Microvascular Disease in Patients With Diabetes With Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction.

OBJECTIVEThis study examined the prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction (HFpEF).RESEARCH DESIGN AND METHODSThis analysis included 3,385 patients (mean age 69 ± 9.6 years; 49% male; 89% white) with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT). Diabetes and microvascular complications were ascertained by self-reported history and medical record review. Microvascular complications included neuropathy, nephropathy, and retinopathy. Outcomes included hospitalization, hospitalization for heart failure, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with diabetes and microvascular complications.RESULTSOf the 1,109 subjects (32%) with diabetes, 352 (32%) had at least one microvascular complication. Patients with diabetes and microvascular complications had an increased risk for hospitalization (no diabetes: referent; diabetes + no microvascular complication: hazard ratio [HR] 1.18, 95% CI 1.01, 1.37; diabetes + microvascular complications: HR 1.54, 95% CI 1.25, 1.89; P-trend <0.001), hospitalization for heart failure (no diabetes: referent; diabetes + no microvascular complication: HR 1.51, 95% CI 1.14, 1.99; diabetes + microvascular complications: HR 1.97, 95% CI 1.38, 2.80; P-trend <0.001), death (no diabetes: referent; diabetes + no microvascular complication: HR 1.35, 95% CI 1.04, 1.75; diabetes + microvascular complications: HR 1.73, 95% CI 1.22, 2.45; P-trend = 0.0017), and cardiovascular death (no diabetes: referent; diabetes + no microvascular complication: HR 1.34, 95% CI 0.96, 1.86; diabetes + microvascular complications: HR 1.70, 95% CI 1.09, 2.65; P-trend = 0.018). When the analysis was limited to participants who reported prior hospitalization for heart failure (n = 2,449), a higher risk of rehospitalization for heart failure was observed across diabetes categories (no diabetes: referent; diabetes + no microvascular complication: HR 1.40, 95% CI 1.01, 1.96; diabetes + microvascular complications: HR 1.78, 95% CI 1.18, 2.70; P-trend = 0.0036).CONCLUSIONSDiabetes is associated with adverse cardiovascular outcomes in HFpEF, and the inherent risk of adverse outcomes in HFpEF patients with diabetes varies by the presence of microvascular complications.

As described in Part I of this 2-part article,1 diastolic heart failure is common and causes significant alterations in prognosis. In Part II, experimental studies that have provided insight into the mechanisms that cause diastolic heart failure will be described.2–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ In addition, current treatment strategies and the design of future clinical trials of diastolic heart failure will be discussed. The development of truly effective therapy for diastolic heart failure depends on gaining a clear understanding of the basic mechanisms that alter diastolic function and the ability to efficiently target these mechanisms to correct these abnormalities in diastolic function. Conceptually, the mechanisms that cause abnormalities in diastolic function that lead to the development of diastolic heart failure can be divided into factors intrinsic to the myocardium itself (myocardial) and factors that are extrinsic to the myocardium (extramyocardial; Table 1). Myocardial factors can be divided into structures and processes within the cardiac muscle cell (cardiomyocyte), within the extracellular matrix (ECM) that surrounds the cardiac muscle cell, and that activate the autocrine or paracrine production of neurohormones. Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure. Myocardial and extramyocardial mechanisms, cellular and extracellular mechanisms, and neurohumoral activation each play a role in the development of diastolic heart failure caused by ischemia, pressure-overload hypertrophy, and restrictive and hypertrophic cardiomyopathy. View this table: Table 1105290. Diastolic Heart Failure: Mechanisms ### Cardiomyocyte Diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves. These include changes in calcium homeostasis caused by (1) abnormalities in the sarcolemmal channels responsible for short- and long-term extrusion of calcium from the cytosol, such as the sodium calcium exchanger and the calcium pump; (2) …

Treatment of Diabetes in People with Heart Failure

H eart 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. 2Despite 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 highpriority topic for research in cardiovascular disease. Article see p 550A 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, indepth, detailed examinations of tissues and organs in humans.In this issue of Circulation, Mohammed and colleagues 3 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 mellitus, obesity, and clinical coronary artery disease (CAD).

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

Do Existing Definitions Identify Subgroup Phenotypes or Reflect the Natural History of Heart Failure With Preserved Ejection Fraction?

Vascular Dysfunction in Heart Failure with Preserved Ejection Fraction

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he ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and&#13;\naccurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

The global epidemic of type 2 diabetes mellitus (T2DM) has substantial implications for cardiovascular disease–related morbidity and mortality.1 The prevalence of T2DM in patients with heart failure (HF) is high, with strong and independent association between T2DM and incident HF observed in multiple prospective studies and in randomized-controlled clinical trials. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which enrolled subject’s ≥55 years of age with hypertension and ≥1 risk factor, patients with T2DM had a 2-fold risk for HF hospitalization or death after adjustment for other risk factors (RR, 1.95). The association with T2DM was independent of coronary artery disease and at least equivalent in magnitude and greater than that for electrocardiographic left ventricular (LV) hypertrophy.2 All measures of glycemia including fasting, postprandial, measures of insulin resistance, and hemoglobin A1c (HbA1c) have been associated with risk of developing HF, with the association extending to both HF with preserved ejection fraction and to HF with reduced ejection fraction.3,4 A substantial body of evidence from preclinical studies, endomyocardial biopsies in humans and more recently with cardiac MRI, support increased myocardial stiffness in T2DM related to alteration in extracellular matrix. There are multiple proximate mediators that have been hypothesized to play a role including advanced glycation end product deposition and reactive oxygen species that may increase myocardial stiffness during diastole, by cross-linking collagen or by enhancing collagen formation.5,6 Another pernicious proximal mediator is the elevation in postprandial lipids, such as remnant lipoproteins, characteristic of atherogenic dyslipidemia, a highly prevalent abnormality in T2DM, that may result in direct myocellular deposition of lipid, leading to microcirculatory dysfunction, alteration in substrate use and mitochondrial dysfunction.7,8 Indeed, positron emission tomography studies show reduced myocardial glucose uptake in favor of fatty acid …

In contrast to systolic heart failure (SHF), for which knowledge of pathophysiology and therapy has advanced rapidly over the past decade, little is known about diastolic heart failure (DHF). The article by van Heerebeek et al1 in this issue of Circulation that describes an abnormal distribution of titin isoforms in DHF may herald a new approach to understanding the pathophysiology of this syndrome. Article p 1966 Recognition of 2 forms of heart failure is not new; almost 70 years ago, Fishberg2 described “those forms of cardiac insufficiency which are due to inadequate diastolic filling of the heart (hypodiastolic failure) [and] the far more common ones in which the heart fills adequately but does not empty to the normal extent (hyposystolic failure)” (p 23). This distinction has stood the test of time, because there is a growing consensus that these 2 clinical syndromes differ in epidemiology, demographics, and origin. Because DHF and SHF represent subgroups of patients with heart failure, they share many clinical features, notably the hemodynamic findings, but it is now clear that they are caused by different pathophysiological mechanisms. Hearts in SHF are characterized by eccentric hypertrophy, progressive left ventricular (LV) dilation, and abnormal LV systolic properties, whereas in DHF, the hearts generally exhibit concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function.3,4 In addition, cardiomyocyte size, shape, and molecular composition differ in these 2 syndromes. Diastolic dysfunction refers to mechanical and functional abnormalities present during relaxation and filling, whereas DHF refers to clinical syndromes in which patients with heart failure have little or no ventricular dilatation and significant, often dominant diastolic dysfunction. Diastolic dysfunction can be quantified with indices of LV pressure decline and filling. Abnormal pressure decline is characterized by decreased peak −dP/dt, prolonged isovolumic time constant (τ), and …

Coronary microvascular dysfunction in heart failure with preserved ejection fraction - adding new pieces to the jigsaw puzzle.

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Section 5: Management of Asymptomatic Patients with Reduced Left Ventricular Ejection Fraction