Objectives The purpose of this study was to comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF). Background ...Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilation, endothelial function, and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF. Methods Subjects with HFpEF (n = 21), hypertension without heart failure (n = 19), and no cardiovascular disease (control, n = 10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry, and gas exchange. Results Exercise capacity and tolerance were reduced in HFpEF compared with hypertensive subjects and controls, with lower VO2 and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensive subjects as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility, and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve. Conclusions HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.
This study sought to define the prevalence, severity, and significance of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) in the general community.
Although ...HFpEF is known to cause PH, its development is highly variable. Community-based data are lacking, and the relative contribution of pulmonary venous versus pulmonary arterial hypertension (HTN) to PH in HFpEF is unknown. We hypothesized that PH would be a marker of symptomatic pulmonary congestion, distinguishing HFpEF from pre-clinical hypertensive heart disease.
This community-based study of 244 HFpEF patients (age 76 +/- 13 years; 45% male) was followed up using Doppler echocardiography over 3 years. Control subjects were 719 adults with HTN without HF (age 66 +/- 10 years; 44% male). Pulmonary artery systolic pressure (PASP) was derived from the tricuspid regurgitation velocity and PH defined as PASP >35 mm Hg. Pulmonary capillary wedge pressure (PCWP) was estimated from the ratio of early transmitral flow velocity to early mitral annular diastolic velocity.
In HFpEF, PH was present in 83% and the median (25th, 75th percentile) PASP was 48 (37, 56) mm Hg. PASP increased with PCWP (r = 0.21; p < 0.007). Adjusting for PCWP, PASP was higher in HFpEF than HTN (p < 0.001). The PASP distinguished HFpEF from HTN with an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) and strongly predicted mortality in HFpEF (hazard ratio: 1.3 per 10 mm Hg; p < 0.001).
PH is highly prevalent and often severe in HFpEF. Although pulmonary venous HTN contributes to PH, it does not fully account for the severity of PH in HFpEF, suggesting that a component of pulmonary arterial HTN also contributes. The potent effect of PASP on mortality lends support for therapies aimed at pulmonary arterial HTN in HFpEF.
Obesity and heart failure with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st ...century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.
Recent studies have examined haemodynamic changes with stressors such as isometric handgrip and rapid atrial pacing in heart failure with preserved ejection fraction (HFpEF), but little is known ...regarding left ventricular (LV) pressure-volume responses during dynamic exercise.
To assess LV haemodynamic responses to dynamic exercise in patients with HFpEF.
Twenty subjects with normal ejection fraction (EF) and exertional dyspnoea underwent invasive haemodynamic assessment during dynamic exercise to evaluate suspected HFpEF.
LV end-diastolic pressure was elevated at rest (>15 mm Hg, n=18) and with exercise (≥20 mm Hg, n=20) in all subjects, consistent with HFpEF. Heart rate (HR), blood pressure, arterial elastance and cardiac output increased with exercise (all p<0.001). Minimal and mean LV diastolic pressures increased by 43-56% with exercise (both p<0.0001), despite a trend towards a reduction in LV end-diastolic volume (p=0.08). Diastolic filling time was abbreviated with increases in HR and the proportion of diastole that elapsed prior to estimated complete relaxation increased (p<0.0001), suggesting inadequate relaxation reserve relative to the shortening of diastole. LV diastolic chamber elastance acutely increased 50% during exercise (p=0.0003). Exercise increases in LV filling pressures correlated with changes in diastolic relaxation rates, chamber stiffness and arterial afterload but were not related to alterations in preload volume, HR or cardiac output.
In patients with newly diagnosed HFpEF, LV filling pressures increase during dynamic exercise in association with inadequate enhancement of relaxation and acute increases in LV chamber stiffness. Therapies that enhance diastolic reserve function may improve symptoms of exertional intolerance in patients with hypertensive heart disease and early HFpEF.
Patients with heart failure, coronary artery disease, and no atrial fibrillation were randomly assigned to receive 2.5 mg of rivaroxaban twice daily or placebo. Rivaroxaban did not have a significant ...effect on the composite outcome of death, myocardial infarction, or stroke.
Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free ...survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.
Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400mg twice daily or cediranib 30mg daily and olaparib capsules 200mg twice daily until disease progression.
In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2months, hazard ratio 0.50; P=0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7months, P=0.002) and OS (37.8 versus 23.0months, P=0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3months, hazard ratio 0.64; P=0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.
Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.
Clinicaltrials.gov Identifier NCT0111648
In contrast to the wealth of data on isolated systolic hypertension involving the systemic circulation in the elderly, much less is known about age-related change in pulmonary artery systolic ...pressure (PASP) and its prognostic impact in the general population. We sought to define the relationship between PASP and age, to evaluate which factors influence PASP, and to determine whether PASP is independently predictive of mortality in the community.
A random sample of the Olmsted County, Minn, general population (n=2042) underwent echocardiography and spirometry and was followed up for a median of 9 years. PASP was measured from the tricuspid regurgitation velocity. Left ventricular diastolic pressure was estimated with Doppler echocardiography (E/e' ratio), and arterial stiffening was assessed from the brachial artery pulse pressure. Among 1413 subjects (69%) with measurable PASP (age, 63+/-11 years; 43% male), median PASP was 26 mm Hg (25th to 75th percentile, 24 to 30 mm Hg) and increased with age (r=0.31, P<0.001). Independent predictors of PASP were age, pulse pressure, and mitral E/e' (all P< or =0.003). Increasing PASP was associated with higher mortality (hazard ratio, 2.73 per 10 mm Hg; P<0.001). In subjects without cardiopulmonary disease (any heart failure, coronary artery disease, hypertension, diabetes mellitus, or chronic obstructive lung disease), the age-adjusted hazard ratio was 2.74 per 10 mm Hg (P=0.016).
We provide the first population-based evidence of age-related increase in pulmonary artery pressure, its association with increasing left heart diastolic pressures and systemic vascular stiffening, and its negative impact on survival. Pulmonary artery pressure may serve as a novel cardiovascular risk factor and potential therapeutic target.
We sought to compare left ventricular (LV) systolic stiffness and contractility in normal subjects, hypertensive patients without heart failure, and patients with heart failure and preserved ejection ...fraction (HFpEF) and to determine whether LV systolic stiffness or myocardial contractility is associated with the rate of mortality in patients with HFpEF.
Arterial load is increased in patients with hypertension and is matched by increased end-systolic LV stiffness (ventricular-arterial coupling). Increased end-systolic LV stiffness may be mediated by enhanced myocardial contractility or processes that increase passive myocardial stiffness.
Healthy control patients (n = 617), hypertensive patients (no heart failure, n = 719), and patients with HFpEF (n = 244, 96% hypertensive) underwent echo-Doppler characterization of arterial (Ea) and LV end-systolic (Ees) stiffness (elastance), ventricular-arterial coupling (Ea/Ees ratio), and chamber-level and myocardial contractility (stress-corrected midwall shortening).
We found that Ea and Ees were similarly increased in hypertensive patients with or without HFpEF compared with control patients, but ventricular-arterial coupling was similar across groups. In hypertensive patients, increased Ees was associated with enhanced chamber-level and myocardial contractility, whereas in patients with HFpEF, chamber and myocardial contractility were depressed compared with both hypertensive and control patients. Group differences persisted after adjusting for geometry. In patients with HFpEF, impaired myocardial contractility (but not Ees) was associated with increased age-adjusted mortality.
Although arterial load is increased and matched by increased LV systolic stiffness in hypertensive patients with or without HFpEF, the mechanisms of systolic LV stiffening differ substantially. These data suggest that myocardial contractility increases to match arterial load in asymptomatic hypertensive heart disease, but that progression to HFpEF may be mediated by processes that simultaneously impair myocardial contractility and increase passive myocardial stiffness.
When advanced, heart failure with preserved ejection fraction (HFpEF) is readily apparent. However, diagnosis of earlier disease may be challenging because exertional dyspnea is not specific for ...heart failure, and biomarkers and hemodynamic indicators of volume overload may be absent at rest.
Patients with exertional dyspnea and ejection fraction >50% were referred for hemodynamic catheterization. Those with no significant coronary disease, normal brain natriuretic peptide assay, and normal resting hemodynamics (mean pulmonary artery pressure <25 mm Hg and pulmonary capillary wedge pressure PCWP <15 mm Hg) (n=55) underwent exercise study. The exercise PCWP was used to classify patients as having HFpEF (PCWP ≥25 mm Hg) (n=32) or noncardiac dyspnea (PCWP <25 mm Hg) (n=23). At rest, patients with HFpEF had higher resting pulmonary artery pressure and PCWP, although all values fell within normal limits. Exercise-induced elevation in PCWP in HFpEF was confirmed by greater increases in left ventricular end-diastolic pressure and was associated with blunted increases in heart rate, systemic vasodilation, and cardiac output. Exercise-induced pulmonary hypertension was present in 88% of patients with HFpEF and was related principally to elevated PCWP, as pulmonary vascular resistances dropped similarly in both groups. Exercise PCWP and pulmonary artery systolic pressure were highly correlated. An exercise pulmonary artery systolic pressure ≥45 mm Hg identified HFpEF with 96% sensitivity and 95% specificity.
Euvolemic patients with exertional dyspnea, normal brain natriuretic peptide, and normal cardiac filling pressures at rest may have markedly abnormal hemodynamic responses during exercise, suggesting that chronic symptoms are related to heart failure. Earlier and more accurate diagnosis using exercise hemodynamics may allow better targeting of interventions to treat and prevent HFpEF progression.
Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac ...death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case-control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033-0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predictors of a variety of individual CV events.
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