Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction: Pathophysiology, Assessment, Prevalence and Prognosis
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ABSTRACT:
SUBMITTER: Bilak J
PROVIDER: S-EPMC9274364 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart.
| S-EPMC6848263 | biostudies-literature
Project description:AimsTo date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population.Methods and resultsThis prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations).ConclusionsPROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.
| S-EPMC6927847 | biostudies-literature
Project description:Aims:Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown. Methods and results:Consecutive patients (n?=?201) undergoing evaluation for suspected coronary artery disease (CAD) with stress myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up (median 4.1?years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure. Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation (e') velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2, n?=?108) demonstrated linearly decreasing e' and increasing E/e' consistent with worsening diastolic function (P for trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired CFR (interaction P?=?0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunction (E/e'septal?>?15, adjusted OR 2.58, 95%CI 1.22-5.48) and composite cardiovascular outcomes or HFpEF hospitalization alone (adjusted HR 2.47, 95%CI 1.09-5.62). Patients with both impaired CFR and diastolic dysfunction demonstrated >five-fold increased risk of HFpEF hospitalization (P?<?0.001). Conclusion:In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.
| S-EPMC5939665 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and is commonly seen in the elderly and diabetic and hypertensive patients. Despite its rising prevalence, the pathophysiology of HFpEF is poorly understood and its optimal treatment remains undefined. Recent clinical studies indicate that coronary microvascular rarefaction (reduced myocardial capillary density) with reduced coronary flow reserve (CFR) is a major contributor to diastolic dysfunction in HFpEF patients. On a molecular level, endothelial cells (EC) are dependent on glycolysis for supporting their functions and vascular homeostasis. Sirtuin 3 (SIRT3) has a critical role in the regulation of endothelial glycolytic metabolism and thus affects angiogenesis. Disruption of SIRT3-mediated EC metabolism and impairment of angiogenesis may promote cardiomyocyte hypoxia and myocardial fibrosis, leading to diastolic dysfunction and HFpEF. This review summarizes current knowledge of SIRT3 in EC metabolism, coronary microvascular rarefaction and HFpEF.
| S-EPMC6403466 | biostudies-literature
Project description:Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.
| S-EPMC3056204 | biostudies-other
Project description:BackgroundIn women with evidence of ischemia and no obstructive coronary artery disease the underlying mechanism is most often attributed to coronary microvascular dysfunction. Higher rates of adverse cardiovascular events, specifically heart failure with preserved ejection fraction, are present in women with coronary microvascular dysfunction, leading to the hypothesis that coronary microvascular dysfunction may contribute to the progression of heart failure with preserved ejection fraction. A 55-year-old, Caucasian woman with a past medical history of chest pain and shortness of breath was referred to our tertiary care center and diagnosed as having coronary microvascular dysfunction by invasive coronary reactivity testing. After 10 years of follow-up care for coronary microvascular dysfunction, she presented to an emergency room in acute heart failure and was diagnosed as having heart failure with preserved ejection fraction.DiscussionThe current case report provides a specific example in support of existing studies that demonstrate that coronary microvascular dysfunction may be a precursor of heart failure with preserved ejection fraction. Further research is needed to establish causality and management.Trial registrationClinical Trial Registration: ClinicalTrials.gov Identifier: NCT02582021 .
| S-EPMC6501452 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.
| S-EPMC6414077 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and has no guideline-recommended therapy, related in part to a lack of mechanism. Traditionally, HFpEF was thought to be secondary to afterload overload due to systemic hypertension; however, accumulating evidence suggests that HFpEF continues to worsen despite adequate control of blood pressure. Emerging data support the suggestion that myocardial ischemia secondary to coronary microvascular dysfunction could be the new paradigm pathophysiology. Several prospective, observational cohort studies indicate that the outcomes of patients with microvascular dysfunction, after an interval of several years, are dominated by HFpEF hospitalizations. Further, the most prevalent clinical phenotype (eg older women with multiple comorbidities) of patients with HFpEF resembles those with coronary microvascular dysfunction, albeit older. In this review, we provide in-depth insight about this emerging HFpEF paradigm, discuss potential therapeutic implications of this pathophysiology, and summarize some important knowledge gaps.
| S-EPMC7722793 | biostudies-literature
Project description:Heart Failure (HF) is the most common cause of hospitalization in the Western societies. HF is a heterogeneous and complex syndrome that may result from any dysfunction of systolic or diastolic capacity. Abnormal diastolic left ventricular function with impaired relaxation and increased diastolic stiffness is characteristic of heart failure with preserved ejection fraction (HFpEF). HFpEF accounts for more than 50% of all cases of HF. The prevalence increases with age: from around 1% for those aged <55 years to >10% in those aged 70 years or over. Nearly 50% of HF patients have HFrEF and the other 50% have HFpEF/HFmrEF, mainly based on studies in hospitalized patients. The ESC Long-Term Registry, in the outpatient setting, reports that 60% have HFrEF, 24% have HFmrEF, and 16% have HFpEF. To some extent, more than 50% of HF patients are female. HFpEF is closely associated with co-morbidities, age, and gender. Epidemiological evidence suggests that HFpEF is highly represented in older obese women and proposed as 'obese female HFpEF phenotype'. While HFrEF phenotype is more a male phenotype. In addition, metabolic abnormalities and hemodynamic perturbations in obese HFpEF patients appear to have a greater impact in women then in men (Sorimachi et al., European J of Heart Fail, 2022, 22). To date, numerous clinical trials of HFpEF treatments have produced disappointing results. This outcome suggests that a "one size fits all" approach to HFpEF may be inappropriate and supports the use of tailored, personalized therapeutic strategies with specific treatments for distinct HFpEF phenotypes. The most important mediators of diastolic stiffness are the cardiomyocytes, endothelial cells, and extracellular matrix (ECM). The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of HFpEF pathologies. These signalling networks contribute to the development of the diseases. Inhibition and/or attenuation of these signalling networks also delays the onset of disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress and emphasize the nature of the contribution of most important cells to the development of HFpEF via increased inflammation and oxidative stress.
| S-EPMC9301384 | biostudies-literature
Project description:There is a paucity of data characterizing right ventricular performance in heart failure with preserved ejection fraction (HFpEF) using the gold standard of cardiovascular magnetic resonance imaging (CMR). We aimed to assess the proportion of right ventricular systolic dysfunction (RVD) in HFpEF and the relation to clinical outcomes. As part of a single-centre, prospective, observational study, 183 subjects (135 HFpEF, and 48 age- and sex-matched controls) underwent extensive characterization with CMR. transthoracic echocardiography, blood sampling and six-minute walk testing. Patients were followed for the composite endpoint of death or HF hospitalization. RVD (defined as right ventricular ejection fraction < 47%) controls was present in 19% of HFpEF. Patients with RVD presented more frequently with lower systolic blood pressure, atrial fibrillation, radiographic evidence of pulmonary congestion and raised cardiothoracic ratio and larger right ventricular volumes. During median follow-up of 1429 days, 47% (n = 64) of HFpEF subjects experienced the composite endpoint of death (n = 22) or HF hospitalization (n = 42). RVD was associated with an increased risk of composite events (Log-Rank p = 0.001). In multivariable Cox regression analysis, RVD was an independent predictor of adverse outcomes (adjusted Hazard Ratio [HR] 3.946, 95% CI 1.878-8.290, p = 0.0001) along with indexed extracellular volume (HR 1.742, CI 1.176-2.579, p = 0.006) and E/E' (HR 1.745, CI 1.230-2.477, p = 0.002). RVD as assessed by CMR is prevalent in nearly one-fifth of HFpEF patients and is independently associated with death and/or hospitalization with HF.The trial was registered retrospectively on ClinicalTrials.gov (Identifier: NCT03050593). The date of registration was February 06, 2017.
| S-EPMC7878207 | biostudies-literature