Left Ventricular Gene Expression in Heart Failure With Preserved Ejection Fraction-Profibrotic and Proinflammatory Pathways and Genes.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and has few treatments. The molecular mechanisms and resultant signaling pathways that underlie the development of HFpEF are poorly defined. It has been proposed that activation of proinflammatory pathways plays a role in the development of cardiac fibrosis. The signature of gene expression (transcriptome) of previously validated left ventricular biopsies obtained from patients with HFpEF and matched referent controls allows for an unbiased assessment of proinflammatory and profibrotic signaling pathways and genes. METHODS: Epicardial left ventricular biopsies from stringently selected HFpEF patients (HFpEF, n=16) and referent control patients (CTR, n=14) were obtained during aortocoronary bypass surgery. The subepicardial myocardium was flash-frozen to build a repository that was parallel-processed for RNA sequencing to allow for an unsupervised in-depth comparison of the left ventricular transcriptome. RESULTS: The average patient age was 67±10 years. When compared with controls, patients with HFpEF were hypertensive with a higher body mass index (kg/m2: 30±5 versus 37±6; P<0.01) and elevated NT-proBNP levels (pg/mL: 155 [89-328] versus 1554 [888-2178]; P<0.001). The transcriptome analysis revealed differential expression of 477 genes many of which were involved in profibrotic pathways including extracellular matrix production and posttranslational modification but no proinflammatory signature. CONCLUSIONS: The transcriptome analysis of left ventricular myocardial samples from patients with HFpEF confirms an overabundant extracellular matrix gene expression, the basis of myocardial fibrosis, without a signature of activated proinflammatory pathways or genes.

Relaxation and the Role of Calcium in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Relaxation characteristics and Ca2+ homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study, we evaluated relaxation parameters, myocardial calcium (Ca2+), and sodium (Na+) handling, as well as ion transporter expression and tested the effect of Na+-influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF. METHODS AND RESULTS: Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60 and 180 per minute. Intracellular Ca2+ and Na+ were simultaneously assessed using Fura-2 and AsanteNATRIUMGreen-2, whereas elemental analysis was used to measure total myocardial concentrations of Ca, Na, and other elements. Quantitative polymerase chain reaction was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na+-influx inhibitors ranolazine, furosemide, and amiloride was evaluated. Myocardial left ventricular biopsies were obtained from 36 control patients, 29 HHD and 19 HHD+HFpEF. When compared with control patients, half maximal relaxation time (RT50) at 60 per minute was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both P<0.05). Elevated resting Ca2+ levels and a tachycardia-induced increase in diastolic Ca2+ were associated with incomplete relaxation and an increase in diastolic tension in HHD and HHD+HFpEF. Na+ levels were not increased, and expression levels of Ca2+- or Na+-handling proteins were not altered. Na+-influx inhibitors did not improve relaxation or prevent incomplete relaxation at high stimulation rates. CONCLUSIONS: Contraction and relaxation are prolonged in isolated myocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither a result of an impaired Na+ gradient nor expression changes in key ion transporters and regulatory proteins.