Atrial Fibrillation (AF) and Heart Failure With Preserved Ejection Fraction (HFpEF): Advances and Challenges

Figures

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  Figure 2. (A) Prevalence of atrial fibrillation (AF) in clinical trials and registries of subjects with heart failure with preserved ejection fraction (HFpEF). (B) Prevalence of HFpEF in clinical trials performed in AF populations.

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  Figure 3. Comorbidities potentially involved in the development of HFpEF. Iron deficiency, diabetes mellitus, obesity, renal failure, hypertension, and pulmonary hypertension increase the risk of HFpEF through structural and functional cardiac change and systemic inflammation (Reproduced with permission from [16]).

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  Figure 4. Outcomes of subjects without (no AF) and with atrial fibrillation (history of AF and AF on ECG at enrollment) in the TOPCAT trial (Reproduced with permission from [21]).

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  Figure 5. AF‐induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF induction by premature ectopic beats, conduction slowing, and moderate atrial fibrosis, whereas ventricular arrhythmia, that is, mimicked by rapid ventricular pacing, slightly increased vulnerability, slowed conduction, and induced moderate fibrosis without affecting repolarization/refractoriness. Combined atrial and ventricular arrhythmia‐abbreviated refractoriness strongly increased vulnerability and fibrosis and greatly increased AF stability as well as duration (Reproduced with permission from [31]).

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  Figure 6. Interrelationship between heart failure (HF) and atrial fibrillation (AF). Multifactorial and intricate interactions occur among structural changes, physiologic alterations, cardiac tissue remodeling, and circulatory and intracardiac hemodynamics, including left atrial pressure and left ventricular filling and performance. Structural disease due to comorbidities impacts both hemodynamics and substrate in the atrium and ventricle. Remodeling of the substrate and hemodynamic complications leads to the progression of both HF and AF.

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  Figure 7. Pathophysiology of HFpEF. HFpEF patients are older, mostly female, and exhibit a higher burden of noncardiac comorbidities, such as DM, obesity, hypertension, and renal dysfunction. These comorbidities lead to systemic inflammation, causing microvascular damage. This drives endothelial dysfunction, leading to reduced NO levels, higher infiltration of monocytes, and activation of cardiac resident macrophages, which express profibrotic factors TGF‐β, IFN‐γ, galectin‐3, and CTGF, leading to proliferation and activation of cardiac fibroblasts, promoting the deposition of ECM proteins and collagen. Endothelial dysfunction also impairs paracrine signaling of CMECs to cardiomyocytes. Cardiomyocyte remodeling is also evident from cardiomyocyte hypertrophy, altered calcium handling, increased energy consumption, and increased passive stiffness. Eventually, this leads to diastolic dysfunction and HFpEF. DM, diabetes mellitus; CRP, C‐reactive protein; CMEC, cardiac microvascular endothelial cell; CM, cardiomyocyte; ECM, extracellular matrix; NO, nitric oxide; HFpEF, heart failure with preserved ejection fraction (Reproduced with permission from [42]). Other abbreviations are in Figure 2.

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  Figure 8. Involvement of noncoding microRNAs in specific processes in HFpEF pathophysiology (Reproduced with permission from [42]). Abbreviations: miRNA = microRNA, lncRNA = long noncoding RNA, circRNA = circular RNA, ⊣, inhibition, →, activation.

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  Figure 9. Prevalent AF in HFpEF is associated with increased CV mortality. This incremental mortality is independently associated with a selective and disproportionate increase in pump failure deaths (A) rather than sudden deaths (B) and is also associated with worsening of symptomatic heart failure in earlier stages (C) and increased pump failure mortality in advanced heart failure (D).

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  Figure 10. (A) Mortality outcomes with rate and rhythm strategies in propensity score‐matched AFFIRM study populations. See text for details. Graph A = Time to death from cardiovascular cause. Graph B = Time to death from any cause. (B) HF emergence in AFFIRM propensity score‐matched population. Principal and secondary outcomes with rate and rhythm strategies in the study population. Graph A = Time to development of NYHA class II or greater HF or death from cardiovascular cause. Graph B = Time to development of NYHA class II or greater HF. Abbreviations are in Figure 2. (C) Impact of HF emergence on clinical outcomes. Time‐dependent impact of HF emergence on clinical outcomes in study population (Forrest plot). The x‐axis shows HR on the log scale. The y‐axis is the clinical outcome (Modified and reproduced with permission from [19]).

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  Figure 11. Secondary outcomes with rate and rhythm strategies in the study population. Time to development of NYHA class II or greater HF in each treatment strategy stratified by recorded AF frequency during follow‐up visits in the study population. Graph A = Rate control cohort. Graph B = Rhythm control cohort. Different strata of documented atrial fibrillation (AF) during follow‐up are shown (Reproduced with permission from [19]).

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  Figure 12. (A) Kaplan–Meier survival analysis for risk of worsening heart failure (defined as symptomatic HF progression from NYHA classes I/II to III/IV) (percentage: y‐axis) during follow‐up (years: x‐axis) in propensity score‐matched cohorts of TOPCAT Americas trial subjects with and without Any AF (left panel) and with and without AF on ECG (right panel). Subjects at risk and percentage with worsening heart failure are shown below the x‐axis of the graph at each time. (B) Kaplan–Meier survival analysis for risk of hospitalization due to heart failure (percentage: y‐axis) during follow‐up (years: x‐axis) in propensity score‐matched cohorts of subjects with and without any AF (left panel) and with and without AF on ECG (right panel). Subjects at risk and the percentage of hospitalizations due to heart failure are shown below the x‐axis of the graph at each time. ACA, aborted cardiac arrest; AF, atrial fibrillation; AF ECG, AF on ECG cohort; no AF ECG, no AF on ECG cohort; SCD, sudden cardiac death (Reproduced with permission from [54]).

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  Figure 13. The Corvia InterAtrial Shunt Device. Note the nitinol cage array to anchor the device and central opening or tunnel for controlled shunting of blood (Reproduced with permission from [71]).