Heart Failure With Preserved Systolic Function Research Articles

Role of the vascular endothelial sodium channel activation in the genesis of pathologically increased cardiovascular stiffness.

Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se, this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females.

Aicar treatment reduces interstitial fibrosis in aging mice: Suppression of the inflammatory fibroblast

In 2030, elderly people will represent 20% of the United States population. Even now, chronic cardiac diseases, especially heart failure with preserved systolic function (HFpEF), are the most expensive DRGs for Medicare. Progressive interstitial fibrosis in the aging heart is well recognized as an important component of HFpEF. Our recent studies suggested an important pathophysiologic role for reduced TGF-β receptor 1 (TGFβR1) signaling in mesenchymal stem cells (MSCs) and their mesenchymal fibroblast progeny in the development of interstitial fibrosis.This report arises from our previous studies, which suggest that an inflammatory phenotype exists in these mesenchymal fibroblasts as a result of a reduced TGF-β-Smad-dependent pathway but upregulated farnesyltransferase (FTase)-Ras-Erk signaling. In this report we provide evidence for a therapeutic approach that downregulates Erk activation through an adenosine monophosphate-activated kinase (AMPK) pathway. Aging C57BL/6J mice were treated with AICAR (an AMPK activator) for a 30-day period. This treatment suppressed excessive monocyte chemoattractant protein-1 (MCP-1) generation, which diminished leukocyte infiltration and in consequence suppressed the formation of macrophage-derived myeloid fibroblasts. Interestingly, the number of mesenchymal fibroblasts was also reduced. In addition, we observed changes in extracellular matrix (ECM) deposition, specifically that collagen type I and the alternatively spliced variant of fibronectin (EDA) expressions were reduced. These data suggest that the upregulation of AMPK activity is a potential therapeutic approach to fibrosis in the aging heart.

The role of insulin resistance in patients with heart failure with preserved systolic function of the left ventricle

The serum levels of TNF-α, Gal-3 in patients with heart failure with preserved systolic function (HFPSF) with and without insulin resistance (IR) and type 2 diabetes mellitus (T2DM) and their relationship have been investigated. Seventy-two patients (39 males and 33 females; the average age is 62.1±9.2 years old) with HFPSF of ischemic genesis, EF LV > 45% with and without concomitant IR and T2DM were examined. The content of Gal-3, TNF-α and insulin were measured in the serum by ELISA according to the manufacturer’s instructions. The Homeostasis Model Assessment (HOMA) index was calculated as a measure of IR at fasting state (IR=fasting glucose . fasting insulin/22.5), after that the patients were divided into three groups: 30 patients with HFPSF and IR, 31 patients with HFPSF and T2DM and 11 patients with HFPSF and without T2DM and IR. Spearman’s correlation analysis and Kruskal-Wallis test were used. All statistical tests were 2-tailed, and p<0.05 was considered statistically significant. The results obtained showed that Gal-3, TNF-α and insulin levels in patients with HF and IR were significantly higher than in patients with HF without IP and T2DM and patients with HF and T2DM (p<0.05, p<0.05 and p<0.0001, respectively). The association between Gal-3 level and the ratio of transmitral flow peak velocities (E/A) (r = -0.272; p<0.05); the serum TNF-alpha levels (r = 0.610; p<0.001); insulin levels (r = 0.331; p<0.01); the value of HOMA index (r = 0.293; p<0.02) was found. Significant relationships of the serum Gal-3 and serum TNF-α levels in patients with HF and IR and patients with HF and T2DM was also revealed. The reliability of difference in the strength of relationship was searched. Analysis has shown that the strength of the serum level relationship of TNF-α and Gal-3 increases from patients with HF and IR (r = 0.520) to patients with HF and T2DM (r = 0.709) (prr<0.05).

Pathological ventricular remodeling: therapies: part 2 of 2.

ing morbidity and mortality in patients with systolic heart failure (HF). 3 However, in many instances, disease progression continues unabated. Whereas novel disease targets are continually being discovered, most innovative therapies do not demonstrate consistent efficacy in patients; indeed, many prove to be ineffective, even deleterious, before reaching phase III clinical trials. Here, we review therapeutic strategies targeting cellular pathways governing left ventricular remodeling in the 2 major types of HF, HF with reduced systolic function (HFrEF) and HF with preserved systolic function (HFpEF). In an accompanying article, we highlight recent advances in our understanding of mechanisms underlying pathological ventricular remodeling. 4 Advances in this field are conditioned by the highly heterogeneous nature of HF. Notably, within the 2 broad categories of HFrEF and HFpEF, a wide variety of disease types dictate pathogenesis. 5 In other words, HF, a syndrome defined on clinical terms, derives from numerous different diseases such as myocardial infarction, hypertension, cytokine or neuroendocrine dyscrasias, genetic disorders, and more. 5 It seems likely that the therapies that have emerged with efficacy are those targeting features that are shared among these disorders. As a corollary, it is conceivable that some of the therapies that have failed in clinical trials target relevant elements of pathogenesis that are not common to all. As personalized medicine emerges in the discipline of HF, we envision therapies tailored to the specifics of molecular and cellular pathogenesis.

Management of Heart Failure with Preserved and Impaired Systolic Function: The New Zealand Heart Failure Registry

Background: The incidence and management of heart failure with preserved systolic function (HFPSF) is unknown in New Zealand. We report our experience with the New Zealand Heart Failure Registry (NZHFR).

Caveat anicula! Beware of quiet little old ladies

To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD). A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital. Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival. Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912). Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

115 Diagnostic and management of patients with heart failure with preserved systolic function in hospital settings: a French observational cohort survey

Few data are available about real life and management of patients heart failure with preserved systolic function (HF-PSF). To describe patients, disease characteristics and treatment strategies implemented in HF-PSF patients hospitalized for confirmed acute HF with LVEF≥45%. An observational study was conducted in 68 hospital in France with 2 steps: (1) a registry part in patients hospitalized for confirmed acute HF for estimation of proportion of HF-PSF patients in the overall HF patients. (2) a detailed part with data collection of patients recently diagnosed for HF-PSF (LVEF ≥ 45% evaluated within 8 days following hospitalization date). 707 HF patients were enrolled in the registry with a proportion of 51% with HF-PSF. In detailed part 364 HF-PSF patients were selected, with a mean age of 79 years, 59%female, and a mean BMI 27.7kg/m. Main cardiovascular characteristics of HF-PSF patients were: atrial fibrillation (51%), coronary heart disease (32%), peripheral arterial disease (15%) and stroke (13%) as CV antecedents and hypertension (78%), obesity (45.5%) and diabetes (29%) as risk factors. Mean values were: blood pressure 133/86mmHg, HR 92beats/min, creatinine 13.8mg/l, haemoglobin 12.0g/dl. BNP was performed in 243 patients with a median value of 684 pg/ml and Nt-pro-BNP in 77 patients with a median value of 3999 pg/ml. Mean ejection fraction was 58±8%. Non CV co-morbidities were: renal failure(39%), COPD(20%), walking disorders (22%), depression(12%),cognitive disorders(8%)and cancers(5%). Treatment at discharge included: diur. (85%), ACE-i(57%), βB (56%), Ca antag (27%), ARB (20%), aldosterone blockers (13%), digoxin (16%), anticoagulants (52%), statins (48%), aspirin (32%) and amiodarone (28.5%). Much is not known about the epidemiology and management of HF-FSP in France but our study try to improve the knowledge on this disease with real life data even if until today there is no specific treatment.

Mortality and morbidity of newly diagnosed heart failure with preserved systolic function treated with β-blockers: A propensity-adjusted case–control populational study

The effect of treatment with β-blockers on the prognosis of patients newly diagnosed with heart failure with preserved systolic function (HF-PSF) is unknown. To analyze the relationship of commencing treatment with the β-blockers bisoprolol or carvedilol (CT-βB) with the mortality and the morbidity of newly diagnosed HF-PSF. Prospective propensity-adjusted cohort study over 5 years on 1085 adults diagnosed with HF-PSF for the first time, in an integrated university-based health organization in Spain. The independent relationship between CT-βB and mortality and morbidity was analyzed, stratifying patients for comorbidity, after a multivariable adjustment for potential confounders. The 378 patients (34.8%) who CT-βB were more frequently older women, with more cardiovascular comorbidity. Of the total patients 554 (51.0%) died, and 711 (65.5%) were hospitalized. Using an intent-to-treat approach, CT-βB was associated with a lower risk of mortality (all-cause: RR [CI 95%] 0.37 [0.21 to 0.50], and cardiovascular: 0.31 [0.18 to 0.45]), and a lower age- and sex-adjusted hospitalization rate (per 100 persons/year), 13.6 vs. 19.2, (P<0.001 in all cases), even after adjustment for the propensity to take β-blockers, or other medications, comorbidities, and other potential confounders. In this observational study, commencing treatment with the β-blockers bisoprolol or carvedilol is associated with a reduced mortality and morbidity of patients with newly diagnosed heart failure with preserved systolic function.

Prolonged Electrocardiogram QRS Duration Independently Predicts Long-Term Mortality in Patients Hospitalized for Heart Failure With Preserved Systolic Function

Background Prolonged electrocardiogram (ECG) QRS duration (≥120 ms) is a risk factor for death in systolic heart failure, but its effects in heart failure with preserved systolic function (HFPSF) have not been extensively studied. We hypothesized that prolonged ECG QRS duration would independently predict long-term mortality in hospitalized HFPSF patients. Methods and Results We analyzed 872 HFPSF patients (defined as left ventricular ejection fraction ≥50%) admitted to Michigan community hospitals between 2002 and 2004 and followed for a median of 660 days. We used Cox proportional hazards models to assess mortality hazard for prolonged QRS duration (≥120 ms) on the last available predischarge ECG, first on a univariable basis and then after multivariable adjustment for other known risk factors. Prolonged QRS duration increased univariable all-cause mortality (HR 1.71; 95% CI 1.33-2.19, P < .001) and after multivariable adjustment (HR 1.31; 95% CI 1.01-1.71, P = .04). The univariable effect size was larger in younger patients. In multivariable models, there was no significant interaction between prolonged QRS and age, hypertension, or coronary artery disease status. Conclusions Prolonged QRS duration (≥120 ms) on a predischarge ECG is an independent and consistent predictor of long-term mortality in hospitalized HFPSF patients.

Mortality and morbidity of non-systolic heart failure treated with angiotensin-converting enzyme inhibitors: A propensity-adjusted case–control study

BackgroundThe effect of treatment with angiotensin-converting enzyme inhibitors (ACEIs) on the prognosis of patients newly diagnosed with heart failure with preserved systolic function (HF-PSF) is unclear. We evaluate the relationship of commencing ACEI therapy (C-ACEI-T) with the morbidity and mortality of patients with HF-PSF. MethodsProspective propensity-adjusted cohort study over 5 years on 1120 adults diagnosed with HF-PSF for the first time, within an integrated health organization in Spain. We analyzed the independent relationship between C-ACEI-T and mortality, and morbidity, stratifying patients according to comorbidity, after a multivariable adjustment for potential confounders. ResultsThe 865 patients (77.2%) who C-ACEI-T were younger, with more cardiovascular comorbidity. During the median follow-up of 908.3 days (interquartile range 558.6–1302.0) 580 patients (51.8%) died, and 727 (64.9%) were hospitalized. Using an intention-to-treat analysis, C-ACEI-T was associated with a lower risk of all-cause (RR [CI 95%] 0.34 [0.23 to 0.46]), and cardiovascular (RR 0.28 [0.20 to 0.36]) mortality, and a lower age- and sex-adjusted rate of hospitalization (per 100 persons-year), 12.3 vs. 19.4, (P<0.001 in all cases), even after adjustment for the propensity to take ACEIs, or other medications, comorbidities, and other potential confounders. ConclusionIn this prospective observational study the establishment of ACEI therapy is associated with a reduced mortality and morbidity of patients with newly diagnosed non-systolic heart failure.

Myocardial Degradation and Left Bundle Branch Block Predict Conversion to Low Ejection Fraction in Heart Failure With Preserved Systolic Function

The authors prospectively investigated whether left bundle branch block (LBBB) and myocardial degradation as indicated by elevated troponin T (tnT) predict the phenomenon of systolic conversion to low ejection fraction (EF <or=40%) in patients with nonsignificant coronary disease and heart failure with preserved systolic function (HFPSF) (initial EF >40%). Thirty consecutive patients with HFPSF were included and followed over a 4-year interval. A follow-up EF assessment was performed in 25 patients. Six of 15 patients with tnT >or=0.01 ng/mL demonstrated systolic conversion to low EF on follow-up, while none of the 10 patients with tnT <0.01 ng/mL experienced this phenomenon (P=.03). Five of the 6 converters presented with LBBB, while only 1 of the 19 nonconverters had this abnormality (P=.0007). Four of the 6 converters had an initial EF >50%. Myocardial degradation and LBBB predicted systolic conversion in HFPSF patients with nonsignificant coronary disease.

Treatment of Heart Failure with Preserved Systolic Function in the Elderly

Heart failure with preserved systolic function (HF-PSF) may account for 50% or more of patients with heart failure, occurring more commonly in the elderly with comorbid conditions such as hypertension, diabetes, obesity and coronary artery disease. HF-PSF is associated with high morbidity and mortality. A recent study demonstrated that, although survival improved significantly over time among heart failure patients with reduced ejection fraction, there was no such trend toward improvement among patients with HF-PSF. There exists an urgent need to develop effective treatment strategies, specifically for patients with HF-PSF. Current therapeutic recommendations for HF-PSF are aimed at the symptomatic management as well as the treatment of concomitant comorbidities, including hypertension, atrial fibrillation and myocardial ischemia. In spite of two large, recent studies evaluating therapies for HF-PSF, no specific strategies have been proven to substantially benefit outcomes in patients with HF-PSF. This review evaluates the development of therapeutic strategies for HF-PSF and provides an overview of recently completed and currently ongoing clinical trials in patients with HF-PSF, as well as possible therapeutic targets for future study.

Comparison of B-type natriuretic peptide with left atrial enlargement by echocardiography for the diagnosis of new-onset congestive heart failure with a preserved left ventricular systolic function in the setting of longstanding hypertension

The present study attempted to determine the accuracy of B-type natriuretic peptide (BNP) compared with left atrial enlargement at echocardiography in the emergency diagnosis of new-onset heart failure with preserved systolic function (HFPSF) related to longstanding hypertension. The study comprised 57 patients in sinus rhythm hospitalized for acute dyspnea, 30 with hypertensive HFPSF and 27 with noncardiac cause. By stepwise logistic regression analysis, BNP provided independent and incremental diagnostic information over the score of Boston criteria. There was a trend toward superiority of this biomarker compared to the left atrial area index for the diagnosis of HFPSF. A BNP concentration > 142 pg/ml was 93% sensitive and 85% specific for the diagnosis of HFPSF in this clinical setting (area under the ROC curve of 0.91 [0.8–0.97], p < 0.001).

Prevalence and prognostic impact of bundle branch block in patients with heart failure: Evidence from the CHARM programme

Bundle branch block (BBB) is a powerful independent predictor of cardiovascular mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The prognostic implications in HF with preserved systolic function (HF-PSF) are less well understood. The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic HF to receive candesartan or placebo. The primary outcome comprised cardiovascular death or HF hospitalisation. The relative risk conveyed by BBB relative to a normal electrocardiogram was examined. The prevalence of BBB was significantly lower in patients with preserved compared with reduced systolic function (CHARM-Preserved 14.4%, Alternative 29.6%, Added 30.5%), p<0.0001. Overall, the adjusted hazard ratio for the primary outcome was 1.48 (95% confidence interval 1.22-1.78), p<0.0001, reflecting increased risk in patients with reduced LVEF (1.72 [1.28-2.31], p=0.0003). The apparently more modest risk among patients with HF-PSF was significant in unadjusted (1.80 [1.37-2.37], p<0.0001) but not adjusted analysis (1.16 [0.88-1.54], p=0.2897). However, no formal statistical difference was observed between the two cohorts, and interpretation is limited by the unknown prevalence of left and right BBB morphologies in each. Comparing BBB presence with absence yielded qualitatively similar results. The simple clinical finding of BBB is a powerful independent predictor of worse clinical outcomes in patients with HF and reduced LVEF. It is less frequent, with a more modest predictive effect, in patients with preserved systolic function.

246 An epidemiological and clinical study of heart failure with preserved systolic function (HF-PSF) in a developing country

246 An epidemiological and clinical study of heart failure with preserved systolic function (HF-PSF) in a developing country

Treatment of heart failure with preserved systolic function: a review of the evidence

The importance of heart failure with preserved systolic function (HF-PSF) has been increasingly recognised during the last decade. However, until recently there were no large, randomised, controlled clinical outcome trials in patients with this condition. Indeed, the best evidence of symptom improvement came from two very small studies with the rate-limiting calcium-channel blocker verapamil, in a total of fewer than 50 patients. The largest outcome trial was an ancillary study (with about 900 patients) of the Digitalis Investigators Group (DIG) trial, in which digoxin was reported to have a proportionately similar effect on morbidity to that seen in patients with reduced systolic function. Recently, the CHARM-Preserved study randomised over 3000 patients to placebo or candesartan. There was a trend to a reduction in cardiovascular death or hospitalisation for heart failure with candesartan (333 vs. 366 patients, unadjusted p = 0.118; co-variate adjusted p = 0.051), and clear reductions in the proportion of patients admitted (by 15% from 270 to 230 patients, p = 0.017) and the total number of hospital admissions for worsening heart failure (by 29% from 566 to 402 admissions, p = 0.014). Overall the results of the CHARM Programme showed that candesartan exerted a favourable effect across a broad spectrum of patients with heart failure, irrespective of left-ventricular function, co-morbidity, symptomatic class or concomitant treatment.