Bharathi Upadhya

Heart failure with preserved ejection fraction in the elderly: scope of the problem

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults, particularly women, and is increasing in prevalence as the population ages. With morbidity and mortality on par with HF with reduced ejection fraction, it remains a most challenging clinical syndrome for the practicing clinician and basic research scientist. Originally considered to be predominantly caused by diastolic dysfunction, more recent insights indicate that HFpEF in older persons is typified by a broad range of cardiac and non-cardiac abnormalities and reduced reserve capacity in multiple organ systems. The globally reduced reserve capacity is driven by: 1) inherent age-related changes; 2) multiple, concomitant co-morbidities; 3) HFpEF itself, which is likely a systemic disorder. These insights help explain why: 1) co-morbidities are among the strongest predictors of outcomes; 2) approximately 50% of clinical events in HFpEF patients are non-cardiovascular; 3) clinical drug trials in HFpEF have been negative on their primary outcomes. Embracing HFpEF as a true geriatric syndrome, with complex, multi-factorial pathophysiology and clinical heterogeneity could provide new mechanistic insights and opportunities for progress in management. This article is part of a Special Issue entitled CV Aging.

Exercise intolerance in heart failure with preserved ejection fraction: more than a heart problem

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in older adults, and is increasing in prevalence as the population ages. Furthermore, HFpEF is increasing out of proportion to HF with reduced EF (HFrEF), and its prognosis is worsening while that of HFrEF is improving. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. A cardinal feature of HFpEF is reduced exercise tolerance, which correlates with symptoms as well as reduced quality of life. The traditional concepts of exercise limitations have focused on central dysfunction related to poor cardiac pump function. However, the mechanisms are not exclusive to the heart and lungs, and the understanding of the pathophysiology of this disease has evolved. Substantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and exercise tolerance among patients with HF. In fact, physical training can improve exercise tolerance via peripheral adaptive mechanisms even in the absence of favorable central hemodynamic function. In addition, the drug trials performed to date in HFpEF that have focused on influencing cardiovascular function have not improved exercise capacity. This suggests that peripheral limitations may play a significant role in HF limiting exercise tolerance, a hallmark feature of HFpEF.

Myocardial infarction in thrombotic thrombocytopenic purpura : a single-center experience and literature review

Background:  Several case reports and series have described myocardial infarctions (MIs) in patients hospitalized for thrombotic thrombocytopenic purpura (TTP). The exact magnitude and outcome of this complication are unknown.

Heart failure with preserved ejection fraction: a heterogenous disorder with multifactorial pathophysiology.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of HF in the population.1 Among elderly women living in the community, HFpEF comprises nearly 90% of incident HF cases.2 Furthermore, HFpEF is increasing out of proportion to HF with reduced EF (HFrEF), and its prognosis is worsening while that of HFrEF is improving.3 The health and economic impact of HFpEF is at least as great as that of HFrEF, with similar severity of chronic exercise intolerance,4 acute hospitalization rates3,5 and substantial mortality.3

What the Dead Can Teach the Living Systemic Nature of Heart Failure With Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. Approximately 90% of new HF cases in older women are HFpEF.1 Adverse outcomes – exercise intolerance, poor quality of life, frequent hospitalizations, and reduced survival – approach those of HF with reduced EF (HFrEF). In contrast to HFrEF, the prevalence of HFpEF is increasing and its prognosis is worsening.2 Despite the strong public health importance of HFpEF, its pathogenesis is poorly understood. Our lack of understanding of HFpEF and its treatment is punctuated by the fact that 6 large, well-designed, randomized, clinical trials and several smaller ones were all neutral on their primary outcomes. The combination of high prevalence and lack of evidence-based treatments makes HFpEF a high-priority topic for research in cardiovascular disease. Article see p 550 A glaring absence among HFpEF studies has been a systematic autopsy-based study. Such studies have become more difficult as autopsy rates have declined with the availability of advanced multimodality imaging and deep-tissue biopsy techniques. Despite the increasing array of modern research techniques, postmortem methods continue to be uniquely valuable because of the ability to perform comprehensive, in-depth, detailed examinations of tissues and organs in humans. In this issue of Circulation , Mohammed and colleagues3 at the Mayo Clinic fill this critical gap with the first autopsy series of HFpEF. From a tissue registry patiently accumulated over a period of 19 years, their multidisciplinary team methodically collected and comprehensively analyzed specimens, medical records, electrocardiograms, and echocardiograms from 255 individuals, including patients with premortem diagnosis of HFpEF (n=124) and HFrEF (n=27), and from age-matched case controls who died of noncardiovascular causes (n=104). Characteristics of the HFpEF patients were relatively similar to community-based reports, including advanced age and a high prevalence of common comorbidities, including hypertension, diabetes …

Sarcopenic Obesity and the Pathogenesis of Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults. The primary chronic symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance. Cardiac and peripheral functions contribute equally to exercise intolerance in HFpEF, though the latter has been the focus of fewer studies. Of note, multiple studies with exercise training have shown that exercise intolerance can improve significantly in the absence of improvements in exercise cardiac output, indicating a role of peripheral, noncardiac adaptations. In addition, clinical drug trials performed to date in HFpEF, all of which have focused on influencing cardiovascular function, have not been positive on primary clinical outcomes and most have not improved exercise capacity. Mounting evidence indicates that sarcopenic obesity, characterized by the coexistence of excess fat mass and decreased muscle mass, could contribute to the pathophysiology of exercise intolerance in older HFpEF patients and may provide avenues for novel treatments.

Prolongation of QTc intervals and risk of death among patients with sickle cell disease

Unexplained sudden death is common among patients with sickle cell diseases (SCD). QTc prolongation is a risk factor for fatal arrhythmias among adults. This study sought to identify the predictors for QTc prolongation and determine whether QTc prolongation is associated with increased mortality in patients with SCD.

Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction

To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF).

Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial.

Background— Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age ≥75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (⩽132 versus >132 to <145 versus ≥145 mm Hg). Methods and Results— ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46–0.85; P value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (P<0.001) in cardiovascular death. Conclusions— Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062

Delay of left ventricular longitudinal expansion with diastolic dysfunction: impact on load dependence of e′ and longitudinal strain rate

The effect of diastolic dysfunction (DD) on the timing of left ventricular (LV) diastolic longitudinal and circumferential expansion and their load dependence is not known. This study evaluated the timing of the peak early diastolic LV inflow velocity (E), mitral annular velocity (e′), and longitudinal and circumferential global strain rates (SRE) in 161 patients in sinus rhythm. The intraventricular pressure difference (IVPD) from the left atrium to the LV apex was obtained using color M‐mode Doppler data to integrate the Euler equation. The diastolic function was graded according to the guidelines. In normals (N = 57), E, e′, longitudinal SRE, and circumferential SRE occurred nearly simultaneously during the IVPD. With DD (N = 104), e′ and longitudinal SRE were delayed occurring after the IVPD (e′: 18 ± 23 msec, longitudinal SRE: 13 ± 21 msec from the IVPD), whereas circumferential SRE (−8 ± 28 msec) and E (−2 ± 13 msec) were not delayed. The normal dependence of e′ and longitudinal SRE on IVPD was reduced in DD; while the relation of circumferential SRE and E to IVPD were unchanged in DD. Thus, normally, the LV expands symmetrically during early diastole and both longitudinal and circumferential expansions are related to the IVPD. With DD, early diastolic longitudinal LV expansion is delayed, occurring after the IVPD and LV filling, resulting in their relative independence from the IVPD. In contrast, with DD, circumferential SRE and mitral inflow are not delayed and their normal relation to the IVPD is unchanged.