence of cardiovascular (CV) death or heart failure hospitalization (HF Hosp.) stratified according to smoking status. Models are adjusted for age, sex, N-terminal pro-B-type natriuretic peptide, body mass index, previous hypertension, estimated glomerular filtration rate, and use of β-blockers, diuretics, and insulin. p.y. indicates person-years. The associations between hs-cTnT (hazard ratio, 1.56 [95% CI, 1.30–1.88]) and hs-cTnI (hazard ratio, 1.29 [95% CI, 1.16–1.43]) and the incidence of cardiovascular death or heart failure hospitalization remained significant in adjusted models for nonsmokers, whereas this association was attenuated in current smokers (hs-cTnT: hazard ratio, 1.23 [95% CI, 0.87–1.72]; hs-cTnI: hazard ratio, 1.17 [95% CI, 0.88–1.56]). The association did not differ significantly between smokers and nonsmokers in unadjusted models (hs-cTnT: P-for-interaction=0.18; hs-cTnI: P-for-interaction=0.82) or adjusted models (hs-cTnT: P-for-interaction=0.27; hs-cTnI: P-for-interaction=0.55) (Figure B). The area under the receiver operating characteristics curve was 0.74 (0.70–0.77) and 0.71 (0.67–0.75) in nonsmokers and 0.68 (0.58–0.78) and 0.69 (0.60–0.79) in smokers for hs-cTnT and hs-cTnI, respectively. The current findings for hs-cTnT and hs-cTnI in patients with chronic CAD extend previous observations of an inverse association between hs-cTnI concentrations and current smoking in the general population.5 The reason smoking was associated with lower hs-cTnT but not hs-cTnI concentrations in stable CAD is unclear, but could theoretically be related to substances in tobacco smoke that interfere differentially with the analysis or, perhaps more likely, the release and kinetic patterns of hs-cTnT and hs-cTnI. The mechanisms responsible for the inverse association between smoking and concentrations of cardiac troponins remain unknown, and the effect of tobacco smoking on troponin release and degradation merits further investigation. A higher proportion of smokers among patients with low cardiac troponin concentrations and CAD could potentially be attributed, in part, to the very low risk of CAD in nonsmokers with low concentrations of troponins. In contrast to observations made for hs-cTnI in a general population cohort, we did not observe a significant interaction by smoking status on the association between hs-cTnT or hs-cTnI and cardiovascular events in the PEACE cohort, but this may be attributable to the smaller sample size and subsequent lower statistical power. Strengths of the current study include the prospective observational study design, the long-term follow-up, and the use of adjudicated end points. A limitation is that tobacco habits were self-reported. Furthermore, we cannot rule out the presence of survival bias and residual confounding. In conclusion, our study demonstrates that cigarette smoking is associated with lower concentrations of circulating hs-cTnT, but not hs-cTnI in patients with stable CAD. Moreover, the association between both hs-cTnT and hs-cTnI and the incidence of cardiovascular events in current smokers with stable CAD is attenuated and nonsignificant in adjusted models. The PEACE trial was sponsored by the National Heart, Lung, and Blood Institute with support from Knoll Pharmaceuticals and Abbott Laboratories. This biomarker substudy was also supported by Roche Diagnostics and Abbott Diagnostics. Dr Myhre has received consulting fees from Novartis. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott Laboratories; Amgen; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; Gilead; GlaxoSmithKline; Intarcia; Janssen Research and Development; The Medicines Company; MedImmune; Merck; Novartis; Poxel; Pfizer; Quark Pharmaceuticals; Roche Diagnostics; and Takeda. Consulting for Alnylam; Amgen; AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dyrnamix; Esperion; IFM Therapeutics; Intarcia; Ionis; Janssen Research and Development; The Medicines Company; MedImmune; Merck; MyoKardia; and Novartis. Dr Pfeffer has received consulting fees from AstraZeneca, DalCor, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi; research grant support from Novartis; and stock Options in DalCor. Dr Omland reports consulting fees and research grant support via Akershus University Hospital from Abbott Laboratories, CardiNor, Novartis, Roche Diagnostics, Singulex, and SomaLogic. The other authors report no conflicts. https://www.ahajournals.org/journal/circ Data sharing: The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. Guest editor for this article was Allan Jaffe, MD.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research.

The fundamentals of cardiac resuscitation include the immediate provision of high-quality cardiopulmonary resuscitation combined with rapid defibrillation (as appropriate). These mainstays of therapy set the groundwork for other possible interventions such as medications, advanced airways, extracorporeal cardiopulmonary resuscitation, and post–cardiac arrest care, including targeted temperature management, cardiorespiratory support, and percutaneous coronary intervention. Since 2015, an increased number of studies have been published evaluating some of these interventions, requiring a reassessment of their use and impact on survival from cardiac arrest. This 2019 focused update to the American Heart Association advanced cardiovascular life support guidelines summarizes the most recent published evidence for and recommendations on the use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest. It includes revised recommendations for all 3 areas, including the choice of advanced airway devices and strategies during cardiac arrest (eg, bag-mask ventilation, supraglottic airway, or endotracheal intubation), the training and retraining required, the administration of standard-dose epinephrine, and the decisions involved in the application of extracorporeal cardiopulmonary resuscitation and its potential impact on cardiac arrest survival.

Survival after out-of-hospital cardiac arrest requires an integrated system of care (chain of survival) between the community elements responding to an event and the healthcare professionals who continue to care for and transport the patient for appropriate interventions. As a result of the dynamic nature of the prehospital setting, coordination and communication can be challenging, and identification of methods to optimize care is essential. This 2019 focused update to the American Heart Association systems of care guidelines summarizes the most recent published evidence for and recommendations on the use of dispatcher-assisted cardiopulmonary resuscitation and cardiac arrest centers. This article includes the revised recommendations that emergency dispatch centers should offer and instruct bystanders in cardiopulmonary resuscitation during out-of-hospital cardiac arrest and that a regionalized approach to post–cardiac arrest care may be reasonable when comprehensive postarrest care is not available at local facilities.

This 2019 focused update to the American Heart Association pediatric advanced life support guidelines follows the 2018 and 2019 systematic reviews performed by the Pediatric Life Support Task Force of the International Liaison Committee on Resuscitation. It aligns with the continuous evidence review process of the International Liaison Committee on Resuscitation, with updates published when the International Liaison Committee on Resuscitation completes a literature review based on new published evidence. This update provides the evidence review and treatment recommendations for advanced airway management in pediatric cardiac arrest, extracorporeal cardiopulmonary resuscitation in pediatric cardiac arrest, and pediatric targeted temperature management during post–cardiac arrest care. The writing group analyzed the systematic reviews and the original research published for each of these topics. For airway management, the writing group concluded that it is reasonable to continue bag-mask ventilation (versus attempting an advanced airway such as endotracheal intubation) in patients with out-of-hospital cardiac arrest. When extracorporeal membrane oxygenation protocols and teams are readily available, extracorporeal cardiopulmonary resuscitation should be considered for patients with cardiac diagnoses and in-hospital cardiac arrest. Finally, it is reasonable to use targeted temperature management of 32°C to 34°C followed by 36°C to 37.5°C, or to use targeted temperature management of 36°C to 37.5°C, for pediatric patients who remain comatose after resuscitation from out-of-hospital cardiac arrest or in-hospital cardiac arrest.