Borlaug, Barry A.

Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.

Background— Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV–pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV–PA coupling may be uniquely sensitive to sildenafil. Methods and Results— In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV–PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO 2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO 2 slope were unchanged with sildenafil. There was no interaction between RV–PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO 2 in patients with pulmonary hypertension and RVD. Conclusions— HFpEF patients with RVD and impaired RV–PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV–PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Abstract Aims The goal of the study was to examine the prognostic impact, haemodynamic and clinical features associated with lung congestion in patients with chronic heart failure (HF). Methods and results HF patients (n = 186) and HF-free controls (n = 21) underwent right heart catheterization, echocardiography, pulmonary function testing and chest radiography that was blindly scored for the presence and severity of lung oedema. Lung congestion correlated directly with pulmonary vascular resistance (PVR, P = 0.004) and inversely with pulmonary artery (PA) compliance (P < 0.001) and the diffusion limit for carbon monoxide (DLCO, P = 0.009). Compared with dry lung HF, wet lung HF patients (congestion score > median) had 25% lower PA compliance and 25–35% higher PVR, transpulmonary gradients and PA pressures (40 vs. 32 mmHg, P < 0.001) despite marginally higher PA wedge pressure (PAWP; 22 vs. 19 mmHg, P = 0.002). Wet lung HF patients displayed more right ventricular (RV) dilatation and dysfunction, more restrictive ventilation and greater reduction of DLCO. The strongest correlates of lung congestion were NT-proBNP, haemoglobin, albumin, and glomerular filtration, all surpassing PAWP. After a median of 333 days (interquartile range 80–875), 59 patients (32%) died. Lung congestion was associated with reduced survival (P < 0.0001), even after adjusting for PAWP, NT-proBNP, anaemia, CAD and renal dysfunction. Conclusion Interstitial lung oedema is associated with pulmonary vascular disease, RV overload and dysfunction and increased mortality in HF. These data reinforce the importance of aggressive decongestion in HF and suggest that novel agents aimed at reducing lung water may help to deter progression of pulmonary vascular disease and biventricular HF.

Background— Low-flow, low-gradient aortic stenosis (AS), associated with a poor prognosis, can be caused by a reduced stroke volume despite a preserved ejection fraction (left ventricular ejection fraction). We hypothesized that impaired ventricular diastolic filling secondary to constrictive pericarditis (CP) could contribute to reduced transaortic gradients in patients with AS+CP. We sought to examine the characteristics and outcomes of this unique cohort. Methods and Results— We analyzed 84 patients with different degrees of AS and preserved left ventricular ejection fraction (≥50%): 28 diagnosed with concomitant CP by echocardiography and 56 patients without CP matched by age, sex, and AS severity during 1998 to 2013. Prior mediastinal radiation (32.1% versus 5.4%; P =0.0072) and cardiac surgery (50.0% versus 3.6%; P =0.0016) were more common in AS+CP patients than those with AS only. AS+CP patients had lower left ventricular stroke volume index and mean transaortic gradients. Five-year survival was 34.3% for AS+CP patients and 89.1% for those with AS only ( P <0.001). In univariate analysis, prior mediastinal radiation (hazard ratio, 8.35; 95% confidence interval, 3.38–20.62; P <0.001), reduced left ventricular stroke volume index of <35 mL/m 2 (hazard ratio, 12.52; 95% confidence interval, 3.97–39.48; P <0.001), and concomitant CP (hazard ratio, 13.65; 95% confidence interval, 4.85–38.41; P <0.001) were highly associated with increased mortality. Conclusions— Our findings highlighted the possibility of CP as a pathophysiological mechanism for low-flow, low-gradient AS. Left ventricular stroke volume index and transaortic gradients were commonly reduced in AS in the setting of CP despite a preserved left ventricular ejection fraction, which may result in underestimation of AS severity. Prior mediastinal radiation, lower left ventricular stroke volume index, and concomitant CP were associated with poorer survival in AS patients.

Background— Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV–pulmonary artery (PA) functional reserve responses and RV–PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. Methods and Results— In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV d P /d t max /IP and s′) and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure–flow relationship when compared with controls (all P <0.001). RV–PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Conclusions— Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01418248.