Masaru Obokata

Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects. Methods: Subjects with obese HFpEF (body mass index ≥35 kg/m2; n=99), nonobese HFpEF (body mass index <30 kg/m2; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing. Results: Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563–4333 mL] versus 2772 mL [2555–3133 mL], and 2680 mL [2380–3006 mL]; P<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm, P=0.0005; length, 66±7 versus 61±7 and 61±7 mm, P<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm; P<0.0001), and greater total epicardial heart volume (945 mL [831–1105 mL] versus 797 mL [643–979 mL] and 632 mL [517–768 mL]; P<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both P<0.05) but not in nonobese HFpEF (P≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20; P=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12; P<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (P for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg; P<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve. Conclusions: Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.

Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection FractionClinical Perspective: A Simultaneous Invasive-Echocardiographic Study

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure). Current guidelines recommend use of natriuretic peptides (N-terminal pro-B type natriuretic peptide) and rest/exercise echocardiography (E/e′ ratio) to make this determination. Data to support this practice are conflicting. Methods: Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). Results: N-Terminal pro-B type natriuretic peptide levels were below the level considered to exclude disease (⩽125 pg/mL) in 18% of subjects with HFpEF. E/e′ ratio was correlated with directly measured pulmonary capillary wedge pressure at rest (r=0.63, P<0.0001) and during exercise (r=0.57, P<0.0001). Although specific, current guidelines were poorly sensitive, identifying only 34% to 60% of subjects with invasively proven HFpEF on the basis of resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e′ ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). Conclusions: Currently proposed HFpEF diagnostic guidelines on the basis of resting data are poorly sensitive. Adding exercise E/e′ data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF on the basis of resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01418248.

Is it time to recognize a new phenotype? Heart failure with preserved ejection fraction with pulmonary vascular disease.

Pulmonary hypertension (PH) is common and contributes to increased morbidity and mortality in people with heart failure (HF) with preserved ejection fraction (HFpEF). Pulmonary hypertension in HFpEF is initially felt to be a reflection of passive elevation in downstream pulmonary artery wedge pressure (PAWP), but in some patients, sustained PAWP elevation leads to pulmonary vascular remodelling. This causes further elevation in pulmonary artery (PA) pressure that leads to development of right ventricular (RV) dysfunction and pulmonary gas exchange abnormalities, which ultimately contribute to adverse outcomes. These changes in the right heart and lungs were formerly considered to be limited to end-stage HFpEF, but recent data have revealed abnormalities in PA vasodilation and dynamic RV-PA coupling even in the earliest stages of HFpEF. The current evidence base is not sufficient to recommend pulmonary vascular targeting therapies for people with HFpEF, but novel therapies that target the PA vasculature may hold promise in this regard. In this issue of Eur Heart J, Hoeper and colleagues provide an elegant and timely summary on the current state of the art regarding PH in HFpEF. The authors discuss critical knowledge gaps in classification and phenotyping in this disorder that require further study. The provocative and insightful suggestions provided help inform what should be our roadmap for the future in PH and HFpEF, while raising important unanswered questions that strike at the heart of this emerging clinical syndrome.

Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease

Aims Short-term studies have reported left ventricular (LV) dilatation following surgical creation of arteriovenous fistulas (AVF) or arteriovenous grafts (AVGs), but chronic cardiac structural and functional changes have not been examined or related to clinical outcomes following AVF/AVG. We sought to characterize the long-term changes in cardiac structure and function in patients undergoing shunt creation for haemodialysis. Methods and results A retrospective analysis was performed of patients undergoing echocardiography before and after surgical AVF/AVG creation for the initiation of haemodialysis. 137 patients underwent echocardiographic examinations prior to AVF and 2.6 years (median) after AVF creation. Following AVF and dialysis initiation, there were reductions in blood pressure, body weight and estimated plasma volume coupled with modest reverse LV remodelling. In contrast, AVF/AVG creation was associated with significant right ventricular (RV) dilatation and deterioration in RV function. Incident heart failure (HF) developed in 43% of patients in tandem with greater RV remodeling. The development of RV dilation following surgical AVF/AVG was independently associated with increased risk of death [HR 3.9, 95% CI (1.7-9.2), P = 0.001]. Conclusion In long-term follow-up, RV remodelling and dysfunction develop following AVF/AVG creation and dialysis initiation, despite improved control of LV pressure load through dialysis. Deleterious effects on right heart structure and function are coupled with development of incident HF and increased risk of death. Further study is required to identify patients at greatest risk for detrimental AVF/AVG changes who may benefit from alternate forms of dialysis or potentially ligation of existing AVF.

Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease

Aims Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Little is known about the impact of PVD on the pathophysiology of exercise intolerance. Methods and results Heart failure with preserved ejection fraction patients (n = 161) with elevated pulmonary capillary wedge pressure (≥15 mmHg) at rest were classified into three groups: non-PH-HFpEF (n = 21); PH but no PVD (isolated post-capillary PH, IpcPH; n = 95); and PH with PVD (combined post- and pre-capillary PH, CpcPH; n = 45). At rest, CpcPH-HFpEF patients had more right ventricular (RV) dysfunction and lower pulmonary arterial (PA) compliance compared to all other groups. While right atrial pressure (RAP) and left ventricular transmural pressure (LVTMP) were similar in HFpEF with and without PH or PVD at rest, CpcPH-HFpEF patients demonstrated greater increase in RAP, enhanced ventricular interdependence, and paradoxical reduction in LVTMP during exercise, differing from all other groups (P < 0.05). Lower PA compliance was correlated with greater increase in RAP with exercise. During exercise, CpcPH-HFpEF patients displayed an inability to enhance cardiac output, reduction in forward stroke volume, and blunted augmentation in RV systolic performance, changes that were coupled with marked limitation in aerobic capacity. Conclusion Heart failure with preserved ejection fraction patients with PVD demonstrate unique haemodynamic limitations during exercise that constrain aerobic capacity, including impaired recruitment of LV preload due to excessive right heart congestion and blunted RV systolic reserve. Interventions targeted to this distinct pathophysiology require testing in patients with HFpEF and PVD.

Haemodynamics, dyspnoea, and pulmonary reserve in heart failure with preserved ejection fraction

Aims Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in heart failure with preserved ejection fraction (HFpEF). However, very little is known regarding how elevated filling pressures cause pulmonary abnormalities or symptoms of dyspnoea. We sought to determine the relationships between simultaneously measured central haemodynamics, symptoms, and lung ventilatory and gas exchange abnormalities during exercise in HFpEF. Methods and results Subjects with invasively-proven HFpEF (n = 50) and non-cardiac causes of dyspnoea (controls, n = 24) underwent cardiac catheterization at rest and during exercise with simultaneous expired gas analysis. During submaximal (20 W) exercise, subjects with HFpEF displayed higher pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, higher Borg perceived dyspnoea scores, and increased ventilatory drive and respiratory rate. At peak exercise, ventilation reserve was reduced in HFpEF compared with controls, with greater dead space ventilation (higher VD/VT). Increasing exercise PCWP was directly correlated with higher perceived dyspnoea scores, lower peak exercise capacity, greater ventilatory drive, worse New York Heart Association (NYHA) functional class, and impaired pulmonary ventilation reserve. Conclusion This study provides the first evidence linking altered exercise haemodynamics to pulmonary abnormalities and symptoms of dyspnoea in patients with HFpEF. Further study is required to identify the mechanisms by which haemodynamic derangements affect lung function and symptoms and to test novel therapies targeting exercise haemodynamics in HFpEF.

A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure with Preserved Ejection Fraction

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging in euvolemic patients with dyspnea, and no evidence-based criteria are available. We sought to develop and then validate noninvasive diagnostic criteria that could be used to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea to guide further testing. Methods: Consecutive patients with unexplained dyspnea referred for invasive hemodynamic exercise testing were retrospectively evaluated. Diagnosis of HFpEF (case) or noncardiac dyspnea (control) was ascertained by invasive hemodynamic exercise testing. Logistic regression was performed to evaluate the ability of clinical findings to discriminate cases from controls. A scoring system was developed and then validated in a separate test cohort. Results: The derivation cohort included 414 consecutive patients (267 cases with HFpEF and 147 controls; HFpEF prevalence, 64%). The test cohort included 100 consecutive patients (61 with HFpEF; prevalence, 61%). Obesity, atrial fibrillation, age >60 years, treatment with ≥2 antihypertensives, echocardiographic E/e’ ratio >9, and echocardiographic pulmonary artery systolic pressure >35 mm Hg were selected as the final set of predictive variables. A weighted score based on these 6 variables was used to create a composite score (H2FPEF score) ranging from 0 to 9. The odds of HFpEF doubled for each 1-unit score increase (odds ratio, 1.98; 95% CI, 1.74–2.30; P<0.0001), with an area under the curve of 0.841 (P<0.0001). The H2FPEF score was superior to a currently used algorithm based on expert consensus (increase in area under the curve of 0.169; 95% CI, 0.120–0.217; P<0.0001). Performance in the independent test cohort was maintained (area under the curve, 0.886; P<0.0001). Conclusions: The H2FPEF score, which relies on simple clinical characteristics and echocardiography, enables discrimination of HFpEF from noncardiac causes of dyspnea and can assist in determination of the need for further diagnostic testing in the evaluation of patients with unexplained exertional dyspnea.

High Prevalence of Occult Heart Failure With Preserved Ejection Fraction Among Patients With Atrial Fibrillation and Dyspnea

Atrial fibrillation (AF) is common in patients with heart failure and preserved ejection fraction (HFpEF).1,2 Like people with HFpEF, patients with AF commonly describe exertional dyspnea. Treatments directed at AF are often undertaken by using antiarrhythmic drugs, rate control, or AF ablation with the ultimate goal of improving these symptoms. However, recent data indicate that some patients with apparently lone AF display myocardial abnormalities that persist even when sinus rhythm has been restored, suggesting the coexistence of an underlying cardiomyopathic process.3 Viewed in this light, AF might be conceptualized as a consequence rather than a cause of symptoms of heart failure. There is little information available regarding the prevalence of HFpEF among patients presenting with dyspnea, normal ejection fraction (EF), and AF. Because history, physical examination, and echocardiography are insensitive to the diagnosis of HFpEF, the only method to accurately determine whether HFpEF is present or absent in this group is to ascertain disease status by using the gold standard of invasive hemodynamic cardiopulmonary exercise testing.4,5 We examined the relationships between AF and HFpEF among consecutive patients presenting with …

Response by Obokata and Borlaug to Letter Regarding Article, “Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study”

We thank Drs Smiseth and Nagueh for their interest in our recent publication testing the role of invasive and noninvasive diastolic stress testing in the evaluation of heart failure with preserved ejection fraction (HFpEF).1 The authors point out how the hemodynamic data collected in our study provides a unique opportunity to understand more about the determinants of exercise capacity in patients with HFpEF. We agree, and in fact we have published a different article from this cohort specifically devoted to that question.2 The goal of this article was not to characterize the pathophysiology but to examine the role of exercise testing in the …

Right ventricular dysfunction and pulmonary hypertension in heart failure with preserved ejection fraction.

In 2009, Lam and colleagues first reported that pulmonary hypertension (PH) is both common and lethal among people suffering heart failure with preserved ejection fraction (HFpEF).1 Since that time, others have demonstrated that abnormalities beyond the pulmonary vasculature, extending to the right heart and the lung parenchyma itself are common and further contribute to increased morbidity and mortality in HFpEF.1–10 While the presence of PH and right ventricular dysfunction (RVD) have been independently associated with adverse outcome in some studies,1–3 others have reported much lower prevalences of PH and RVD in HFpEF, and less clear associations with outcome.5 Numerous clinical trials have, and are being undertaken with the primary or secondary goal of reducing pulmonary artery (PA) pressures in people with HFpEF,10–17 but there remains uncertainty regarding the overall prevalence and prognostic importance of PH/RVD in this syndrome across the disease spectrum.5 In this issue of the European Journal of Heart Failure, Gorter et al.18 present the findings of a comprehensive systematic review and meta-analysis aimed at clarifying the prevalence and prognostic value of RVD and PH in HFpEF. The authors included 38 studies that reported RVD and/or PH in subjects with HFpEF; HFpEF was defined by signs and symptoms of heart failure (HF) (or hospitalization owing to HF <12 months) and normal or mildly reduced ejection fraction (EF ≥45%). Because there are potential concerns about the specificity of these criteria, the authors also performed a sensitivity analysis using more stringent criteria according to the 2012 European Society of Cardiology (ESC) guidelines. Right ventricular dysfunction was defined using echocardiography [tricuspid annular plane systolic excursion (TAPSE) <16 mm, fractional area change (FAC) <35%, or tricuspid annular systolic velocity