AIMS Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is currently no established pharmacological therapy. We hypothesized that ORM-11035, a novel specific Na+ /Ca2+ exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF. METHODS AND RESULTS Rats were subjected to subtotal nephrectomy (NXT) or sham operation. Eight weeks after intervention, treatment for 16 weeks with ORM-11035 (1 mg/kg body weight) or vehicle was initiated. At 24 weeks, blood pressure measurements, echocardiography and pressure-volume loops were performed. Contractile function, Ca2+ transients and NCX-mediated Ca2+ extrusion were measured in isolated ventricular cardiomyocytes. NXT rats (untreated) showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV end-diastolic pressure (LVEDP) elevation, increased brain natriuretic peptide (BNP) levels, preserved ejection fraction and pulmonary congestion. In cardiomyocytes from untreated NXT rats, early relaxation was prolonged and NCX-mediated Ca2+ extrusion was decreased. Chronic treatment with ORM-11035 significantly reduced LV hypertrophy and cardiac remodelling without lowering systolic blood pressure. LVEDP [14 ± 3 vs. 9 ± 2 mmHg; NXT (n = 12) vs. NXT + ORM (n = 12); P = 0.0002] and BNP levels [71 ± 12 vs. 49 ± 11 pg/mL; NXT (n = 12) vs. NXT + ORM (n = 12); P < 0.0001] were reduced after ORM treatment. LV cardiomyocytes from ORM-treated rats showed improved active relaxation and diastolic cytosolic Ca2+ decay as well as restored NCX-mediated Ca2+ removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF. CONCLUSION Chronic inhibition of NCX with ORM-11035 significantly attenuated cardiac remodelling and diastolic dysfunction without lowering systemic blood pressure in this model of HFpEF. Therefore, long-term treatment with selective NCX inhibitors such as ORM-11035 should be evaluated further in the treatment of heart failure.

中文翻译：

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在保留射血分数的心力衰竭模型中，ORM-11035对Na + / Ca2 +交换子的长期抑制作用可改善心脏功能和重塑，而不会降低血压。

AIMS保留射血分数（HFpEF）的心力衰竭越来越普遍，但目前尚无确定的药物治疗方法。我们假设ORM-11035，一种新型的特定Na + / Ca2 +交换剂（NCX）抑制剂，可改善心功能和重塑，而不受心肾HFpEF模型中动脉血压的影响。方法和结果对大鼠进行了次全肾切除术（NXT）或假手术。干预后八周，开始用ORM-11035（1 mg / kg体重）或赋形剂治疗16周。在第24周时，进行血压测量，超声心动图检查和压力-容量循环。在孤立的心室心肌细胞中测量收缩功能，Ca2 +瞬变和NCX介导的Ca2 +挤出。NXT大鼠（未经治疗）表现出HFpEF表型，伴有左心室（LV）肥大，LV舒张末期压力（LVEDP）升高，脑钠肽（BNP）水平升高，射血分数和肺充血得以保留。在未经处理的NXT大鼠的心肌细胞中，早期放松被延长，NCX介导的Ca2 +挤出减少。长期使用ORM-11035进行治疗可显着降低左室肥大和心脏重塑，而不会降低收缩压。LVEDP [14±3 vs. 9±2 mmHg；NXT（n = 12）与NXT + ORM（n = 12）；P = 0.0002]和BNP水平[71±12 vs. 49±11 pg / mL；NXT（n = 12）与NXT + ORM（n = 12）；P <0.0001]在ORM治疗后降低。来自ORM治疗的大鼠的LV心肌细胞显示出改善的主动放松和舒张性胞质Ca2 +衰减，以及恢复的NCX介导的Ca2 +去除，表明用ORM-11035作为有希望的靶点治疗HFpEF的NCX调节。结论在该HFpEF模型中，ORM-11035对NCX的长期抑制作用可显着减轻心脏重塑和舒张功能障碍，而不会降低全身血压。因此，在心力衰竭的治疗中应进一步评估使用选择性NCX抑制剂（例如ORM-11035）的长期治疗。