Advanced Therapies for Heart Failure with Preserved Ejection Fraction and Amyloidosis: The Role of Weight Loss and Genetic Interventions View PDF

HFpEF represents nearly 50% of all heart failure cases worldwide, making it a substantial burden on healthcare systems (Figure 1) [1]. The condition is particularly prevalent among individuals with obesity, which is considered one of the primary risk factors contributing to its development. Obesity drives a complex interplay of pathophysiological changes, including increased blood volume, heightened cardiac output, and systemic inflammation, all of which place additional stress on the heart’s diastolic function. These changes ultimately result in impaired left ventricular filling, elevated filling pressures, and reduced exercise tolerance, hallmark features of HFpEF [2, 3]. In addition to its cardiovascular effects, obesity is frequently accompanied by comorbid conditions such as hypertension, diabetes mellitus, and obstructive sleep apnea, which further exacerbate HFpEF symptoms and worsen long-term outcomes [4, 5]. 

The rising incidence of HFpEF aligns closely with the global obesity epidemic, which has seen rates triple since the 1970s [6]. As obesity rates continue to climb, particularly in aging populations, the prevalence of HFpEF is projected to increase, creating an urgent need for effective weight management strategies to mitigate its impact (Figure 2) [1]. Research suggests that intentional weight loss can alleviate many of the hemodynamic and metabolic abnormalities associated with obesity in HFpEF, thereby improving cardiac function and quality of life [7]. However, achieving sustainable weight loss in this population remains a challenge due to factors such as limited physical activity tolerance and the complex interplay of hormonal and metabolic dysregulation [8]. Despite these barriers, recent advances in lifestyle interventions, pharmacological therapies, and bariatric procedures offer promising avenues for addressing obesity and improving outcomes in HFpEF patients [9, 10]. 

Moreover, the link between obesity and HFpEF extends beyond mechanical and hemodynamic burdens to include systemic inflammation and adipose tissue dysfunction [11]. Obesity is associated with the release of pro-inflammatory cytokines and adipokines, which contribute to endothelial dysfunction, oxidative stress, and myocardial fibrosis-key pathophysiological processes in HFpEF [12, 13]. Excess visceral adiposity also promotes ectopic fat deposition around the heart, such as epicardial adipose tissue, which has been shown to directly impair myocardial function and exacerbate diastolic dysfunction [14, 15]. Furthermore, obesity-related metabolic abnormalities, such as insulin resistance and altered lipid metabolism, add another layer of complexity to the management of HFpEF [11]. These metabolic disturbances not only worsen cardiovascular outcomes but also reduce the efficacy of conventional heart failure therapies, emphasizing the need for targeted interventions. As such, addressing obesity through a combination of lifestyle changes, pharmacological treatments, and innovative approaches like anti-inflammatory therapies could play a pivotal role in alleviating the burden of HFpEF in this high-risk population [16].

The most effective weight loss treatments for patients with HFpEF in conjunction with gene editing therapies for cardiac amyloidosis involve a combination of lifestyle interventions and advanced gene therapy techniques [17]. The treatment of HFpEF in combination with gene editing for cardiac amyloidosis presents a multifaceted approach to managing complex cardiovascular conditions. HFpEF, often associated with obesity, is a prevalent form of heart failure with limited treatment options. Weight loss interventions have shown promise in improving outcomes for HFpEF patients, while gene editing offers potential therapeutic avenues for cardiac amyloidosis, a condition characterized by protein misfolding and deposition in the heart [17, 18]. Lifestyle interventions, particularly those focusing on diet and exercise, have shown significant benefits in reducing body weight and improving cardiovascular health in HFpEF patients [19]. Concurrently, gene editing therapies, such as CRISPR-Cas9, offer promising avenues for addressing the genetic underpinnings of cardiac amyloidosis, a condition often associated with HFpEF [20]. Table 1 summarizes the general information about the combination of weight loss treatment in patients with HFpEF and gene editing for the treatment of cardiac amyloidosis.

Weight loss and gene editing therapies have shown promising potential in impacting the progression of cardiac amyloidosis in patients with HFpEF. These interventions target different aspects of the disease, offering a multifaceted approach to treatment. Weight loss primarily addresses the metabolic and hemodynamic aspects of heart failure, while gene editing therapies focus on the molecular pathology of amyloidosis [21]. Together, they may provide synergistic benefits in managing cardiac amyloidosis in HFpEF patients.