Spotlight On Heart Failure Pathophysiology: Coronary Microvascular Dysfunction
Overview
In the comprehensive investigation of heart failure with preserved ejection fraction (HFpEF), a multitude of underlying mechanisms were explored, among which coronary microvascular dysfunction (CMD) emerged as a pivotal contributor to the pathophysiology. Through a rigorous systematic review and meta-analysis, the research aimed to elucidate the prevalence, echocardiographic associations, and prognostic ramifications of CMD within the HFpEF patient population.
Conducted across 14 observational studies encompassing a cohort of 1138 HFpEF patients, the analysis unveiled CMD as prevalent in slightly over half of the cases, marking a substantial presence within this clinical context. Notably, individuals afflicted with both HFpEF and CMD displayed distinct echocardiographic signatures, including enlarged left atrial volume index (LAVi) and elevated E/e′ ratio, indicative of more pronounced diastolic dysfunction.
Furthermore, the investigation unearthed a noteworthy correlation between CMD and atrial fibrillation (AF), with CMD-positive HFpEF patients exhibiting a heightened prevalence of this cardiac arrhythmia. This association underscores the intricate interplay between microvascular dysfunction and electrical disturbances within the cardiac milieu.
Of paramount clinical significance, the presence of CMD exerted a tangible impact on patient outcomes, with CMD-positive HFpEF individuals facing a significantly elevated risk of adverse events, encompassing both mortality and hospitalization due to heart failure. This heightened vulnerability underscores the prognostic implications of CMD within the HFpEF paradigm, necessitating tailored management strategies to mitigate associated risks and improve patient outcomes.
In summation, this comprehensive analysis underscores the multifaceted role of CMD in HFpEF, shedding light on its prevalence, echocardiographic correlates, and prognostic significance. By delineating these intricate relationships, the study advocates for heightened clinical awareness and targeted interventions aimed at ameliorating the impact of CMD on HFpEF patient outcomes.
Introduction
The global prevalence of heart failure (HF) is steadily increasing, primarily driven by the emergence of heart failure with preserved ejection fraction (HFpEF), which accounts for a substantial proportion of new HF cases, especially in individuals over 70 years old. HFpEF is characterized by the presence of signs and symptoms of HF despite a normal left ventricular ejection fraction (LVEF ≥50%), often resulting from elevated left ventricular (LV) filling pressure.
While treatment strategies have shown efficacy for other forms of HF, such as heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF), the therapeutic landscape for HFpEF remains challenging. Recent studies have indicated that only sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated positive outcomes for HFpEF patients. In contrast, trials involving neurohormonal antagonists have failed to show significant improvements in survival or reductions in HF hospitalization risk. This lack of efficacy may stem from the heterogeneous nature of HFpEF, which encompasses various underlying mechanisms, referred to as endotypes, each with distinct clinical manifestations and responses to treatment.
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Among these endotypes, coronary microvascular dysfunction (CMD) has garnered increasing attention as a key contributor to the pathophysiological features of HFpEF. However, understanding the relationship between CMD and structural alterations characteristic of HFpEF, such as left ventricular diastolic impairment, left ventricular mass, and left atrial dimension, remains limited. Furthermore, the prognostic significance of reduced coronary flow reserve (CFR) in HFpEF patients remains uncertain.
To address these knowledge gaps, a systematic review and meta-analysis were conducted to comprehensively evaluate the prevalence of CMD in HFpEF patients and its association with specific echocardiographic variables and clinical outcomes. This research aimed to provide valuable insights into the pathophysiology and management of HFpEF, ultimately guiding the development of more effective therapeutic approaches for this challenging condition.
Method
The meta-analysis was meticulously conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prior to commencement, the protocol was registered in the international prospective register of systematic reviews (PROSPERO CRD42022361360), ensuring transparency and rigor in the methodology.
To identify relevant studies, comprehensive searches were performed in PubMed, Scopus, and the Wiley online library up to May 1st, 2023, utilizing specific keywords such as ‘heart failure’, ‘preserved ejection fraction’, ‘HFpEF’, ‘microvascular dysfunction’, and ‘coronary microcirculation’. Additionally, the reference lists of relevant articles and reviews were screened for additional sources. The inclusion criteria were meticulously defined, encompassing studies reporting the prevalence of coronary microvascular dysfunction (CMD) in HFpEF patients and/or comparing HFpEF patients with and without CMD across various parameters, including echocardiographic variables, adverse clinical outcomes, and the prevalence of atrial fibrillation (AF). Exclusion criteria ensured the inclusion of only English-language studies with available full texts.
To ensure consistency and reliability, four investigators independently reviewed the titles, abstracts, and full texts of potential studies, resolving any conflicts through consensus.
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Data extraction was performed by two authors using a standardized worksheet, collecting essential information such as the author’s name, year of publication, study design, baseline demographic and clinical characteristics of the population, total follow-up time, CMD definition, and diagnostic methods.
The quality of included studies was assessed using a revised version of the Methodological Index for Non-Randomized Studies (MINORS) scale, ensuring the validity and reliability of the findings.
Coronary microvascular dysfunction (CMD) was defined primarily by a reduction in coronary flow reserve (CFR), with variations in thresholds across studies. Both structural and functional aspects of CMD were considered, including endothelial-independent and endothelial-dependent microvascular dysfunctions.
Prevalence analyses were conducted in multiple steps, encompassing various types of CMD and considering both invasive and non-invasive diagnostic methods. Echocardiographic variables, aligned with the current HFA-PEFF diagnostic score, were assessed to understand the impact of CMD on the phenotype of HFpEF patients. Clinical endpoints, including a composite of death and hospitalization due to heart failure, were analyzed to evaluate the prognostic significance of CMD. Additionally, the prevalence of atrial fibrillation (AF) was examined in HFpEF patients with and without CMD.
In summary, this meta-analysis employed rigorous methodology to comprehensively assess the prevalence and impact of coronary microvascular dysfunction in patients with heart failure and preserved ejection fraction, contributing valuable insights to the field of cardiovascular medicine.
Statistical Analysis
The prevalence of cardiovascular and metabolic disorders (CMD) was analyzed using rigorous statistical methods including random-effects modeling and sensitivity analysis. Wilson’s score was employed to calculate confidence intervals for individual studies, while prediction intervals were computed to assess variability across studies. Subgroup analyses and meta-regressions were conducted to explore sources of heterogeneity based on various factors such as age, sex, and medical history.
Echocardiographic variables were summarized using mean difference (MD) with 95% confidence intervals and two-sided P values, employing random-effect models to accommodate expected differences. Clinical endpoints, including time-to-event data for composite outcomes, were analyzed using hazard ratios (HRs) with 95% CI, estimated via Cox proportional hazard models. Odds ratios were calculated to analyze the prevalence of atrial fibrillation (AF) among different groups.
Heterogeneity was assessed using Q-statistics and the I2 index, with sensitivity analyses performed to evaluate the influence of individual studies. Potential publication bias was assessed using funnel plot visual examination and Egger’s test.
Statistical analyses were conducted using Stata 17, ensuring robust and comprehensive evaluation of the data.
Result
The analysis employed the MOOSE flowchart to systematically assess 14 studies, encompassing a total of 1138 patients, focusing on the prevalence and implications of coronary microvascular dysfunction (CMD) within the context of heart failure with preserved ejection fraction (HFpEF). The study revealed that 58% of patients exhibited some form of CMD, with hypertension being significantly associated with its prevalence. Moreover, when CMD was defined by impaired coronary flow reserve (CFR), the prevalence decreased to 51%, with variations observed depending on the method of estimation and the threshold utilized.
Echocardiographic assessments indicated that CMD patients had elevated left atrial volume index (LAVi) and E/e′ ratio compared to those without CMD. However, there was no significant difference in left ventricular mass index (LVMi) between the two groups.
Regarding clinical outcomes, patients with CMD-HFpEF demonstrated a notably higher incidence of the composite clinical endpoint, including death and hospitalization for heart failure, with a hazard ratio of 3.19. Additionally, they exhibited a higher likelihood of developing atrial fibrillation. Notably, the use of beta-blockers showed a significant negative correlation with adverse clinical outcomes, suggesting a potential therapeutic benefit in this patient population.
Conclusion
The study’s main findings suggest that in heart failure with preserved ejection fraction (HFpEF), about 51% of patients have impaired coronary flow reserve (CFR), which is associated with more severe diastolic impairment and a higher risk of atrial fibrillation (AF) development. Reduced CFR in HFpEF doubles the hazard of death or HF hospitalization compared to HFpEF patients with normal CFR. This impairment is linked to coronary microvascular dysfunction (CMD), primarily characterized by structural changes in microvessels, such as capillary rarefaction and fibrosis. CMD appears to play a crucial role in the pathophysiology of HFpEF, potentially resulting from inflammatory-mediated reduction of nitric oxide availability, microvascular structural changes, and diastolic dysfunction.
Echocardiographic variables indicating elevated left ventricular filling pressures, such as increased E/e’ ratio and left atrial volume index (LAVi), are associated with CMD-HFpEF. CMD-HFpEF also demonstrates a worse clinical prognosis compared to non-CMD HFpEF, with a higher risk of death or HF hospitalization. Systemic inflammation and CMD may represent targets for novel interventions in HFpEF.
However, the study has limitations, including reliance on observational studies, variability in CMD diagnosis criteria, and differences in HFpEF definitions across studies. Nonetheless, identifying CMD in HFpEF could help stratify patients for targeted treatments in future randomized controlled trials, potentially leading to more effective interventions for this subset of patients.
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