Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction

Over 2.5 million patients in the USA suffer from heart failure with preserved ejection fraction (HFpEF), and pulmonary hypertension (PH) is present in the majority of these patients. PH represents an adverse prognostic factor in HFpEF and has been identified as a potential therapeutic target to improve symptoms and outcomes. The recognition and investigation of a subset of patients with superimposed pulmonary vascular disease (on top of pulmonary venous hypertension) has led to further subclassification of PH due to left heart disease (PH-LHD) into two categories: isolated post-capillary PH and combined post- and pre-capillary PH (CpcPH). In this review, we (1) describe the evolution of the diagnostic criteria of PH-LHD; (2) identify the diagnostic modalities that can be utilized for the identification of patients with CpcPH-HFpEF; (3) review the literature on the prevalence, clinical characteristics, and prognostic factors of CpcPH-HFpEF; (4) discuss recent and ongoing clinical trials investigating the effectiveness of selective pulmonary vasodilators in PH-LHD; and (5) propose future areas for further investigation of the etiology and pathophysiological mechanisms contributing to the development of CpcPH and highlight important considerations in the design of future trials to promote better characterization of this clinical entity. CpcPH-HFpEF is a distinct subset within HFpEF and one that may respond to targeted therapeutics.     

Treatment for Pulmonary Hypertension of Left Heart Disease

OPINION STATEMENT: Pulmonary hypertension (PH) secondary to left heart disease is a largely underestimated target of therapy. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular mechanical assist device or candidates for transplantation, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly and in HF with preserved ejection fraction (pEF). Studies have defined PH-HFpEF as a new entity typically defining the evolving nature of disease. Although the prevalence of PH in these populations is not well-defined, the potential for effective pharmacological approaches that might impact the natural history of the disease starting from earlier stages is promising. However, it should be recognized that pharmacological studies performed to date with traditional pulmonary vasodilators in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic side effects. This evidence along with the lack of studies specifically performed in the elderly and HFpEF often lead Guidelines to give neutral recommendations or even arbitrary assumptions. Recent availability of selective well-tolerated pulmonary vasodilators, such as phosphodiesterase type 5 (PDE5) inhibitors, however, seem to offer a solid background for treating left-sided PH at both early and later stages of the disease process.     

Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is defined as clinical features of heart failure, ideally with biomarker evidence such as elevated plasma natriuretic peptide levels, in the setting of an ejection fraction (EF) greater than 50% and imaging evidence of diastolic left ventricular dysfunction [1], [2]. In the absence of cardiac imaging or invasive hemodynamics, this is a clinical syndrome that is often indistinguishable from heart failure with reduced ejection fraction (HFrEF). HFpEF and HFrEF present with a cadre of comparable signs and symptoms including jugular venous distention, pulmonary rales on auscultation, breathlessness, orthopnea, exercise intolerance, exertional dyspnea, fatigue and peripheral edema. HFpEF accounts for at least half of all diagnoses of heart failure [1], [2]. Pulmonary hypertension (PH) is a common complication of HFpEF that is linked to worse disease morbidity and mortality. In fact, mortality has been linked to increases in the intrinsic pulmonary vascular resistance in the setting of increased left ventricular end diastolic pressure, characterized hemodynamically by rises in the transpulmonary pressure gradient, pulmonary vascular resistance or diastolic pressure gradient. Despite being the most common form of PH, there are no approved therapies for the treatment of PH secondary to HFpEF. This review will summarize the hemodynamic classifications of PH in the setting of HFpEF, mechanisms of disease, the potential contribution of pulmonary vascular disease to poor outcomes in patients with HFpEF, and new approaches to therapy.     

Pulmonary Vascular Resistance Is Associated With Brachial-Ankle Pulse-Wave Velocity and Adverse Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction

BackgroundThe precise mechanisms underlying the high prevalence of pulmonary hypertension (PH) with increased pulmonary vascular resistance (PVR) in heart failure with preserved ejection fraction (HFpEF) remain largely unknown. Measurements of brachial-ankle pulse wave velocity (baPWV) have been shown to be useful for risk assessment in HF patients. Thus, this study sought to define the association of PVR with baPWV and clinical outcomes in HFpEF.Methods and ResultsPatients with HFpEF (n = 198) had measurements of baPWV and PVR by right heart catheterization, and were prospectively followed-up for <96 months or until the occurrence of a composite of all-cause death, hospitalization with worsening HF, and nonfatal acute coronary syndrome.ResultsMultivariate logistic analysis showed that baPWV was independently associated with PH with increased PVR (P < .001). During the follow-up period, 46 clinical events occurred. Multivariate Cox proportional hazards analysis showed that PH with increased PVR was a significant predictor of adverse outcomes after adjustment for conventional risk factors (HR 1.96, 95% CI 1.03–3.76, P = .04).ConclusionsPH with increased PVR was associated with increased baPWV and adverse clinical outcomes in HFpEF. Thus, increased arterial stiffness may contribute to increased risk predictability of PVR for patients with HFpEF.     

The impact of left ventricular ejection fraction on heart failure patients with pulmonary hypertension

BackgroundThe most common cause of pulmonary hypertension (PH) in developed countries is left heart disease (LHD, group 2 PH). The development of PH in heart failure (HF) patients is indicative of worse outcomes.ObjectiveThe aim of this study was to evaluate the long term outcomes of HF patients with PH in a national long-term registry.MethodsStudy included 9 cardiology centers across Israel between 01/2013–01/2015, with a 12-month clinical follow-up and 24-month mortality follow-up. Patients were age ≥18 years old with HF and pre-inclusion PH due to left heart disease determined by echocardiography [estimated systolic pulmonary arterial pressure (SPAP) ≥ 50 mmHg]. Patients were categorized into 3 groups: HF with reduced (HFrEF < 40%), mid-range (HFmrEF 40–49%), and preserved (HFpEF ≥ 50%) ejection fraction.ResultsThe registry included 372 patients, with high prevalence of cardiovascular risk factors. Median HF duration was 4 years and 65% were in severe HF New York Heart Association (NYHA) classification ≥3. Mean systolic pulmonary artery pressure (SPAP) was 62 ± 11 mmHg. During 2-years of follow-up, 54 patients (15%) died. Univariable predictors of mortality included NYHA grade 3–4, chronic renal failure, and SPAP ≥ 65 mmHg. Severe PH was associated with mortality in HFpEF, but not HFmrEF or HFrEF, and remained significant after multivariable adjustment with an adjusted hazard ratio of 2.99, (95%CI 1.29–6.91, p = 0.010).ConclusionsThe combination of HFpEF with severe PH was independently associated with increased mortality. Currently, HFpEF patients are included with group 2 PH patients. Defining HFpEF with severe PH as a sub-class may be more appropriate, as these patients are at increased risk and deserve special consideration.     

A Clinical and Echocardiographic Score to Identify Pulmonary Hypertension Due to HFpEF

Background

Heart failure with preserved ejection fraction (HFpEF) is a frequent cause of pulmonary hypertension (PH) that is not easy to differentiate from precapillary PH. We aimed to determine whether the characteristic features of the patients may help differentiate between HFpEF and precapillary PH.

Dynamic Nature of Pulmonary Artery Systolic Pressure in Decompensated Heart Failure With Preserved Ejection Fraction: Role of Functional Mitral Regurgitation

BackgroundPulmonary hypertension (PH) is prevalent in decompensated heart failure with preserved ejection fraction (HFpEF). We investigated the effect of a return to a compensated state on pulmonary artery systolic pressure (PASP) and functional mitral regurgitation (FMR).Methods and ResultsTwo-dimensional Doppler echocardiography was prospectively performed before initiation of standard therapy and 48 hours later in 37 patients hospitalized for HFpEF-related dyspnea and in 26 patients hospitalized for non-HFpEF–related dyspnea. Left atrial volume index, and E/e′ ratio, and PASP were significantly greater and E-wave deceleration time significantly shorter in HFpEF than in non-HFpEF patients. Thirty-two of the 37 HFpEF had FMR on admission whereas none of the non-HFpEF patients had FMR. After 48 hours of therapy, the reduction in PASP was significantly greater in the 26 HFpEF patients who improved than in the 11 HFpEF patients who did not (?24 vs ?9 mm Hg, respectively; P < .0001), whereas PASP remained unchanged in non-HFpEF patients. The decrease in PASP correlated in HFpEF patients with reductions in blood pressure, heart rate, left ventricular end-diastolic volume, inferior vena cava diameter, E/A ratio, E/e′ ratio, mitral effective regurgitant orifice area (EROA), and E-wave deceleration time. The correlation between PASP and mitral EROA was the only one that remained significant by multivariate analysis.ConclusionsNoninvasive monitoring of PASP and FMR during an episode of HFpEF decompensation reveals that the return to a compensated state is associated with a significant reduction in PASP and FMR.     

Unexplained pulmonary hypertension in elderly patients

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) preferentially affects young women. However, a subset of patients with IPAH is elderly. Our objective was to compare elderly (age >/= 65 years) vs younger persons with unexplained pulmonary hypertension (PH) and a presumptive diagnosis of IPAH. METHODS: Clinical, echocardiographic, hemodynamic, and survival data were collected on consecutive patients with suspected IPAH after evaluation in a large tertiary center PH clinic. RESULTS: Of 197 patients (mean age +/- SD, 52 +/- 16 years; 80% female), 48 patients (24%) were elderly. Elderly and younger patients had similar symptom severity, systolic pulmonary artery (PA) pressure (82.7 +/- 20.3 mm Hg vs 86.9 +/- 18.8 mm Hg, respectively; p = 0.21), and severity of right ventricular enlargement and dysfunction. Elderly patients had higher pulmonary capillary wedge pressure (PCWP) [15.3 +/- 7.3 mm Hg vs 11.1 +/- 5.3 mm Hg; p < 0.0001] and more frequently failed (56%) to meet hemodynamic criteria for IPAH (PH with PCWP < 15 mm Hg) than did younger patients (19%). Elderly patients also had higher systemic systolic (p < 0.0001) and pulse (p < 0.0001) pressures and more cardiovascular disease. Among those patients with normal PCWP, elderly patients had worse survival than young patients (p = 0.007). Among those patients with elevated PCWP, elderly patients had lower PA pressures (p = 0.04) and better survival (p = 0.02). CONCLUSIONS: Elderly patients with clinically suspected IPAH often fail to meet hemodynamic criteria for IPAH due to elevated PCWP. Studies to define the proper diagnostic strategy and the safety and efficacy of pulmonary vasodilators in elderly patients with unexplained PH are needed.     

Role of Physical Training in Heart Failure with Preserved Ejection Fraction

About 50 % or more of heart failure (HF) patients living in the community have preserved left ventricular ejection fraction (HFpEF), and the proportion is higher among women and the very elderly. A cardinal feature of HFpEF is reduced aerobic capacity, measured objectively as peak exercise pulmonary oxygen uptake (peak VO₂), that results in decreased quality of life. Specifically, peak VO₂ of HFpEF patients is 30–70 % lower than age-, sex-, and comorbidity-matched control patients without HF. The mechanisms for the reduced peak VO₂ are due to cardiovascular and skeletal muscle dysfunction that results in reduced oxygen delivery to and/or utilization by the active muscles. Currently, four randomized controlled exercise intervention trials have been performed in HFpEF patients. These studies have consistently demonstrated that 3–6 months of aerobic training performed alone or in combination with strength training is a safe and effective therapy to increase aerobic capacity and endurance and quality of life in HFpEF patients. Despite these benefits, the physiologic mechanisms underpinning the improvement in peak exercise performance have not been studied; therefore, future studies are required to determine the role of physical training to reverse the impaired cardiovascular and skeletal muscle function in HFpEF patients.     

Heart failure with preserved ejection fraction: Classification based upon phenotype is essential for diagnosis and treatment

Heart failure (HF) is classified based upon the left ventricular ejection fraction (LVEF). Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disorder with increasing prevalence in the elderly that remains incompletely understood and inadequately treated as no therapy has shown favorable effects. In this review, we summarize the current theories regarding HFpEF pathogenesis, propose a phenotype-based classification of HFpEF, discuss prevention strategies, explain why clinical trials on HFpEF treatment have failed, and make suggestions for the future.     

老年人衰弱和射血分数保留性心力衰竭病理生理学机制的研究进展

衰弱和射血分数保留性心力衰竭是具有密切关联的疾病,二者具有共通的病理生理学机制,如慢性炎症、氧化应激、内分泌代谢和神经激素调节异常等,通过上述多种潜在机制的相互作用加速了二者的疾病进程,从而共同导致老年患者的不良预后。目前针对衰弱及射血分数保留性心力衰竭的干预方式有限,尤其是药物治疗尚存在局限性,深入认识衰弱和射血分数保留性心力衰竭的病理生理学机制有助于探索二者潜在的治疗靶点,以期改善老年患者的预后。     

GLP-1 Improves Diastolic Function and Survival in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) has emerged as a public health burden with currently no effective medication. We assessed the treatment effects of the incretin hormone glucagon-like peptide-1 (GLP-1) on cardiac metabolism and function in a model of HFpEF. Following aortic banding, rats developed HFpEF characterized by diastolic dysfunction, pulmonary congestion, and poor survival (38%). A 4-week GLP-1 treatment via osmotic pumps significantly improved survival (70%) and reduced left ventricular stiffness, diastolic dysfunction, and pulmonary congestion. Isolated heart perfusion revealed preserved cardiac glucose oxidation (GO) and a shift in cardiac substrate utilization towards GO. While GLP-1 may boost insulin secretion and responsiveness, the protective effects were not related to cardiac insulin action. GLP-1 improves diastolic function and survival in rats with HFpEF, which was associated with a cardiac substrate switch towards GO. The therapeutic role of GLP-1 in HFpEF is new and warrants further investigation.     

Current Management and Future Directions of Heart Failure With Preserved Ejection Fraction: a Contemporary Review

Heart failure with preserved ejection fraction (HFpEF), a complex and debilitating syndrome, is commonly seen in elderly populations. Exacerbation of HFpEF is among the most common reasons for hospital admission in the USA. The high rate of morbidity and mortality from this condition underscores the fact that HFpEF is heterogeneous, complex, and poorly characterized. Randomized, controlled trials have been very successful at identifying treatments for HF with reduced ejection fraction (HFrEF), but effective treatment options for HFpEF are lacking. Here, we discuss (1) the pathophysiology of HFpEF, (2) a standardized diagnostic and therapeutic approach, (3) a comparison of the management of recent guidelines, and (4) challenges and future directions for HFpEF management. The authors believe that it is important to identify new subtypes of HFpEF to better classify genotypes and phenotypes of HFpEF and to develop novel targeted therapies. It is our hypothesis that big data analytics will shine new light on unique HFpEF phenotypes that better respond to treatment modalities.     

Independent predictors of developing pulmonary hypertension in heart failure with reduced versus preserved ejection fraction

Objectives

To investigate the different clinical and echocardiographic predictors of evolving PH in patients with heart failure with and without reduced ejection fraction.

Insulin Growth Factor Phenotypes in Heart Failure With Preserved Ejection Fraction,an INSPIRE Registry and CATHGEN Study

BackgroundThe insulin-like growth factor (IGF) axis emerged as an important pathway in heart failure with preserved ejection (HFpEF). We aimed to identify IGF phenotypes associated with HFpEF in the context of high-dimensional proteomic profiling.MethodsFrom the INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry), we identified 96 patients with HFpEF and matched controls. We performed targeted proteomics, including IGF-1,2, IGF binding proteins (IGFBP) 1–7 and 111 other proteins (EMD Millipore and ELISA). We used partial least square discriminant analysis (PLS-DA) to identify a set of proteins associated with prevalent HFpEF, pulmonary hypertension and 5-year all-cause mortality. K-mean clustering was used to identify IGF phenotypes.ResultsPatients with HFpEF had a high prevalence of systemic hypertension (95%) and coronary artery disease (74%). Using PLS-DA, we identified a set of biomarkers, including IGF1,2 and IGFBP 1,2,7, that provided a strong discrimination of HFpEF, pulmonary hypertension and mortality with an area under the curve of 0.91, 0.77 and 0.83, respectively. Using K mean clustering, we identified 3 IGF phenotypes that were independently associated with all-cause 5-year mortality after adjustment for age, NT-proBNP and kidney disease (P = 0.004). Multivariable analysis validated the prognostic value of IGFBP-1 and 2 in the CATHeterization GENetics (CATHGEN) biorepository.ConclusionIGF phenotypes were associated with pulmonary hypertension and mortality in HFpEF.     

Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic Peptide levels in heart failure with preserved ejection fraction

B-type natriuretic peptide (BNP) is used widely to exclude heart failure (HF) in patients with dyspnea. However, most studies of BNP have focused on diagnosing HF with reduced ejection fraction (EF). The aim of this study was to test the hypothesis that a normal BNP level (≤100 pg/ml) is relatively common in HF with preserved EF (HFpEF), a heterogenous disorder commonly associated with obesity. A total of 159 consecutive patients enrolled in the Northwestern University HFpEF Program were prospectively studied. All subjects had symptomatic HF with EF >50% and elevated pulmonary capillary wedge pressure. BNP was tested at baseline in all subjects. Clinical characteristics, echocardiographic parameters, invasive hemodynamics, and outcomes were compared among patients with HFpEF with normal (≤100 pg/ml) versus elevated (>100 pg/ml) BNP. Of the 159 patients with HFpEF, 46 (29%) had BNP ≤100 pg/ml. Subjects with normal BNP were younger, were more often women, had higher rates of obesity and higher body mass index, and less commonly had chronic kidney disease and atrial fibrillation. EFs and pulmonary capillary wedge pressures were similar in the normal and elevated BNP groups (62 ± 7% vs 61 ± 7%, p = 0.67, and 25 ± 8 vs 27 ± 9 mm Hg, p = 0.42, respectively). Elevated BNP was associated with enlarged left atrial volume, worse diastolic function, abnormal right ventricular structure and function, and worse outcomes (e.g., adjusted hazard ratio for HF hospitalization 4.0, 95% confidence interval 1.6 to 9.7, p = 0.003). In conclusion, normal BNP levels were present in 29% of symptomatic outpatients with HFpEF who had elevated pulmonary capillary wedge pressures, and although BNP is useful as a prognostic marker in HFpEF, normal BNP does not exclude the outpatient diagnosis of HFpEF.     

Interaction Between Pulmonary Hypertension and Diastolic Dysfunction in an Elderly Heart Failure Population

BackgroundPulmonary hypertension due to left heart disease is very common. Our aim was to investigate the relationship of the severity of left ventricular diastolic dysfunction with precapillary and postcapillary pulmonary hypertension (PH) in an elderly heart failure (HF) population.Methods and ResultsA post hoc analysis of the Trial of Intensified Medical Therapy in Elderly Patients With Congestive Heart Failure data was done. Baseline transthoracic echocardiography was used to categorize diastolic function, estimate pulmonary artery pressure and pulmonary capillary wedge pressure, and calculate the transpulmonary pressure gradient (TPG). Among 392 HF patients, PH was present in 31% of patients with grade 1, in 37% of patients with grade 2, and in 65% of patients with grade 3 diastolic dysfunction; 54% of all HF patients with PH had a TPG >12 mm Hg, suggesting not only a postcapillary but also an additional precapillary component of PH. Survival was not related to the severity of diastolic dysfunction, but was worse in patients with PH (hazard ratio 1.63, 95% confidence interval 1.07–2.51; P = .024).ConclusionsOur data indicate that HF patients with even mild diastolic dysfunction often have PH. Echocardiographic assessment suggest that the presence of PH might not simply be due to increased PCWP, but in part due to a precapillary component.     

Epidemiology of Heart Failure with Preserved Ejection Fraction

The prevalence of heart failure (HF) and its subtype, HF with preserved ejection fraction (HFpEF), is on the rise due to aging of the population. HFpEF is convergence of several pathophysiological processes, which are not yet clearly identified. HFpEF is usually seen in association with systemic diseases, such as diabetes, hypertension, atrial fibrillation, sleep apnea, renal and pulmonary disease. The proportion of HF patients with HFpEF varies by patient demographics, study settings (cohort vs. clinical trial, outpatient clinics vs. hospitalised patients) and cut points used to define preserved function. There is an expanding body of literature about prevalence and prognostic significance of both cardiovascular and non-cardiovascular comorbidities in HFpEF patients. Current therapeutic approaches are targeted towards alleviating the symptoms, treating the associated comorbid conditions, and reducing recurrent hospital admissions. There is lack of evidence-based therapies that show a reduction in the mortality amongst HFpEF patients; however, an improvement in exercise tolerance and quality of life is seen with few interventions. In this review, we highlight the epidemiology and current treatment options for HFpEF.     

Inspiratory Muscle Training and Functional Electrical Stimulation for Treatment of Heart Failure With Preserved Ejection Fraction: Rationale and Study Design of a Prospective Randomized Controlled Trial

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent form of heart failure in developed countries. Regrettably, there is no evidence‐based effective therapy for HFpEF. We seek to evaluate whether inspiratory muscle training, functional electrical stimulation, or a combination of both can improve exercise capacity as well as left ventricular diastolic function, biomarker profile, quality of life (QoL), and prognosis in patients with HFpEF. A total of 60 stable symptomatic patients with HFpEF (New York Heart Association class II–III/IV) will be randomized (1:1:1:1) to receive a 12‐week program of inspiratory muscle training, functional electrical stimulation, a combination of both, or standard care alone. The primary endpoint of the study is change in peak exercise oxygen uptake; secondary endpoints are changes in QoL, echocardiogram parameters, and prognostic biomarkers. As of March 21, 2016, thirty patients have been enrolled. Searching for novel therapies that improve QoL and autonomy in the elderly with HFpEF has become a health care priority. We believe that this study will add important knowledge about the potential utility of 2 simple and feasible physical interventions for the treatment of advanced HFpEF.