Congestive heart failure in the elderly: the Cardiovascular Health Study.

Left Atrial Volume, Geometry, and Function in Systolic and Diastolic Heart Failure of Persons ≥65 Years of Age (The Cardiovascular Health Study)

Sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: reasons for optimism.

Burden of systolic and diastolic ventricular dysfunction in the community appreciating the scope of the heart failure epidemic

Background Sodium-glucose co-transporter 2 (SGLT-2) inhibitors emerged as a new groundbreaking therapy for patients with heart failure. Recent evidence showed significant benefits in patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetic status. Whether these medications also improve outcomes in patients without a history of heart failure or with heart failure with preserved ejection fraction (HFpEF) remains unknown. Purpose We sought to perform an updated meta-analysis of randomized controlled trials to evaluate the effects of SGLT-2 inhibitors on cardiovascular (CV) outcomes according to the history and type of heart failure. Methods All randomized, placebo-controlled trials of SGLT-2 inhibitors reporting similar CV outcomes were evaluated for inclusion. PubMed was searched from January 1, 2010 to February 1, 2021. Articles were independently reviewed and selected by two reviewers. The primary outcome was the composite of first hospitalization for heart failure and CV death. Secondary outcomes included its single components and all-cause mortality. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were used as effect estimates and calculated with a random-effects model. Heterogeneity was assessed with the I2 index, and random-effects meta-regression was used to assess the interaction between treatment effect and history of heart failure and type of heart failure (HFrEF vs. HFpEF). Results Data from eight trials and a total of 56,665 patients (n=31,609 in SGLT-2 group, n=25,056 in placebo group) were included. Five studies enrolled high-risk patients with diabetes mellitus, while 3 studies enrolled patients with symptomatic heart failure. SGLT-2 inhibitors reduced the risk of first hospitalization for heart failure and CV death in patients with (HR 0.75 95% CI 0.70–0.81) and without (HR 0.78 95% CI 0.67–0.90; Figure 1) a history of heart failure. Similarly, patients with (HR 0.85 95% CI 0.78–0.93) or without (HR 0.85 95% CI 0.74–0.98) a history of heart failure treated with SGLT-2 inhibitors had a significant reduction in all-cause mortality. SGLT-2 inhibitors reduced the risk of CV death regardless of the history of heart failure, although the reduction was border-line statistically significant in patients without a history of heart failure (HR 0.81 95% CI 0.66–1.00; Figure 2). All subgroup interaction testing between patients with and without a history of heart failure was negative for all the above endpoints. Among patients with HFpEF, SGLT-2 inhibitors were associated with a nonsignificant trend towards reduced risk of the primary outcome (HR 0.80 95% CI 0.63–1.02). Conclusions SGLT-2 inhibitors significantly improve CV outcomes in patients with or without history of heart failure, and this effect seems to be consistent among those with HFrEF and HFpEF. Funding Acknowledgement Type of funding sources: None. Figure 1. CV death or HF hospitalizationFigure 2. Meta-analysis CV death

Treatment of Diabetes in People with Heart Failure

Invited Commentary

In this issue of the Journal, Millen et al.[1] report the results of a cross-sectional population-based study aimed at assessing the impact of blood pressure (BP) and clinical indexes of obesity on left-ventricular diastolic function, as assessed by conventional and tissue Doppler imaging (TDI) parameters, in a cohort of 417 black African individuals aged above 16 years (35% men), free of overt cardiovascular disease, but with high prevalence of overweight/obesity. Before addressing the results of the study, available evidence on this issue and related topics may warrant some considerations. Nowadays, congestive heart failure is the most common cause of hospitalization in developed countries, among major forms of cardiovascular disease, followed by cerebrovascular and coronary heart disease; hospitalization rates of congestive heart failure is also continuously increasing worldwide [2]. Congestive heart failure related to left ventricular diastolic dysfunction is an emerging clinical entity involving up to 60% of patients managed in clinical practice [3]. The likelihood of diastolic dysfunction as a dominant cause of heart failure is particularly high in patients with systemic hypertension, left ventricular hypertrophy (LVH), central obesity, type 2 diabetes mellitus, metabolic syndrome, sleep apnea syndrome and permanent atrial fibrillation [4]. Echocardiography is recommended by international guidelines and authoritative scientific bodies for diagnosing heart failure with preserved ejection fraction and identifying early diastolic abnormalities in asymptomatic patients at high cardiovascular risk [5,6]. A large amount of evidence indicates that the assessment of diastolic function by using conventional Doppler and TDI may provide relevant predictive information about cardiovascular morbidity and mortality independently from left ventricular mass, left ventricular geometry and Framingham score [7]. Among the conventional Doppler indexes assessing diastolic function, the ratio of the peak early (E) to peak late (A) mitral inflow velocity (E/A ratio), and deceleration time of the early mitral flow have been widely used in clinical research and current practice. In particular, the relation of E/A ratio with cardiovascular outcomes has a U-shaped form, the lowest and highest values being associated with a poor cardiovascular prognosis in different clinical settings. In the Cardiovascular Health Study [8], the first prospective survey showing that diastolic dysfunction is predictive of incident congestive heart failure, the E/A ratio was related to the relative risk of incident heart failure according to a U-shaped curve; in particular, for E/A values less than 0.7, the risk was 1.9 and for ratios greater than 1.5, the risk was up to 3.5 compared to intermediate E/A values. In the past decade, the TDI technique has been extensively validated in a variety of cardiac diseases. At present time, TDI, as well as new imaging technologies such as strain rate and speckle tracking, offer incremental information on myocardial function compared to conventional echocardiography. It has been shown that invasive measures of diastolic function better correlate with early diastolic TDI velocity than with early mitral flow velocity or E/A ratio. A reduced early myocardial velocity (Ei) velocity in patients with impaired left ventricular systolic function as well as in those with hypertension and LVH has been reported to predict mortality better than clinical and conventional echocardiographic data [9]. Furthermore, the E/Ei ratio reliably correlates with left ventricular filling pressure and is a strong independent predictor of fatal and nonfatal cardiovascular events [10]. The prevalence and correlates of diastolic dysfunction have been extensively investigated in a variety of clinical settings and in general population samples, because the identification of risk factors and mechanisms leading to subclinical left ventricular diastolic alterations is important to identify patients at risk of developing heart failure. Most attention has been focused on hypertension and obesity, due to the high prevalence of these modifiable risk factors in the general population. The Assessment of Prevalence Observational Study of Diastolic Dysfunction (APROS diadys) project, a cross-sectional observational study on elderly hypertensive patients (mean age 70 years, 49% men) without systolic dysfunction consecutively attending hospital outpatient clinics in Italy, evaluated the prevalence and clinical correlates of echocardiographic signs of diastolic dysfunction [11]. Diastolic dysfunction (E/A ratio <0.7 or >1.5) was found in 649 out of the 2425 patients (25.8%). Multiple logistic regression analysis found age, sex, left ventricular mass, systolic and pulse pressures, and mid-wall shortening fraction, but not BMI, as significant covariates. In the Flemish Study on Environment, Genes, and Health Outcomes (FLEMENGHO), 539 participants (49% men, mean age 52 years), selected from a random population sample stratified by sex and age, underwent a comprehensive echocardiographic and Doppler evaluation including TDI measurements [12]. The overall prevalence of left ventricular diastolic dysfunction was as high as 27.3% and increased in frequency with age. Mild diastolic dysfunction or impaired relaxation (abnormally low age-specific trans-mitral E/A ratio and normal left ventricular filling pressure as defined by an E/e′ ratio <9), moderate (elevated left ventricular end-diastolic filling pressure with E/A ratio within the normal age-specific range) and severe diastolic dysfunction (elevated left ventricular end-diastolic filling pressure with abnormally low E/A) were found in 9.8, 14.1 and 3.4%, respectively. Compared with individuals with normal diastolic function, those with moderate-to-severe diastolic impairment had a significantly higher age, BMI, heart rate and SBP. In that study, the association between obesity and diastolic dysfunction was clearly supported by multivariate regression full-adjusted analyses, showing that the risk of diastolic dysfunction increased by 2.5-fold for each 5 kg/m2 increment of BMI. In the Baltimore Longitudinal Study on Aging, a cross-sectional survey involving 843 healthy participants (mean age 67 years, 45% men), the authors investigated the relationship between different fat depots, assessed by dual-energy X-ray absorptiometry and abdominal computed tomography, and left ventricular diastolic function [13]. They found that increased visceral adiposity was independently associated with left ventricular diastolic dysfunction, whereas this was not the case for subcutaneous adiposity. These findings suggest that the redistribution in the pattern of adiposity, due to disproportionate increase in visceral fat as opposed to subcutaneous fat, exerts a detrimental effect on diastolic function. In the paper published by Millen et al.[1], the authors assessed the influence of clinic BP, waist circumference and BMI on indexes of diastolic function in a large cohort of middle-aged asymptomatic black African individuals (mean age 45 years). Only a marginal fraction (9%) of this population-based sample was normal-weight, 68% were obese, 47% were hypertensive, and 27% had type 2 diabetes or an glycated haemoglobin above 6.1%. As many as 70 individuals (16.6%) were found to have echocardiographic LVH (i.e. left ventricular mass index >51 g/m2.7). Diastolic dysfunction was identified in approximately one-third of the entire sample; of note, mild dysfunction (impaired relaxation with E/A ratio <0.75) was present in 13%, moderate dysfunction (E/A >0.75 <1.5 and E/e′ ratio >10) in 12%, and severe dysfunction in 4% (E/A >1.5 and E/e′ >10), respectively. The main results of this study can be summarized as follows: waist circumference, at variance from BMI and waist-to-hip ratio, was independently correlated to E/A and E/e′ ratio, considered as continuous variables; this relation, however, failed to maintain a statistical significance when these indexes of diastolic dysfunction were analysed as categorical variables (i.e. presence or absence of mild or moderate-to-severe diastolic dysfunction); SBP emerged as the most important correlate of diastolic dysfunction, assessed as a continuous or categorical variable; the strength of the association of SBP and diastolic dysfunction remained highly significant even after inclusion of left ventricular mass index in regression models. Some aspects and limitations of this interesting survey deserve to be briefly discussed. First, the lack of an independent association between obesity and diastolic dysfunction found in their series of middle-aged participants was ascribed by the authors to the possibility that the excess of adiposity may impact negatively on diastolic function only in conjunction with advanced age. This hypothesis, however, is challenged by a number of observations made in young overweight/obese individuals. For instance, Dhuper et al.[14], looking at the prevalence and clinical correlates of left ventricular geometric patterns and their relation to cardiac function in a sample of 213 obese African-American patients (mean age 14 years) compared to 130 normal-weight, age-matched counterparts, found that obesity, hypertension and concentric hypertrophy were independent predictors of diastolic dysfunction. The obese group had significantly higher left ventricular mass index, left atrium diameter and E/e′ ratio than the normal-weight group, whereas an opposite trend was noted for the E/A ratio. More in general, it has been shown that isolated obesity (i.e. without LVH, hypertension or type two diabetes mellitus) in young or middle-aged individuals is frequently associated with mild diastolic dysfunction [15]. Second, the results of the study by Millen et al., which show that neither waist circumference nor BMI were independently correlated to mild or moderate-to-severe diastolic dysfunction, cannot be regarded as an incontrovertible proof of a negligible impact of obesity on diastolic function in this general population. Indeed, waist circumference had an independent relationship with continuous variables of diastolic function such as E/A and E/e′ ratio. This finding points towards an association between central adiposity and left ventricular diastolic performance when diastolic indexes are expressed in a continuous way rather than using a dichotomous (and somewhat arbitrary) categorization. Third, recently developed echocardiographic techniques, such as three-dimensional echocardiography and speckle-tracking imaging, provide a more detailed insight into the left ventricular systolic and diastolic mechanics in all three spatial directions. It has been reported that the capability of these innovative techniques in detecting early left ventricular functional alterations is greater than that provided by conventional echocardiography and their use may allow to identify subtle mechanic left ventricular abnormalities even in patients with normal cardiac function as assessed by routine ultrasound examinations [16,17]. In obese patients, the likelihood of impaired left ventricular mechanics (longitudinal, circumferential and radial) is particularly high, due to a variety of adverse hemodynamic and nonhemodynamic factors impacting on myocardium [18,19]. Thus, data on prevalence and correlates of diastolic dysfunction in obesity based on traditional echocardiographic and Doppler parameters, including TDI, may substantially underestimate the real, adverse impact of this condition on the heart. Fourth, a novel information provided by Millen et al.[1] is that SBP clearly emerges as the most important factor associated with E/e' ratio (a validated index of left ventricular filling pressure) in a middle-aged general black African population with a high prevalence of obesity. As stated by the authors, a practical implication of this relevant observation is that an effective antihypertensive treatment may be sufficient to prevent the evolution from subclinical diastolic dysfunction to overt heart failure, independently from lifestyle measures aimed to achieve weight loss. The generalizability of this assumption is disputable. Prevalence rates of adequate BP control in hypertensive patients with persistent obesity are markedly lower than in their counterparts undergoing effective weight loss programs. Rapid weight loss induced by bariatric surgery exerts important cardio-protective effects in the morbid obese through LVH regression, improvement in left ventricular geometry and diastolic function, and reduction in left atrial size, irrespective of the pretreatment BP status and of the magnitude of the BP changes following bariatric procedures [20]. In summary, despite some intrinsic and perhaps unavoidable limitations, the report by Millen et al.[1] provides new data on the 'relative weight' of hemodynamic versus anthropometric variables in causing alterations in diastolic function observed in a general population. Further research (not so easy to be carried out, however) will be needed to confirm the results of the present study by investigating the relative impact of blood pressure and body weight-lowering intervention on the diastolic function. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

Unexplained Pulmonary Hypertension in Elderly Patients: Role of Heart Failure With Normal Ejection Fraction, Bernheim Effect, and Reverse Bernheim Effect

Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure

Addressing the sudden cardiac death conundrum in heart failure with preserved ejection fraction: do we need a microscope or a telescope?

<i>Circulation</i> Editors’ Picks

BackgroundDiabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF) are pathophysiologically linked and increasing in prevalence in Asian populations, but little is known about the interplay of DM and CKD on outcomes in HF. ObjectivesThis study sought to investigate outcomes in patients with heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF) in relation to the presence of DM and CKD. MethodsUsing the multinational ASIAN-HF registry, we investigated associations between DM only, CKD only, and DM+CKD with: 1) composite of 1-year mortality or HF hospitalization; and 2) Kansas City Cardiomyopathy Questionnaire scores, according to HF subtype. ResultsIn 5,239 patients with HF (74.6% HFrEF, 25.4% HFpEF; mean age 63 years; 29.1% female), 1,107 (21.1%) had DM only, 1,087 (20.7%) had CKD only, and 1,400 (26.7%) had DM+CKD. Compared with patients without DM nor CKD, DM+CKD was associated with 1-year all-cause mortality or HF hospitalization in HFrEF (adjusted HR: 2.07; 95% CI: 1.68-2.55) and HFpEF (HR: 2.37; 95% CI: 1.40-4.02). In HFrEF, DM only and CKD only were associated with 1-year all-cause mortality or HF hospitalization (both HRs: 1.43; 95% CI: 1.14-1.80), while in HFpEF, CKD only (HR: 2.54; 95% CI: 1.46-4.41) but not DM only (HR: 1.01; 95% CI: 0.52-1.95) was associated with increased risk (interaction P < 0.01). Adjusted Kansas City Cardiomyopathy Questionnaire scores were lower in patients with DM+CKD (HFrEF: mean 60.50, SEM 0.77, HFpEF: mean 70.10, SEM 1.06; P < 0.001) than with no DM or CKD (HFrEF: mean 66.00, SEM 0.65; and HFpEF: mean 75.80, SEM 0.99). ConclusionsCombined DM and CKD adversely effected outcomes independently of HF subtype, with CKD a consistent predictor of worse outcomes. Strategies to prevent and treat DM and CKD in HF are urgently required.

Obesity or excess visceral adiposity plays a fundamental role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), but it is not clear that an expanded adipose tissue mass contributes importantly to the evolution and progression of heart failure with reduced ejection fraction (HFrEF). Whereas central adiposity characterizes most patients with HFpEF, obesity was not a remarkable feature of HFrEF in the large-scale trials carried out in the 1980s and 1990s, and studies typically characterized obesity as a protective factor against adverse outcomes. In the general community without apparent heart disease, the finding of obesity or central adiposity precedes and predicts the subsequent occurrence of HFpEF, but not HFrEF. The mass of epicardial adipose tissue—an important source of cardioactive molecules—is expanded in HFpEF, but it is diminished in HFrEF, and the decrease has adverse prognostic significance. An increased waist-to-height ratio (a marker of excess abdominal adiposity) is more strongly associated with adverse heart failure outcomes in HFpEF than in HFrEF. Systemic inflammation [as reflected by elevations of high-sensitivity C-reactive protein (hsCRP)] in the general community presages the development of HFpEF, but not HFrEF, presumably because excess adiposity augments hsCRP in HFpEF, whereas increases in hsCRP in HFrEF may be related to coexisting atherosclerosis or clinical congestion. Whereas obesity is the principal determinant of serum levels of leptin and adiponectin in HFpEF, cardiac and neurohormonal signalling may drive circulating levels of these adipokines in HFrEF. Central obesity identifies patients more likely to respond to mineralocorticoid receptor antagonists in both HFpEF and in HFrEF, but this feature also identifies patients more likely to respond neprilysin inhibition or sodium-glucose cotransporter 2 inhibitors if they have HFpEF, but not HFrEF. Weight loss by incretin-based drugs lowers systolic blood pressure in patients with HFpEF, but potentially not with HFrEF, and such weight loss is accompanied by a reduced risk of worsening heart failure events in patients with HFpEF, but without a similar benefit in HFrEF. Taken collectively, these observations raise important questions about the potential role of obesity and visceral adiposity as contributing factors in the evolution and progression of HFrEF.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an often-overlooked form of heart failure with preserved ejection fraction (HFpEF). Previous studies have demonstrated that relatively high proportions of older patients with HFpEF have underlying ATTR-CM. However, while ATTR-CM should not be overlooked as a cause of HFpEF, it also should not be assumed that all patients with ATTR-CM present with HFpEF. Purpose To categorise patients with ATTR-CM from a large clinical trial by left ventricular ejection fraction (LVEF) at enrolment in order to describe the prevalence of HFpEF, HF with mildly reduced EF (HFmrEF), and HF with reduced EF (HFrEF). Methods The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled 441 patients with ATTR-CM, including both hereditary (ATTRv) and wild-type (ATTRwt) patients. In ATTR-ACT, all patients underwent echocardiography at enrolment using a standardised protocol, and all images were reviewed and analysed at an independent central laboratory. In this analysis of patient data at enrolment, all patients in ATTR-ACT were categorised by LVEF as: HFpEF (LVEF ≥50%), HFmrEF (LVEF 41–49%), or HFrEF (LVEF ≤40%). The proportions of patients in these LVEF categories in the sub-groups of race, sex, genotype, and disease severity (by NYHA class) were assessed, together with myocardial contraction fraction (MCF) in each category. Results In ATTR-ACT, there were 220 (50.5%) patients with HFpEF, 119 (27.3%) with HFmrEF, and 97 (22.3%) with HFrEF (Table). Five subjects with missing LVEF at enrolment were not categorized. Asian patients had the highest proportion with HFpEF, followed by White, then Black patients. The ATTRwt group had a higher proportion of patients with HFpEF than the ATTRv group. There were significant differences (as assessed by Chi-square test; P=0.0001) in the proportion of patients in each EF category between NYHA class I or II and NYHA class III patients. Median MCF was higher in NYHA class I/II (16.6%) than NYHA class III (14.8%) patients, and higher in patients with HFpEF compared with HFmrEF and HFrEF. Conclusions Not all patients with ATTR-CM have HFpEF. In this analysis of patients at enrolment in ATTR-ACT half had mildly reduced or reduced LVEF, with even higher proportions of reduced EF observed in Black patients, ATTRv patients, and patients with worse functional class (NYHA class III). These data demonstrate that ATTR-CM should be considered as a possible diagnosis in all patients with HF regardless of EF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer Table 1

Bezlotoxumab is used to prevent recurrent Clostridioides difficile infection. Although well tolerated, heart failure (HF) exacerbations have been reported as adverse events in clinical trials. This study evaluates the incidence and predictors of HF exacerbation following bezlotoxumab. We used the TriNetX research database to identify U.S. adults who received bezlotoxumab and stratified them into three groups based on HF history: no HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). The 90-day cumulative incidence of HF events and mortality were assessed. Cox proportional hazard models identified predictors of HF events. Among 2515 patients, 89% had no HF history, 4% had HFpEF, and 7% had HFrEF. The 90-day HF event rates were 1%, 29%, and 52% for the no HF, HFpEF, and HFrEF groups, respectively (p < 0.001). The 90-day all-cause mortality was 0.9%. Corresponding 90-day all-cause mortality rates were 0.04%, 4%, and 11%, respectively (p < 0.001). Independent positive predictors of HF events included HFrEF (aHR 19.400), HFpEF (adjusted hazard ratio [aHR] 8.632), heart transplant (aHR 7.485), hyperlipidemia (aHR 3.184), valvular heart disease (aHR 2.267), chronic kidney disease stage ≥ 3 (aHR 1.715), and ischemic heart disease (aHR 1.987). Protective factors included non-cardiac solid organ transplant (aHR 0.333). Bezlotoxumab appears safe in patients without HF history but is associated with a significantly increased risk of HF exacerbation in those with pre-existing HF, especially HFrEF.