Background: A systemic pro-inflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. Methods: In 228 HFpEF patients from the multicenter PROMIS-HFpEF study, 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component (PC) analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted co-expression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HF. Results: Comorbidity burden was associated with abnormal cardiac structure/function and with PCs/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation (TR) velocity; and worse right ventricular function (tricuspid annular plane systolic excursion [TAPSE] and right ventricular. [RV] free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19-35%), E/e' ratio (18-29%), TR velocity (27-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all) but not RV free wall strain. TNF-R1, UPAR, IGFBP-7 and GDF-15 were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. Conclusions: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and RV dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazine's effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters. Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature leading to increased pulmonary vascular resistance, elevated pulmonary artery (PA) pressures, and ultimately right ventricular (RV) dysfunction and failure.1,2 Despite significant progress in the treatment of World Health Organization (WHO) group 1 PAH with pulmonary vasodilator therapies, 5-year mortality rates remain high. 3,4 Furthermore, abnormalities in echocardiographic RV parameters have been associated with adverse outcomes in PAH, which may be related to the multifactorial pathophysiology of progressive RV dysfunction in PAH, which includes (1) RV ischemia due to altered right coronary artery blood flow in the setting of near equalization of aortic and RV systolic pressure in systole and increased RV diastolic pressure; 5(2) metabolic abnormalities in the RV; 6,7 and (3) the inability of the RV, a thin-walled structure accustomed to low PA pressures, to withstand the elevated afterload associated with PAH. 8 To date, no PAH-specific therapies have specifically and directly targeted RV ischemia and the altered RV metabolic substrate present in PAH. Ranolazine is an approved therapy for the treatment of chronic stable angina that...

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

Chronotropic incompetence (CI) is common in heart failure with preserved ejection fraction (HFpEF), and may be a key reason underlying exercise intolerance in these patients. However, the determinants of CI in HFpEF are unknown. We prospectively studied 157 consecutive HFpEF patients undergoing cardiopulmonary exercise testing (CPET), and defined CI according to specific thresholds of the percent heart rate reserve (%HRR). CI was diagnosed as present if %HRR < 80 if not taking a β-blocker and < 62 if taking β-blockers. Participants who achieved inadequate exercise effort (respiratory exchange ratio ≤ 1.05) on CPET were excluded. Multivariable-adjusted logistic regression was used to determine the factors associated with CI. Of the 157 participants, 108 (69%) achieved a respiratory exchange ratio > 1.05 and were included in the final analysis. Of these 108 participants, 70% were women, 62% were taking β-blockers, and 38% had chronic kidney disease (CKD). The majority of HFpEF patients met criteria for CI (81/108; 75%). Lower estimated glomerular filtration rate (GFR), higher B-type natriuretic peptide, and higher pulmonary artery systolic pressure were each associated with CI. A 1-standard deviation decrease in GFR was independently associated with CI after multivariable adjustment (adjusted odds ratio 2.2, 95% confidence interval 1.1-4.4; P = 0.02). The association between reduced GFR and CI persisted when considering a variety of measures of chronotropic response. In conclusion, reduced GFR is the major clinical correlate of CI in patients with HFpEF, and further study of the relationship between CKD and CI may provide insight into the pathophysiology of CI in HFpEF.

Anemia is associated with a poor prognosis in heart failure with preserved ejection fraction (HFpEF), but the reasons underlying this association are unclear. Previous studies have reported an association between anemia and diastolic dysfunction. However, these studies used volume- and flow-dependent indexes of diastolic dysfunction. We hypothesized that in HFpEF, anemia is more closely associated with volume status and not markers of intrinsic myocardial dysfunction. We prospectively studied 419 outpatients in a systematic HFpEF program, all of whom underwent hemoglobin measurement and comprehensive echocardiography. Longitudinal, radial, and circumferential strain were also measured in 311 patients. We defined anemia as hemoglobin <12g/dL in women and <13g/dL in men. Linear and Cox regression analyses were used to determine the association between anemia and echocardiographic/strain variables and adverse outcomes, respectively. Over half (224/419 [53%]) of the HFpEF patients had anemia. Anemia was associated with volume (preload)-dependent markers of diastolic dysfunction including echocardiographic E/A (p = 0.004) and E/e' ratio (p = 0.014) and elevated right heart pressures such as right atrial pressure (p = 0.002) and pulmonary artery systolic pressure (p<0.001). Anemia was not associated with markers of intrinsic myocardial dysfunction such as lateral e' (p = 0.16) and septal e' (p = 0.65) velocities or echocardiographic strain parameters (p > 0.05 for all comparisons). Anemia was associated with the combined outcome of cardiovascular hospitalization or death (hazard ratio = 1.50 [95% confidence interval 1.20, 1.88]; p < 0.001). In conclusion, anemia in HFpEF is associated with markers of volume status and not intrinsic markers of myocardial dysfunction.