Citations

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

Abstract Aims Increases in extravascular lung water (EVLW) during exercise contribute to symptoms, morbidity, and mortality in patients with heart failure and preserved ejection fraction (HFpEF), but the mechanisms leading to pulmonary congestion during exercise are not well-understood. Methods and results Compensated, ambulatory patients with HFpEF (n = 61) underwent invasive haemodynamic exercise testing using high-fidelity micromanometers with simultaneous lung ultrasound, echocardiography, and expired gas analysis at rest and during submaximal exercise. The presence or absence of EVLW was determined by lung ultrasound to evaluate for sonographic B-line artefacts. An increase in EVLW during exercise was observed in 33 patients (HFpEFLW+, 54%), while 28 (46%) did not develop EVLW (HFpEFLW−). Resting left ventricular function was similar in the groups, but right ventricular (RV) dysfunction was two-fold more common in HFpEFLW+ (64 vs. 31%), with lower RV systolic velocity and RV fractional area change. As compared to HFpEFLW−, the HFpEFLW+ group displayed higher pulmonary capillary wedge pressure (PCWP), higher pulmonary artery (PA) pressures, worse RV-PA coupling, and higher right atrial (RA) pressures during exercise, with increased haemoconcentration indicating greater loss of water from the vascular space. The development of lung congestion during exercise was significantly associated with elevations in PCWP and RA pressure as well as impairments in RV-PA coupling (area under the curve values 0.76–0.84). Conclusion Over half of stable outpatients with HFpEF develop increases in interstitial lung water, even during submaximal exercise. The acute development of lung congestion is correlated with increases in pulmonary capillary hydrostatic pressure that favours fluid filtration, and systemic venous hypertension due to altered RV-PA coupling, which may interfere with fluid clearance. Clinical trial registration NCT02885636.

AbstractHemodynamics play a central role in the pathophysiology of heart failure (HF), yet their proper assessment and optimization remains challenging. Heart failure is defined as the inability of the heart to deliver adequate perfusion (cardiac output) to the body at rest or exercise, or to require an elevation in cardiac filling pressures in order to do this. This bedrock definition is important because it relies on measurable quantities (filling pressures and output) that are readily assessed in the cardiac catheterization laboratory. Here we present three cases to illustrate how better understanding of the determinants of cardiac output and stroke volume: preload, afterload, contractility, and lusitropy, as well as the determinants of congestion (high filling pressures) may be used to guide optimization of hemodynamic status. The goal is that the readers will be able to think more critically when evaluating the hemodynamics of their patient in HF and recognize the complex interplay that determines the complex balance between cardiac ejection and filling capabilities, and how this alters symptoms and outcomes for patients with HF.Key Points Careful assessment of hemodynamics in the catheterization laboratory allows for actionable insight to a patient's volume status, cardiac function and can help prognosticate outcomes. Exercise hemodynamics in heart failure is a powerful tool to better understand the cause of symptoms and predict outcomes. Clinicians should aim to decrease biventricular filling pressures to normal values to improve morbidity and reduce risk for readmission. In patients with heart failure and reduced ejection fraction, clinicians should aim to decrease afterload as much as can be tolerated by the renal function and patient's symptoms. Low cardiac output can often be improved by optimizing preload and afterload rather than initiating inotropes, which should be reserved until needed. In advanced heart failure, the right heart function becomes a key determinant of symptoms and outcomes.

Abstract Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s′ and e′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e′, r = −0.59 and −0.67, both P < 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P < 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P < 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search

Background: Most pulmonary vascular disease (PVD) is poorly modifiable and incurable even with effective therapy. Therefore, adaptation to stress, the reserve of the cardiopulmonary system, is important for assessment of patient function and prognosis. Methods that assess the adaptation to stress, especially exercise, provide valuable insight into diagnosis, prognosis, and response to therapy.Implications for Clinicians: We provide a comprehensive review of the indications, methodology, and interpretation, as well as practical information of the forms of provocative testing in PVD. We include 6-minute walk testing, noninvasive cardiopulmonary exercise testing (CPET), invasive CPET, and additional forms, including volume loading.Conclusions: Through a clear understanding of the methodology in the assessment of PVD, the clinician can determine which of these “tools of the trade” are best suited to the individual patient and situation.

AbstractObjectiveTo assess the association between elevated ventricular‐end diastolic pressures (VEDP) and pulmonary artery wedge pressure (PAWP) on long‐term survival in adult Fontan patients.BackgroundThe impact of ventricular filling pressures on long‐term survival in adults post‐Fontan palliation is unknown.MethodsWe included 148 adult Fontan patients (age ≥ 18 years) without atrioventricular valve prosthesis or pulmonary vein stenosis undergoing arterial and venous catheterization between December 1999 and November 2017. VEDP was defined as ≥12 mmHg and PAWP as >12 mmHg based on optimal cut‐offs for prediction of mortality on receiver‐operator curves (AUC 0.63 and 0.66, respectively).ResultsMean age was 31.3 ± 9.2 years and 48.6% of patients were females. Most common congenital defects were tricuspid atresia (36.4%) and double‐inlet left ventricle (28.3%); 59.5% patients had atriopulmonary Fontan connections. Mean VEDP was 11.5 ± 4.7 mmHg and PAWP 10.6 ± 4.5 mmHg (correlation coefficient .76). During a follow‐up of 6.0 ± 4.8 years (median 5.4, IQR 1.4–9.4), there were 45 deaths (30.4%). Overall survival was lower in patients with VEDP ≥ 12 compared to those with VEDP < 12 mmHg (p = .02). Similarly, survival was lower in patients with PAWP>12 compared to patients with PAWP ≤ 12 mmHg (p < .0001). In the multivariate model, PAWP was an independent predictor of death (HR 1.1 per mmHg, 95% CI 1.02–1.15, p = .009) whereas VEDP was not (HR 1.1 per mmHg, 95% CI 1.0–1.13; p = .08).ConclusionPAWP but not VEDP was independently associated with long‐term overall mortality in adult Fontan patients. Perhaps PAWP rather than VEDP should be used in the risk stratification of these patients.

Approximately half of the patients with signs and symptoms of heart failure have a left ventricular ejection fraction that is not markedly abnormal. Despite the historically initial surprise, heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal. The recognition of the magnitude of the problem of heart failure with preserved ejection fraction in the past 20 years has spurred an explosion of clinical investigation and growing intensity of informative outcome trials. This article addresses the historic development of this component of the heart failure syndrome, including the epidemiology, pathophysiology, and existing and planned therapeutic studies. Looking forward, more specific phenotyping and even genotyping of subpopulations should lead to improvements in outcomes from future trials.

Abstract Despite improvements in outcomes in the last few decades for heart failure (HF) with reduced ejection fraction (HFrEF), there still remains a need for novel therapies as many patients incompletely recover with existing therapies and progress to advanced HF. In this review, we will discuss recent advances in the management of HFrEF with a focus on upcoming therapies that hold the greatest promise for clinical use. We will discuss novel pharmacological therapies and areas of uncertainty with existing therapies. We will also discuss the potential utility and controversy surrounding novel interventions for HF such as percutaneous mitral valve repair, atrial fibrillation ablation, and other emerging interventions with positive signals for benefit in HFrEF. Finally, we will summarize the current state of stem cell and gene therapy for HFrEF and future directions.