Evidence-based recommendations about anticoagulation in acute type B aortic dissection (TBAD) are completely missing, but there is a diffuse conviction that it could prevent the healing process of the dissected aorta’s false lumen. However, several clinical conditions may lead to the necessity to start anticoagulant therapy among patients with acute type B aortic dissection, ranging from atrial fibrillation to more complicated clinical scenarios and the correct management in this kind of patients is still an open issue. We are presenting a 51-years-old man with multi-infarct encephalopathy referred to us for an acute TBAD and a first diagnosis of ischemic cardiomyopathy complicated by left ventricular (LV) thrombus formation. Coronary angiography revealed a critical stenosis of left anterior descending artery (LAD) treated with drug-eluting stent deployment. The patient was addressed to triple antithrombotic therapy with acetylsalicylic acid, clopidogrel and warfarin with target INR 2.0–2.5. After 6 months, computed tomography angiography revealed the stability of the dissection flap. Cardiac magnetic resonance imaging, however, confirmed the persistence of a small thrombotic formation in LV apex, thus double antithrombotic therapy with warfarin and clopidogrel was instituted. The patient remained asymptomatic during the follow-up period but was advised to suspend his job and physical activities. Current guidelines do not discuss anticoagulant therapy in the setting of TBAD and large randomized trials are lacking. Despite it is generally considered unsafe to administer anticoagulants in patients with TBAD, we present a case in which triple antithrombotic therapy was well tolerated and did not lead to progression of the intimal flap after 6 months.

Background Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful. Methods We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function. Results When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05). Conclusions In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD.

Mechanical heart valve prostheses are based on older designs without changes during the last 40 years. Today, there is an unmet need for less thrombogenic mechanical prostheses. Analysis of the relationship between flow characteristics and thromboembolic complications is possible using numerical and biomolecular flow studies that have shown that the reverse rather than the forward flow is responsible for local platelet activation and thrombosis. After peak flow, leaflets experience flow deceleration and the leaflets are still widely open when the flow becomes zero. The closure of the valve starts with the onset of reverse flow. Therefore, the valve closes extremely fast with most of the leaflet traveling angle occurring in <10 ms with excessively high reverse flow velocities. The pivoting spaces, so-called “Hot Spots” should be eliminated to prevent pathologic shear stress that result in thrombosis. A novel tri-leaflet valve combines favorable hemodynamics with the durability of mechanical heart valve. This valve closes within 60 ms, much slower than bi-leaflet valves and similar to the closing mode of a tissue valve. Micro-particle image velocimetry did not show critical regions of flow stagnation and zones of excessive shear in the pivoting region suggesting low potential for thrombogenic events that should allow to avoid long-term anticoagulation.

Transient receptor potential canonical 1 (TRPC1) protein is abundantly expressed in cardiomyocytes. While TRPC1 is supposed to be critically involved in cardiac hypertrophy, its physiological role in cardiomyocytes is poorly understood. We investigated the subcellular location of TRPC1 and its contribution to Ca2+ signaling in mammalian ventricular myocytes. Immunolabeling, three-dimensional scanning confocal microscopy and quantitative colocalization analysis revealed an abundant intracellular location of TRPC1 in neonatal rat ventricular myocytes (NRVM) and adult rabbit ventricular myocytes. TRPC1 was colocalized with intracellular proteins including sarco/endoplasmic reticulum Ca2+ ATPase 2 in the sarcoplasmic reticulum (SR). Colocalization with wheat germ agglutinin, which labels the glycocalyx and thus marks the sarcolemma including the transverse tubular system, was low. Super-resolution and immunoelectron microscopy supported the intracellular location of TRPC1. We investigated Ca2+ signaling in NRVMs after adenoviral TRPC1 overexpression or silencing. In NRVMs bathed in Na+ and Ca2+ free solution, TRPC1 overexpression and silencing was associated with a decreased and increased SR Ca2+ content, respectively. In isolated rabbit cardiomyocytes bathed in Na+ and Ca2+ free solution, we found an increased decay of the cytosolic Ca2+ concentration [Ca2+]i and increased SR Ca2+ content in the presence of the TRPC channel blocker SKF-96365. In a computational model of rabbit ventricular myocytes at physiological pacing rates, Ca2+ leak through SR TRPC channels increased the systolic and diastolic [Ca2+]i with only minor effects on the action potential and SR Ca2+ content. Our studies suggest that TRPC1 channels are localized in the SR, and not present in the sarcolemma of ventricular myocytes. The studies provide evidence for a role of TRPC1 as a contributor to SR Ca2+ leak in cardiomyocytes, which was previously explained by ryanodine receptors only. We propose that the findings guide us to an understanding of TRPC1 channels as modulators of [Ca2+]i and contractility in cardiomyocytes.

This editorial refers to ‘One-year outcomes in atrial fibrillation presenting during infections: a nationwide registry-based study’, by A. Gundlund et al., doi:10.1093/eurheartj/ehz873.

AimsEndothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). Methods and resultsThree hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. ConclusionWe identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. Trial registrationClinicalTrials.gov: NCT03193294.

Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF, however, the underlying mechanisms leading to the observed brain changes remain unclear.Objective: To study the relationship between impaired heart function, hampered blood circulation and structural brain change in a case-control study.Methods and Results: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) − a biomarker that is used for screening, diagnosis and prognosis of HF. Here we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.Conclusions: We obtained significant correlations between brain structure and markers of heart failure including EF and NT-proBNP. A diminished GMD was found with decreased EF and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition, however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.

Patients with Congenital heart disease (CHD) require repetitive imaging of the pulmonary vasculature throughout their life. In this study, we compared a novel Compressed SENSE accelerated (factor 9) electrocardiogram (ECG)- and respiratory-triggered 3D modified Relaxation-Enhanced Angiography without Contrast and Triggering (modified REACT-non-contrast-enhanced magnetic resonance angiography (modified REACT-non-CE-MRA)) with standard non-ECG-triggered time-resolved 4D CE-MRA for imaging of the pulmonary arteries and veins in patients with CHD. This retrospective analysis of 25 patients (June 2018–April 2019) with known or suspected CHD was independently conducted by two radiologists executing measurements on modified REACT-non-CE-MRA and 4D CE-MRA on seven dedicated points (inner edge): Main pulmonary artery (MPA), right and left pulmonary artery, right superior and inferior pulmonary vein, left superior (LSPV) and inferior pulmonary vein. Image quality for arteries and veins was evaluated on a four-point scale in consensus. Twenty-three of the 25 included patients presented a CHD. There was a high interobserver agreement for both methods of imaging at the pulmonary arteries (ICC ≥ 0.96); at the pulmonary veins, modified REACT-non-CE-MRA showed a slightly higher agreement, pronounced at LSPV (ICC 0.946 vs. 0.895). Measurements in 4D CE-MRA showed higher diameter values compared to modified REACT-non-CE-MRA, at the pulmonary arteries reaching significant difference (e.g. MPA: mean 0.408 mm, p = 0.002). Modified REACT-non-CE-MRA (average acquisition time 07:01 ± 02:44 min) showed significant better image quality than 4D CE-MRA at the pulmonary arteries (3.84 vs. 3.32, p < 0.001) and veins (3.32 vs. 2.72, p = 0.015). Compressed SENSE accelerated (factor 9) ECG- and respiratory-triggered 3D modified REACT-non-CE-MRA allows for reliable and fast imaging of the pulmonary arteries and veins with higher image quality and slightly higher interobserver agreement than 4D CE-MRA without contrast agent and associated disadvantages. Therefore, it represents a clinically suitable technique for patients requiring repetitive imaging of the pulmonary vasculature, e.g. patients with CHD.

Background The impact of pulmonary vein isolation (PVI) performed with cryoballoon (CB) on the intrinsic cardiac autonomic nervous system (ICANS) remains unclear. Objective The purpose of this study was to evaluate the predictors and the clinical meaning of cardiac neuromodulation achieved by CB-ablation as assessed by sinus heart rate (HR) response after the procedure. Methods Patients who underwent CB-ablation for drug-resistant atrial fibrillation (AF) from January 2014 to October 2018 were included. Twelve‑leads rest ECG was taken both before and after the procedure. After discharge, patients were scheduled for follow-up visits at 1, 3, 6, and 12 months and 24 h Holter recordings were obtained at each follow-up visit. All documented AF episodes of >30 s were considered as recurrence. Results Four-hundred seventy-two patients (62.3% male, age 56.7 ± 13.6 years, 97.2% paroxysmal AF) were included. Mean HR before the procedure was 60.17 ± 10.4 bpm, while the morning after the procedure mean HR was 75.48 ± 12.0 bpm. Age at enrollment (R = −0.26; p < 0.001), baseline HR before the CB-A (R = −0.32; p < 0.001), nadir temperature in each right pulmonary vein (R = −0.11, p = 0.022; R = −0.16; p = 0.001) were significantly associated with the ∆HR. At 2-year follow-up, freedom from recurrences was 83.1% for the patients with HR increase ≥15 bpm after CB-A and 66.3% in patients with HR increase ˂15 bpm (p = 0.021). Conclusion Sinus HR increase is a frequent phenomenon after CB-A, that can be predicted by both clinical and procedural factors and that correlates with better outcome after cryo-PVI.

Background Recent evidence suggests that routine exercise-based cardiac rehabilitation (CR) may not lead to a substantial increase in estimated peak oxygen uptake (V̇O2peak). This could reduce the potential benefits of CR and explain why CR no longer improves patient survival in recent studies. We aimed to determine whether routine exercise-based CR increases V̇O2peak using gold-standard maximal cardiopulmonary exercise testing (CPET), and to quantify the exercise training stimulus which might be insufficient in patients undertaking CR. Methods We studied the effects of a routine, twice weekly, exercise-based CR programme for eight weeks (intervention group) compared with abstention from supervised exercise training (control group) in patients with coronary heart disease. The primary outcome was V̇O2peak measured using CPET. We also measured changes in body composition using dual X-ray absorptiometry, carotid intima-media thickness, hs-CRP and N-terminal pro B-type natriuretic peptide at baseline, 10 weeks and one year. We also calculated the Calibre 5-year all-cause mortality risk score. Results Seventy patients (age 63.1 SD 10.0 years; BMI 29.2 SD 4.0 kg·m−2; 86% male) were recruited (n = 48 intervention; n = 22 controls). The mean aerobic exercise training duration was 23 min per training session, and the mean exercise training intensity was 45.9% of heart rate reserve. V̇O2peak was 23·3 ml·kg-1·min−1 at baseline, and there were no changes in V̇O2peak between groups at any time point. The intervention had no effect on any of the secondary endpoints. Conclusion Routine CR does not lead to an increase in V̇O2peak and is unlikely to improve long-term outcomes.

Background Left atrial (LA) sphericity has been proposed as a more sensitive marker of atrial fibrillation (AF)-associated atrial remodeling compared to traditional markers such as LA size. However, mechanisms that underlie changes in LA sphericity are not fully understood and studies investigating the predictive value of LA sphericity for AF ablation outcome have yielded conflicting results. The present study aimed to assess correlates of LA sphericity and to compare LA sphericity in subjects with and without AF. Methods Measures of LA size (LA diameter, LA volume, LA volume index), LA sphericity and thoracic anteroposterior diameter (APd) at the level of the LA were determined using computed tomography (CT) imaging data in 293 AF patients (62% paroxysmal AF) and 110 controls. Results LA diameter (40.1 ± 6.8 mm vs. 35.2 ± 5.1 mm; p < 0.001), LA volume (116.0 ± 33.0 ml vs. 80.3 ± 22.6 ml; p < 0.001) and LA volume index (56.1 ± 15.3 ml/m2 vs. 41.6 ± 11.1 ml/m2; p < 0.001) were significantly larger in AF patients compared to controls, also after adjustment for covariates. LA sphericity did not differ between AF patients and controls (83.7 ± 2.9 vs. 83.9 ± 2.4; p = 0.642). Multivariable linear regression analysis demonstrated that LA diameter, LA volume, female sex, body length and thoracic APd were independently associated with LA sphericity. Conclusions The present study suggests that thoracic constraints rather than the presence of AF determine LA sphericity, implying LA sphericity to be unsuitable as a marker of AF-related atrial remodeling.

Myocardial infarction(MI) not only defines acute MI with obstructed coronary arteries (T1MI) but also myocardial necrosis caused by myocardial oxygen supply/demand mismatch as type 2 MI(T2MI); only T1MI patients benefit from an early invasive management. Myeloid-related protein(MRP)-8/14 is a biomarker described in various inflammatory diseases and in MI patients. Here we evaluate the potential of MRP-8/14 and high-sensitivity troponin I(hs-cTnI) to differentiate T2MI from T1MI. Patients with final diagnosis NSTEMI(n = 254; 33.1% female) enrolled in a prospective biomarker registry between 08/2011 and 10/2016 were analysed. Median baseline MRP-8/14 levels were higher in T2MI(n = 55; 3.37(1.88–6.48)μg/mL) than in T1MI (n = 199; 2.4(1.4–3.79)μg/mL)(p = .013) patients, in contrast to hs-cTnI (T2MI:52[11.65–321.4]ng/L vs. T1MI:436.5 [61.25–1973.8]ng/L; p < .001). To detect the strength of this association odds ratios(OR) were calculated with MRP-8/14 yielding 2.13(1.16–3.92; p = .015) to predict T2MI and 0.47(0.26–0.87; p = .015) for T1MI. As expected, hs-cTnI yielded an OR of to predict T2MI 0.34(0.17–0.65; p = .001) and 2.98(1.53–5.81; p = .001) for T1MI. Both markers show comparable and independent results if adjust to hs-cTnI/MRP-8/14, TIMI risk score and CRP. T2MI is associated with higher MRP-8/14 and lower hs-cTnI concentrations than T1MI. Our data suggest that MRP-8/14 as a marker of inflammation might provide usable discriminatory information complementing hs-cTnI in a diagnostic procedure evaluating the type of MI directly upon hospital admission.

Objective Relationship between STEMI time of presentation, its circadian pattern and cardiovascular outcomes is unclear. Our objective is to analyze clinical outcomes of STEMI according to time of presentation and circadian pattern. Methods We analyzed data from patients treated within the regional STEMI Network from January 2010 to December 2015. On-hour group included patients treated between 8:00 h and 19:59 h on weekdays, the rest were catalogued as off-hour group. The primary endpoint was 1-year all-cause mortality. Secondary endpoints were 30-day all-cause mortality and in-hospital complications. Results A total of 8608 patients were included, 44.1% in the on-hour group and 55.9% in the off-hour group. We observed a shorter patient delay and longer system delay in the off-hour group compared to on-hour group with no difference in total ischemic time. At 30-day and 1-year follow-up there were no differences in adjusted all-cause mortality between groups [OR 0.91 (CI95%: 0.73–1.12; p = 0.35) and OR 0.99 (CI95%: 0.83–1.17; p = 0.87), respectively]. A circadian pattern was observed between 9:00 am and 12:30 pm, with no differences in 30-day and 1-year mortality between patients included in this time interval [OR 1.02 (IC95%: 0.81–1.30; p = 0.85) and OR 1.12 (IC95%: 0.92–1.36; p = 0.25) respectively]. Conclusions Off-hour STEMI presentation was associated with a shorter patient delay and longer system delay without an increase in total ischemic time. The off-hour presentation was not related to an increase in 1-year all-cause mortality when compared to on-hour. A circadian pattern was found, without differences in 30-day and 1-year mortality.

Backgrounds Prognostic value of soluble suppression of tumorigenecity (sST2), a novel circulating biomarker for myocardial fibrosis, remains elusive in the heart failure patients with preserved ejection fraction (HFpEF). Methods 405 consecutive patients with heart failure (HF) were enrolled prospectively, and were grouped into HF with reduced ejection fraction (HFrEF, N = 215), HF with mid-range ejection fraction (HFmrEF, N = 80) and HFpEF (N = 110). The primary endpoint was the composite endpoint of all-cause death and HF rehospitalization. Results After a median of 12 months, 139 patients reached the primary endpoint, with 57 patients died and 82 patients rehospitalized. Multivariate analysis confirmed that sST2 was an independent risk factor of the primary endpoint for all HF patients [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30–4.22, P = 0.004]. Predicting efficacy of sST2 on outcomes was higher for HFpEF (HR 6.48, 95%CI 1.89–22.21, P = 0.003) as compared to HFrEF (HR 3.21, 95% CI 1.67–6.19, P = 0.000). But the association between sST2 and outcomes in HFmrEF is not statistical (HR 3.38, 95%CI 0.82–13.86, P = 0.091). The combined use of sST2 and N terminal pro B type natriuretic peptide (NT-proBNP) could improve the prognostic value compared to using NT-proBNP alone in HFrEF (AUC = 0.794 vs. 0.752, P = 0.034). Conclusion Higher baseline sST2 levels are associated with increased risk of all-cause death and HF rehospitalization in patients with HF independent of ejection fraction. The combined use of sST2 and NT-proBNP could improve the prognostic value than using these two values alone, especially for HFrEF patients.

Introduction Multi-vessel coronary artery disease (MV-CAD) is common among patients with acute coronary syndrome (ACS) and is associated with worse outcomes. Objectives To examine temporal trends of patients presenting with ACS and MV-CAD. Methods Time-dependent analysis of patients enrolled in the ACS Israeli Surveys (ACSIS) between 2004–2016 by 3 time periods: early (2004–2006; n = 2111), mid (2008–2010; n = 2049), and late (2013–2016; n = 2010). MV-CAD was defined as >50% stenosis in ≥2 separate coronary territories at the index coronary catheterization. Outcomes were 30-day MACE and 1-year all-cause mortality. Results Overall 6170/9321 patients (66%) had MV-CAD (age 64.5 ± 12.1, males 80%). Patients from later periods were older with a higher prevalence of cardiovascular risk-factors and comorbidity. Among patients with MV-CAD, STEMI decreased significantly (early-46% vs. late-37%, p < 0.001). The rates of PCI were similar, however rates of MV-PCI have increased (early-16.8% vs. late −37.1%, p < 0.001) while the rates of CABG decreased over-time (early-12.7% vs. late −9.2%, p < 0.001). Thirty-day outcomes improved significantly; MACE (early-18.2%, mid-12.6%, late-11.2%, p < 0.001), mortality (early-4.7%, mid-4.2%, late-3.1%, p = 0.03) and re-infarction (early = 3.0%, mid = 2.4% and late 1.1%, p < 0.001). No significant change in 1-year mortality was observed (early = 9.3%, mid = 7.8%, late = 7.7%, p = 0.13). A multivariate adjusted analysis demonstrated that the mid and late periods (vs. the early period) were associated with significantly reduced risk for 30-day MACE (OR = 0.65 [0.54–0.77] and 0.54 [0.45–0.65], respectively). Conclusions During the last decade, the burden of cardiovascular risk factors among ACS patients with MV- CAD has increased, more invasive treatment was provided and a significant improvement in 30-day outcomes was observed.

Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6–12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific. We focused particularly in parameters associated with age-dependent remodeling of the LV extracellular matrix (ECM) that are involved in collagen metabolism. LV function and anatomical structure were assessed both by conventional echocardiography and strain analysis. We then measured ECM proteins that directly affect LV contractility and remodeling. All data were analyzed across ages and between sexes and were directly linked to LV functional changes. Echocardiography confirmed an age-dependent decrease in chamber volumes and LV internal diameters, indicative of concentric remodeling. As in humans, animals displayed preserved ejection fraction with age. Notably, changes to chamber dimensions and volumes were temporally distinct between sexes. Complementary to the traditional echocardiography, speckle tracking echocardiography (STE) revealed that circumferential strain rate declined in 18 month old females, compared to younger animals, but not in males, suggesting STE as an earlier indicator for changes in cardiac function between sexes. Age-dependent collagen deposition and expression in the endocardium did not differ between sexes; however, other factors involved in collagen metabolism were sex-specific. Specifically, while decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent, periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex-specific differences. Moreover, our data also suggest that with age males and females have distinct TGFβ signaling pathways. Overall, our results give evidence of sex-specific molecular changes during physiological cardiac remodeling that associate with age-dependent structural and functional dysfunction. These data highlight the importance of including sex-differences analysis when studying cardiac aging.

Objective Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function. Recent studies have demonstrated that the acetylation of cardiac myofibril proteins accelerates relaxation and that cTnI is acetylated in the heart. These findings highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to changes in myofilament, myofibril, and/or cellular mechanics. The objective of this study was to determine the effects of mimicking acetylation at a single site of cTnI (lysine-132; K132) on myofilament, myofibril, and cellular mechanics and elucidate its influence on molecular function. Methods To determine if pseudo-acetylation of cTnI at 132 modulates thin filament regulation of the acto-myosin interaction, we reconstituted thin filaments containing WT or K132Q (to mimic acetylation) cTnI and assessed in vitro motility. To test if mimicking acetylation at K132 alters cellular relaxation, adult rat ventricular cardiomyocytes were infected with adenoviral constructs expressing either cTnI K132Q or K132 replaced with arginine (K132R; to prevent acetylation) and cell shortening and isolated myofibril mechanics were measured. Finally, to confirm the changes in cell shortening and myofibril mechanics were directly due to mimicking acetylation of cTnI at K132, we exchanged troponin containing WT or K132Q cTnI into isolated myofibrils and measured myofibril mechanical properties. Results Reconstituted thin filaments containing either WT or K132Q cTnI exhibited decreased calcium sensitivity of motility. Cardiomyocytes expressing K132Q cTnI had faster relengthening and myofibrils isolated from these cells had faster relaxation along with decreased calcium sensitivity compared to cardiomyocytes expressing WT cTnI or cTnI K132R that were not different. Myofibrils exchanged with cTnI K132Q ex vivo demonstrated faster relaxation and decreased calcium sensitivity. Conclusions Our results indicate for the first time that mimicking acetylation of a specific cTnI lysine accelerates myofilament, myofibril, and myocyte relaxation. This work underscores the importance of understanding how acetylation of specific sarcomeric proteins affects cardiac homeostasis and disease and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

This editorial refers to ‘Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort’, by A.D. Elliott et al., doi:10.1093/eurheartj/ehz897.

This editorial refers to ‘Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis’, by E. Freisinger et al., doi:10.1093/eurheartj/ehz698.

AimsPhysical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort. Methods and resultsWe included 402 406 individuals (52.5% female), aged 40–69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74–0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82–1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64–0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias. ConclusionThe risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.

This editorial refers to ‘Clinical impact of conduction disturbances in transcatheter aortic valve replacement recipients: a systematic review and meta-analysis’, by L. Faroux et al., doi:10.1093/eurheartj/ehz924.

This editorial refers to ‘Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction’, by R. Carnevale et al., doi:10.1093/eurheartj/ehz893.

This commentary refers to ‘Genetically modulated educational attainment and coronary disease risk’, by L. Zeng et al., pages 2413–2420.

This commentary refers to ‘Genetic instruments with too many strings: acknowledging pleiotropy and population structure in Mendelian randomization studies’, by J.A. Labrecque et al., doi:10.1093/eurheartj/ehz943.

AimsTo investigate the composition of nocturnal hypoxaemic burden and its prognostic value for cardiovascular (CV) mortality in community-dwelling older men. Methods and resultsWe analysed overnight oximetry data from polysomnograms obtained in 2840 men from the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study (ClinicalTrials.gov Identifier: NCT00070681) to determine the number of acute episodic desaturations per hour (oxygen desaturation index, ODI) and time spent below 90% oxygen saturation (T90) attributed to acute desaturations (T90desaturation) and to non-specific drifts in oxygen saturation (T90non-specific), respectively, and their relationship with CV mortality. After 8.8 ± 2.7 years follow-up, 185 men (6.5%) died from CV disease. T90 [hazard ratio (HR) 1.21, P < 0.001], but not ODI (HR 1.13, P = 0.06), was significantly associated with CV death in univariate analysis. T90 remained significant when adjusting for potential confounders (HR 1.16, P=0.004). Men with T90>12 min were at an elevated risk of CV mortality (HR 1.59; P=0.006). Approximately 20.7 (5.7–48.5) percent of the variation in T90 could be attributed to non-specific drifts in oxygen saturation. T90desaturation and T90non-specific were individually associated with CV death but combining both variables did not improve the prediction. ConclusionIn community-dwelling older men, T90 is an independent predictor of CV mortality. T90 is not only a consequence of frank desaturations, but also reflects non-specific drifts in oxygen saturation, both contributing towards the association with CV death. Whether T90 can be used as a risk marker in the clinical setting and whether its reduction may constitute a treatment target warrants further study.

A 46-year-old man presented with 6 months of progressive exertional dyspnoea. Computed tomography pulmonary angiography showed severe bilateral stenoses of the left and right main pulmonary arteries (Panel A). Exploratory thoracotomy had been performed 2 months earlier for suspected pulmonary embolism, which revealed suspected pulmonary artery malignancy which could not be removed due to high risk of the anatomy. Positron emission tomography-computed tomography did not reveal any other locations suspicious for malignancy. After evaluation by a multidisciplinary team, percutaneous transluminal pulmonary artery biopsy (PTPB) was performed (Panels B and C and Supplementary material onlineSupplementary material online, Video S1) using a biopsy forceps (Panel D) and millet grain sized tissue samples obtained (Panel E). Haematoxylin and eosin staining and immunohistochemical staining were consistent with lymphomatoid granulomatosis (Panel F).

AimsPulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE. Methods and resultsWe analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [β 0.32 (0.26–0.38), P<0.001]. During the same period, in-hospital case fatality rates decreased from 20.4% to 13.9% [β −0.51 (−0.52 to −0.49), P<0.001]. The overall proportion of patients treated with systemic thrombolysis increased from 3.1% in 2005 to 4.4% in 2015 [β 0.28 (0.25–0.31), P<0.001]. Thrombolysis was associated with lower in-hospital mortality rates in patients with haemodynamic instability, both in those with shock not necessitating cardiopulmonary resuscitation (CPR) or mechanical ventilation [odds ratio (OR) 0.42 (0.37–0.48), P<0.001], and in those who underwent CPR [OR 0.92 (0.87–0.97), P=0.002]. This association was independent from age, sex, and comorbidities. However, systemic thrombolysis was administered to only 23.1% of haemodynamically unstable patients. ConclusionAlthough the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.

AimsTo investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. Methods and resultsWe conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). ConclusionEarly discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

This editorial refers to ‘Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany’††, by K. Keller et al., on page 522.

Guidelinespulmonary embolismvenous thrombosisshockdyspnoeaheart failureright ventriclediagnosisrisk assessmentechocardiographybiomarkerstreatmentanticoagulationthrombolysispregnancyvenous thromboembolismembolectomy

A 68-year-old woman with exertional dyspnoea (WHO functional class grade III) was referred to our hospital. She had sternoclavicular joint pain for the past few years. Computed tomography revealed the typical appearance of hyperostosis of the sternoclavicular and sternocostal joints (Panel A, arrowheads). Echocardiogram and a lung ventilation–perfusion scan revealed the multiple segmental ventilation-perfusion mismatches (Panel B) with pulmonary hypertension (PH). Right heart catheterization confirmed PH [mean pulmonary artery pressure (mPAP), 25 mmHg; cardiac index (CI), 1.8 L/min/m2; pulmonary vascular resistance (PVR), 7.5 wood units]. Pulmonary angiography revealed the multiple segmental pulmonary artery stenoses with aneurysmal changes (Panel C, arrowheads). Intravascular optical coherence tomography revealed the absence of an organized thrombus. An 18F-fluorodeoxyglucose positron emission tomography revealed inflammation in the sternoclavicular joint. Based on these findings, we diagnosed her condition as peripheral pulmonic stenosis (PPS) associated with SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome according to the criteria outlined by Benhamou et al. After a combination therapy including pulmonary vasodilation and balloon pulmonary angioplasty, her symptoms and PH improved (WHO functional class grade I; mPAP, 26 mmHg; CI, 2.6 L/min/m2; PVR, 3.6 wood units).

The comment refers to ‘European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism’, by C. Pristipino et al., 2019;40:3182–3195.

When the mark of those before you is so indelible, the worst mistake is to imitate: Davide Capodanno

Strategic meetings are of the upmost importance for planning of research projects and their implementation. Therefore, every year the Royal Brompton and Harefield Hospitals organize a get-together of researchers from all areas of cardiovascular medicine, both from their own institution, as well as worldwide. They take advantage of the presence of eminent scientists from the faculty of the Cardiology Update London as a sounding board.

Background:Estimated glomerular filtration rate (eGFR) based on serum creatinine (sCr) improves early after left ventricular assist device (LVAD) implantation but subsequently declines. Although sCr is a commonly accepted clinical standard, cystatin C (CysC) has shown superiority in assessment of renal function in disease states characterized by muscle wasting. Among patients with an LVAD, we aimed to (1) longitudinally compare CysC-eGFR and sCr-eGFR, (2) assess their predictive value for early postoperative outcomes, and (3) investigate mechanisms which might explain potential discrepancies.Methods:A prospective cohort (n=116) with CysC and sCr concurrently measured at serial time points, and a retrospective cohort (n=91) with chest computed tomography performed within 40 days post-LVAD were studied. In the prospective cohort, the primary end point was a composite of in-hospital mortality, renal replacement therapy, or severe right ventricular failure. In the retrospective cohort, muscle mass was estimated using pectoralis muscle area indexed to body surface area (pectoralis muscle index).Results:In the prospective cohort, sCr-eGFR significantly improved early post-LVAD and subsequently declined, whereas CysC-eGFR remained stable. CysC-eGFR but not sCr-eGFR predicted the primary end point: odds ratio per 5 mL/(min·1.73 m2) decrease 1.16 (1.02–1.31) versus 0.99 (0.94–1.05). In retrospective cohort, for every 5 days post-LVAD, a 6% decrease in pectoralis muscle index was observed (95% CI, 2%–9%, P=0.003). After adjusting for time on LVAD, for every 1 cm2/m2 decrease in pectoralis muscle index, there was a 4% decrease in 30-day post-LVAD sCr (95% CI, 1%–6%, P=0.004).Conclusions:Initial improvement in sCr-eGFR is likely due to muscle wasting following LVAD surgery. CysC may improve assessment of renal function and prediction of early postoperative outcomes in patients with an LVAD.

Background:We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life, and safety of a 12-week feeding trial with 1500- versus 3000-mg daily sodium meals in high-risk patients with heart failure.Methods:Of 196 patients with recent (≤2 weeks) hospitalization for heart failure, ejection fraction ≤40%, on optimal medical therapy, functionally independent, and able to communicate, 83 (47%) consented to participate. Of these, 27 (age, 62±11 years; 22 men; 20 white; ejection fraction, 26±8%) had 24-hour urine sodium ≥3000 mg and agreed to randomly receive either 1500-mg (N=12) or 3000-mg (N=15) sodium meals.Results:On-study retention at 12 weeks was 77% (82% versus 73%; P=0.53); 6 patients (2 in 1500-mg, 4 in 3000-mg arm) withdrew before study completion. Food satisfaction questionnaires indicated that both diets were well tolerated. Quality of life improved in the 1500-mg arm at 12 weeks but did not change in the 3000-mg arm. Average compliance with meals was 52% (based on urinary sodium) and was not significantly different between arms (42% versus 60%; P=0.25). Study meals reduced 24-hour urinary sodium by 137±21 mmol (1500-mg arm) and 82±16 mmol (3000-mg arm), both P<0.001; between-arms difference was 55 mmol (95% CI, 3–107; P=0.037). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was not affected. Hospitalizations and low blood pressure events did not differ significantly between arms. Serum creatinine decreased more (by 0.17 mg/dL [95% CI, 0.06–0.28]; P=0.003) in the 1500-mg arm. Creatinine increases >0.5 mg/dL over baseline only occurred in 1 patient in the 3000-mg arm.Conclusions:Even with prepared meals, investigating optimal dietary sodium in heart failure comes with challenges, including need for extensive screening, reluctance to participate, and compliance issues. Because both diets reduced urinary sodium without adverse safety or quality of life signals, a larger trial, with modifications to improve participation and compliance, would be ethical and feasible.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02467296

Background:Despite advances in reperfusion times, patients presenting with acute myocardial infarction carry an unacceptably high rate of mortality and morbidity. Mechanical unloading of the left ventricle (LV) has been suggested to reduce infarct size after acute myocardial infarction. Although prior studies have investigated LV unloading during ischemia with a delay in reperfusion, little is known about the optimal timing for LV unloading in the setting of acute myocardial infarction.Methods:Studies were conducted in 17 adult Yorkshire swine weighing 67±5 kg. A coronary balloon was inflated in the mid left anterior descending for 60 minutes to induce a myocardial infarction. The coronary balloon was then deflated for 120 minutes (reperfusion). The animals were stratified into 3 groups: group 1 (control, reperfusion with no LV unloading, n=5), group 2 (LV unloading during ischemia with delayed reperfusion, n=6), and group 3 (simultaneous LV unloading and reperfusion, n=6). Staining the hearts with Evans blue and 2,3,5-triphenyltetrazolium chloride was used to identify the area at risk and the infarct area respectively. Infarct percent size was defined as the area of infarcted myocardium divided by the area at risk.Results:Of the 3 groups, group 3 demonstrated significantly smaller infarct percent size compared with controls (54.7±20.3% versus 22.2±13.4%; P=0.03). Comparison between group 1 and group 2 did not reveal significant difference (54.7±20.3% versus 43.3±24.6%; P=0.19).Conclusions:In our large animal experimental model, simultaneous reperfusion and mechanical LV unloading yielded the smallest infarct size compared with no LV unloading or LV unloading with delayed reperfusion. In the context of prior studies showing benefit to unloading before reperfusion, these findings raise questions about how this strategy may be translated to humans.

Background:Although left ventricular noncompaction (LVNC) has been associated with an increased risk of adverse cardiovascular events, the accurate incidence of cardiovascular morbidity and mortality is unknown. We, therefore, aimed to assess the incidence rate of LVNC-related cardiovascular events.Methods:We systematically searched observational studies reporting the adverse outcomes related to LVNC. The primary end point was cardiovascular mortality.Results:We identified 28 eligible studies enrolling 2501 LVNC patients (mean age, 46 years; male/female ratio, 1.7). After a median follow-up of 2.9 years, the pooled event rate for cardiovascular mortality was 1.92 (95% CI, 1.54–2.30) per 100 person-years. LVNC patients had a similar risk of cardiovascular mortality compared with a dilated cardiomyopathy control group (odds ratio, 1.10 [95% CI, 0.18–6.67]). The incidence rates of all-cause mortality, stroke and systemic emboli, heart failure admission, cardiac transplantation, ventricular arrhythmias, and cardiac device implantation were 2.16, 1.54, 3.53, 1.24, 2.17, and 2.66, respectively, per 100 person-years. Meta-regression and subgroup analyses revealed that left ventricular ejection fraction, not the extent of left ventricular trabeculation, had an important influence on the variability of incidence rates. The risks of thromboembolism and ventricular arrhythmias in LVNC patients were similar to dilated cardiomyopathy patients. However, LVNC patients had a higher incidence of heart failure hospitalization than dilated cardiomyopathy patients.Conclusions:Patients with LVNC carry a similar cardiovascular risk when compared with dilated cardiomyopathy patients. Left ventricular ejection fraction—a conventional indicator of heart failure severity, not the extent of trabeculation—appears to be an important determinant of adverse outcomes in LVNC patients.Registration:https://www.crd.york.ac.uk/PROSPERO/ Unique identifier: CRD42018096313.

Background:Myocardial perfusion imaging, including positron emission tomography/computed tomography (PET/CT), is often used to assess for high-grade coronary artery disease (CAD) requiring revascularization. The use of coronary artery calcium (CAC) to predict risk of major adverse cardiovascular events in asymptomatic patients is accepted. However, little is known regarding the use of CAC in PET/CT patients without known CAD in identifying patients unlikely to need revascularization. Here, we determined whether the absence of CAC, using low-dose attenuation correction CT obtained during the PET/CT, identifies patients unlikely to undergo coronary revascularization within 90 days of a PET/CT.Methods:Patients, without a history of CAD and no elevation in troponin, referred for PET/CT at Intermountain Medical Center were studied (n=5528). The presence of CAC was visually assessed using low-dose attenuation correction CT. The association between CAC and 90-day high-grade CAD and revascularization were assessed. Longer-term (up to 4 years) major adverse cardiovascular events, including all-cause death, myocardial infarction, and late revascularization (>90 days), were examined.Results:There were 2510 (45.4%) patients in CAC-present group and 3018 (54.6%) patients in CAC-absent group. The CAC-absent group, compared with the CAC-present group, was less likely to undergo coronary angiography (3.4% versus 10.2%, P<0.0001), have high-grade CAD (0.5% versus 6.5%, P<0.0001), and receive revascularization (0.4% versus 5.8%, [adjusted odds ratio =0.09; 95% CI, 0.05–0.16]; P<0.0001). In patients with an ischemic burden >10%, the CAC-absent group was associated with reduced revascularization (P<0.0001). Longer-term major adverse cardiovascular events were lower in the CAC-absent (2.4%) compared with the CAC-present (6.9%) group (adjusted hazard ratio, 0.45 [95% CI, 0.34–0.60]; P<0.0001).Conclusions:The absence of CAC on low-dose attenuation correction CT identifies PET/CT patients unlikely to have high-grade CAD or require revascularization within 90 days and unlikely to experience longer-term major adverse cardiovascular events. The prognostic value of CAC, beyond ischemic burden, suggests its potential as a first-step screening tool in intermediate-risk patients to identify those who do not need coronary revascularization.

Background:We previously proposed a technique for quantitative measurement of rest and stress absolute myocardial blood flow (MBF) using a 2-injection single-scan imaging session. Recently, we validated the method in a pig model for the long-lived radiotracer 18F-Flurpiridaz with adenosine as a pharmacological stressor. The aim of the present work is to validate our technique for 13NH3.Methods:Nine studies were performed in 6 pigs; 5 studies were done in the native state and 4 after infarction of the left anterior descending artery. Each study consisted of 3 dynamic scans: a 2-injection rest-rest single-scan acquisition (scan A), a 2-injection rest/stress single-scan acquisition (scan B), and a conventional 1-injection stress acquisition (scan C). Variable doses of adenosine combined with dobutamine were administered to induce a wide range of MBF. The 2-injection single-scan measurements were fitted with our nonstationary kinetic model (MGH2). In 4 studies, 13NH3 injections were paired with microsphere injections. MBF estimates obtained with our method were compared with those obtained with the standard method and with microspheres. We used a model-based method to generate separate rest and stress perfusion images.Results:In the absence of stress (scan A), the MBF values estimated by MGH2 were nearly the same for the 2-radiotracer injections (mean difference: 0.067±0.070 mL·min−1·cc−1, limits of agreement: [−0.070 to 0.204] mL·min−1·cc−1), showing good repeatability. Bland-Altman analyses demonstrated very good agreement with the conventional method for both rest (mean difference: −0.034±0.035 mL·min−1·cc−1, limits of agreement: [−0.103 to 0.035] mL·min−1·cc−1) and stress (mean difference: 0.057±0.361 mL·min−1·cc−1, limits of agreement: [−0.651 to 0.765] mL·min−1·cc−1) MBF measurements. Positron emission tomography and microsphere MBF measurements correlated closely. Very good quality perfusion images were obtained.Conclusions:This study provides in vivo validation of our single-scan rest-stress method for 13NH3 measurements. The 13NH3 rest/stress myocardial perfusion imaging procedure can be compressed into a single positron emission tomography scan session lasting less than 15 minutes.

Background:Pulmonary hypertension is an established outcome predictor in patients with aortic stenosis (AS), but the prognostic impact of right ventricular dysfunction has not been well studied.Methods:We included 2181 patients (50.4% men; mean age, 77 years) with aortic valve area <1.3 cm2 and analyzed the occurrence of all-cause death during follow-up according to tricuspid annular plane systolic excursion (TAPSE) quartiles.Results:Patients in the lowest quartile (TAPSE <17 mm) were at a high risk of death, whereas survival was comparable for the 3 other quartiles. Five-year survival was 55±2% for TAPSE <17 mm, 72±2% for TAPSE of 17 to 20 mm, 71±2% for TAPSE of 20 to 24 mm, and 73±2% for TAPSE >24 mm (overall P<0.001). TAPSE <17 mm was associated with increased mortality after adjustment for established prognostic factors (adjusted hazard ratio [HR], 1.55 [95% CI, 1.21–1.97]) and after further adjustment for aortic valve replacement (AVR; adjusted HR, 1.47 [95% CI, 1.15–1.87]). The excess mortality risk associated with TAPSE <17 mm was noticed in both patients managed initially conservatively (adjusted HR, 1.46 [95% CI, 1.20–1.76]) and patients who underwent early (within 3 months after diagnosis) AVR (adjusted HR, 1.61 [95% CI, 1.03–2.52]). In asymptomatic patients with severe AS and preserved ejection fraction, TAPSE <17 mm was independently predictive of mortality (adjusted HR, 2.14 [95% CI, 1.31–3.51]). Early AVR was associated with similar survival benefit in TAPSE <17 and ≥17 mm (adjusted HR, 0.23 [95% CI, 0.16–0.34] for TAPSE <17 mm, adjusted HR, 0.26 [95% CI, 0.19–0.35] for TAPSE ≥17 mm; P for interaction, 0.97).Conclusions:Right ventricular dysfunction is an important and independent predictor of mortality in AS. TAPSE <17 mm at the time of AS diagnosis is a marker of poor survival under conservative management and after AVR even in asymptomatic patients with severe AS. AVR was associated with a pronounced reduction in mortality independent of TAPSE suggesting that AVR should be discussed before right ventricular dysfunction occurs in severe AS.

Background It is unknown whether ethnic differences occur with regard to right heart echocardiographic parameters. The aim of this study therefore was to establish normative values of left and right heart parameters in a black African population and to evaluate the effect of age and body mass index (BMI) on specific right ventricle (RV) parameters. Methods Two hundred fifty-three normal subjects were prospectively studied. A standardized echocardiographic examination was conducted with the RV focused view used to derive RV measurements. All left and right heart measurements were made in accordance with the American Society of Echocardiography 2015 chamber guideline recommendations. Right ventricle free wall strain was assessed using an RV focused apical four-chamber view. Results The average age was 36.3 ± 12.2 years, and 59% of patients were female. The mean left ventricular ejection fraction was 62.3% ± 5.7%. The RV linear measurements (RV base, 31.0 ± 4.5 mm; midcavity, 26.3 ± 5.8 mm) were not associated with sex, age, or BMI except for the RV length (64.6 ± 8.9 mm), which was greater in male patients. Tricuspid annular plane systolic excursion (TAPSE) was 21.7 ± 2.8 mm, fractional area change was 42.1% ± 5.5%, tricuspid annular peak systolic velocity RV S' was 12.1 ± 1.9 m/sec, and RV free wall strain was –31.5% ± 8.6%. Age and BMI were not associated with right atrial (RA) volumetric measurements, RV linear measurements, or any RV functional parameters except TAPSE and RV A', which increased with BMI. Conclusions This study establishes normal left and right heart parameters in a black African population. Aging was not associated with RA or RV parameters except for RV E' and A'. BMI does not affect RA/RV measurements but may cause variability in TAPSE and RV A'.

Background There has been no report about outcome of pitavastatin versus atorvastatin therapy in high-risk patients with hypercholesterolemia. Methods Hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases (n = 664, age = 65, male = 54%, diabetes = 76%, primary prevention = 74%) were randomized to receive pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). Follow-up period was 240 weeks. The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary end point was a composite of the primary end point plus clinically indicated coronary revascularization for stable angina. Results The mean low-density lipoprotein cholesterol (LDL-C) level at baseline was 149 mg/dL. The mean LDL-C levels at 1 year were 95 mg/dL in the pitavastatin group and 94 mg/dL in the atorvastatin group. There were no differences in LDL-C levels between both groups, however, pitavastatin significantly reduced the risk of the primary end point, compared to atorvastatin (pitavastatin = 2.9% and atorvastatin = 8.1%, HR, 0.366; 95% CI 0.170–0.787; P = 0.01 by multivariate Cox regression) as well as the risk of the secondary end point (pitavastatin = 4.5% and atorvastatin = 12.9%, HR = 0.350; 95%CI = 0.189–0.645, P = 0.001). The results for the primary and secondary end points were consistent across several prespecified subgroups. There were no differences in incidence of adverse events between the statins. Conclusion Pitavastatin therapy compared with atorvastatin more may prevent cardiovascular events in hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases despite similar effects on LDL-C levels.

Aims Sirtuin 6 (Sirt6) is a NAD+-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model. Methods and results Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe−/− mice fed a high-cholesterol diet for 12 weeks (n = 12–14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels. Conclusions Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.

Lots of studies demonstrated that CD4+ T cells regulate the development of atherosclerosis (AS). Previously, we reported that LCK, a key molecule in activation of T cell receptor (TCR) signalling and T cells, adversely affects reverse cholesterol transport (RCT), which ameliorates AS in vitro. To investigate the effect of LCK on AS in vivo, we injected the LCK inhibitor, PP2, into ApoE−/− mice fed a chow diet or a high-fat diet (HFD). Although, AS plaques were not affected by PP2 in chow diet-fed mice, PP2 significantly reduced the lesion percentage and necrotic core areas in HFD-fed mice. We further analysed the plaque contents and found that the accumulation of lipids and macrophages were decreased, while the contents of collagen and smooth muscle cells were increased by the LCK inhibitor. Thus, inhibiting LCK enhanced the plaque stability. We also found the LCK inhibitor improved cholesterol efflux capacity of HDL and up-regulated RCT regulatory proteins in the spleen. Moreover, inhibiting LCK regulated differentiation of T cells by increasing regulatory T (Treg) cells and decreasing the number of T helper 1 (Th1) cells in the aorta, thymus and spleen. Consistent with these results, infiltration of CD4+ T cells in plaques, secretion of pro-atherosclerotic cytokines, INF-γ and TNF-α synthesized mostly by Th1 cells, and the activation of PI3K/AKT/mTOR signalling were inhibited by the LCK inhibitor. Moreover, the effect of LCK inhibitor on the ratio of Th1 to Treg cells were compromised by activation of mTOR. Together, these data indicate that inhibiting LCK in TCR signalling attenuated the development of AS and promoted plaque stability. Improving RCT by upregulating RCT regulatory proteins and decreasing the Th1/Treg ratio by inhibiting PI3K/AKT/mTOR signalling may contribute to the anti-atherosclerotic effects of LCK inhibition.

The SCN5A gene encodes Nav1.5, which, as the cardiac voltage-gated Na+ channel's pore-forming α subunit, is crucial for the initiation and propagation of atrial and ventricular action potentials. The arrhythmogenic propensity of inherited SCN5A mutations implicates the Na+ channel in determining cardiomyocyte excitability under normal conditions. Cytosolic kinases have long been known to alter the kinetic profile of Nav1.5 inactivation via phosphorylation of specific residues. Recent substantiation for both the role of calmodulin-dependent kinase II (CaMKII) in modulating the properties of the Nav1.5 inactivation gate and the significant rise in oxidation-dependent autonomous CaMKII activity in structural heart disease has raised the possibility of a novel pathway for acquired arrhythmias – the CaMKII-Nav1.5 relationship. The aim of this review is to: (1) outline the relationship's transition from physiological adaptation to pathological vicious circle; and (2) discuss the relative merits of each of its components as pharmacological targets.

Atrial fibrillation (AF) is characterized by potentiated growth of atrial fibroblasts and excessive deposition of the extracellular matrix. Atrial fibrosis has emerged as a hallmark of atrial structural remodeling linked to AF. Nonetheless, the specific mechanism underlying the progression of atrial fibrosis to AF is still largely unknown. MFGE8 (milk fat globule-EGF factor 8) is a soluble glycoprotein associated with many human diseases. Recently, a number of studies revealed that MFGE8 plays a crucial role in heart disease. Yet, MFGE8 regulation and function in the process of atrial fibrosis and vulnerability to AF remain unexplored. In this study, we found that the expression of MFGE8 was downregulated in the atriums of patients with AF compared with individuals without AF. In addition, the expression of MFGE8 was lower in atriums of angiotensin II (Ang-II)-stimulated rats as compared with the sham group. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. Moreover, we found that the activated TGF-β1/Smad2/3 pathway after Ang-II treatment was significantly potentiated by the MFGE8 knockdown but inhibited by rhMFGE8 in vitro. Inhibition of integrin β3 which is the receptor for MFGE8, suppressed the TGF-β1/Smad2/3 activating effects of the MFGE8 knockdown in Ang-II-treated rat atrial fibroblasts. Finally, we administered rhMFGE8 to rats; it attenuated atrial fibrosis and remodeling and further reduced AF vulnerability induced by Ang-II, indicating that MFGE8 might have the potential both as a novel biomarker and as a therapeutic target in atrial fibrosis and AF.

Aims: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. Methods and Results: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. Conclusions: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.

Although late sodium current (INa-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of INa-late in canine and guinea pig ventricular cells and compare them to INa-late recorded in undiseased human hearts. INa-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic- or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human INa-late monotonically decreased during the plateau (decrescendo-profile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine INa-late could not be converted to a crescendo-morphology by application of ramp-like command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo INa-late profile in guinea pig was due to the slower decay of INa-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of INa-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of INa-late. These results should be taken into account when pharmacological studies with INa-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with INa-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of INa-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics.

T1 mapping using modified Look-Locker inversion recovery (MOLLI) provides quantitative information on myocardial tissue composition. T1 results differ between sites due to variations in hardware and software equipment, limiting the comparability of results. The aim was to test if Z-scores can be used to compare the results of MOLLI T1 mapping from different cardiovascular magnetic resonance (CMR) platforms. First, healthy subjects (n = 15) underwent 11 combinations of native short-axis T1 mapping (four CMR systems from two manufacturers at 1.5 T and 3 T, three MOLLI schemes). Mean and standard deviation (SD) of septal myocardial T1 were derived for each combination. T1 maps were transformed into Z-score maps based on mean and SD values using a prototype post-processing module. Second, Z-score mapping was applied to a validation sample of patients with cardiac amyloidosis at 1.5 T (n = 25) or 3 T (n = 13). In conventional T1 analysis, results were confounded by variations in field strength, MOLLI scheme, and manufacturer-specific system characteristics. Z-score-based analysis yielded consistent results without significant differences between any two of the combinations in part 1 of the study. In the validation sample, Z-score mapping differentiated between patients with cardiac amyloidosis and healthy subjects with the same diagnostic accuracy as standard T1 analysis regardless of field strength. T1 analysis based on Z-score mapping provides consistent results without significant differences due to field strengths, CMR systems, or MOLLI variants, and detects cardiac amyloidosis with the same diagnostic accuracy as conventional T1 analysis. Z-score mapping provides a means to compare native T1 results acquired with MOLLI across different CMR platforms.

4D flow cardiovascular magnetic resonance (CMR) enables visualization of complex blood flow and quantification of biomarkers for vessel wall disease, such as wall shear stress (WSS). Because of the inherently long acquisition times, many efforts have been made to accelerate 4D flow acquisitions, however, no detailed analysis has been made on the effect of Cartesian compressed sensing accelerated 4D flow CMR at different undersampling rates on quantitative flow parameters and WSS. We implemented a retrospectively triggered 4D flow CMR acquisition with pseudo-spiral Cartesian k-space filling, which results in incoherent undersampling of k-t space. Additionally, this strategy leads to small jumps in k-space thereby minimizing eddy current related artifacts. The pseudo-spirals were rotated in a tiny golden-angle fashion, which provides optimal incoherence and a variable density sampling pattern with a fully sampled center. We evaluated this 4D flow protocol in a carotid flow phantom with accelerations of R = 2–20, as well as in carotids of 7 healthy subjects (27 ± 2 years, 4 male) for R = 10–30. Fully sampled 2D flow CMR served as a flow reference. Arteries were manually segmented and registered to enable voxel-wise comparisons of both velocity and WSS using a Bland-Altman analysis. Magnitude images, velocity images, and pathline reconstructions from phantom and in vivo scans were similar for all accelerations. For the phantom data, mean differences at peak systole for the entire vessel volume in comparison to R = 2 ranged from − 2.3 to − 5.3% (WSS) and − 2.4 to − 2.2% (velocity) for acceleration factors R = 4–20. For the in vivo data, mean differences for the entire vessel volume at peak systole in comparison to R = 10 were − 9.9, − 13.4, and − 16.9% (WSS) and − 8.4, − 10.8, and − 14.0% (velocity), for R = 20, 25, and 30, respectively. Compared to single slice 2D flow CMR acquisitions, peak systolic flow rates of the phantom showed no differences, whereas peak systolic flow rates in the carotid artery in vivo became increasingly underestimated with increasing acceleration. Acquisition of 4D flow CMR of the carotid arteries can be highly accelerated by pseudo-spiral k-space sampling and compressed sensing reconstruction, with consistent data quality facilitating velocity pathline reconstructions, as well as quantitative flow rate and WSS estimations. At an acceleration factor of R = 20 the underestimation of peak velocity and peak WSS was acceptable (< 10%) in comparison to an R = 10 accelerated 4D flow CMR reference scan. Peak flow rates were underestimated in comparison with 2D flow CMR and decreased systematically with higher acceleration factors.

Acute heart failure is a rapid onset of new or worsening of signs and symptoms of heart failure that requires hospitalization or a visit to the emergency department. The aim of this study was to evaluate treatment outcome and determine factors that predict a poor treatment outcome in acute heart failure patients at a Tertiary Care Hospital in Ethiopia. A prospective observational study design was used. Data were collected using a structured questionnaire as a tool. Outcome variables were assessed at the time of discharge from the hospital. Bivariate and multivariate logistic regression analyses were used to determine factors that predict in-hospital mortality. A p-value ≤0.05 was considered as statistically significant. Out of the 169 patients, the median age of patients with acute heart failure was 34 years (IQR = 23 to 50) and median hospital stay was 4.0 days (IQR = 3.0 to 6.0). The leading precipitating factor and underlying disease at the time of admission were pneumonia (47.5%) and chronic rheumatic heart disease (48.5%), respectively. The in-hospital mortality was found to be 17.2%. Smoking (adjusted odds ratio (AOR) = 8.7, p = 0.006), diabetes mellitus (AOR = 10.2, p = 0.005), pulmonary hypertension (AOR = 4.3, p = 0.016), and the presence of adverse drug events (AOR = 4.2, p = 0.003) were predictors of in-hospital mortality. High in-hospital mortality was observed among acute heart failure patients admitted to a Tertiary Care Hospital in Ethiopia. Smoking, diabetes mellitus, pulmonary hypertension and the presence of adverse drug events were predictors of in-hospital mortality.

Sarcoidosis is a systemic granulomatous disease that may affect the myocardium. This study evaluated the diagnostic and prognostic value of 2-dimensional speckle tracking echocardiography in cardiac sarcoidosis (CS). Eighty-three patients with extracardiac, biopsy-proven sarcoidosis and definite/probable diagnosis of cardiac involvement diagnosed from January 2005 through December 2016 were included. Strain parameters in early stages of CS, in a subgroup of 23 CS patients with left ventricular ejection fraction (LVEF) within normal limits (LVEF> 52% for men: > 54% for women, mean value: 57.3% ± 3.8%) and no wall motion abnormalities was compared with 97 controls (1:4) without cardiac disease. LV and right ventricular (RV) global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain and strain rate (SR) analyses were performed with TomTec software and correlated with cardiac outcomes (including heart failure and arrhythmias). This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed written consent to participate. Mean age of CS patients was 53.6 ± 10.8 years, and 34.9% were women. Mean LVEF was 43.2% ± 12.4%; LV GLS, − 12.4% ± 3.7%; LV GCS, − 17.1% ± 6.5%; LV GRS, 29.3% ± 12.8%; and RV wall GLS, 14.6% ± 6.3%. In the 23 patients with early stage CS with normal LVEF and RV systolic function, strain parameters were significantly reduced when compared with controls (respectively: LV GLS, − 15.9% ± 2.5% vs − 18.2% ± 2.7% [P = .001]; RV GLS, − 16.9% ± 4.5% vs − 24.1% ± 4.0% [P < .001]). A LV GLS value of − 16.3% provided 82.2% sensitivity and 81.2% specificity for the diagnosis of CS (AUC 0.91), while a RV value of − 19.9% provided 88.1% sensitivity and 86.7% specificity (AUC 0.93). Hospital admission and heart failure significantly correlated to impaired LV GLS (> − 14%). Reduced strain values in the LV GLS and RV GLS can be used in the diagnostic algorithm in patients with suspicion of cardiac sarcoidosis. These values also correlate with adverse cardiovascular events.

TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as “pathogenic” according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.