Therapeutic perspective on cardiomyopathy and heart failure in older adults through the lens of chronic inflammation

Abstract

Cardiomyopathy is a disorder of the myocardium characterized by structural and functional abnormalities that result in impaired cardiac mechanical and/or electrical function. Aging induces a natural, gradual decline in cardiac structure and function (cardiac aging) that increases susceptibility to cardiomyopathy and exacerbates pre-existing cardiomyopathy. Despite ongoing research, the complex, multifactorial nature of this process substantially increases the risk of heart failure and remains a significant clinical and scientific challenge. With rising global life expectancy, effective pharmacological strategies are urgently needed. Here, we discuss chronic inflammation as a key driver of cardiomyopathy in older adults and explore perspectives on anti-inflammatory interventions that may slow disease progression and improve outcomes for the older population.

Although cardiomyopathy can present at any age, it is prevalent in older adults, highlighting aging as a major determinant of disease susceptibility. With advancing age, progressive decline in cardiovascular structure and function occurs, even in apparently healthy individuals, spanning a continuum from physiological adaptive remodeling to pathological dysfunction and constituting a key risk factor for cardiomyopathy. Aging-associated molecular damage further accelerates the progression of pre-existing cardiomyopathy. The integration of age-related cardiac remodeling and functional decline (cardiac aging) with cardiomyopathic processes culminates in aggravation of underlying cardiomyopathy, which markedly increases the risk of heart failure (HF) in older adults [1-4].

Despite extensive research efforts, cardiomyopathy in older adults continues to pose a significant challenge in both research and clinical practice due to its complexity and multifactorial nature.

Here, we discuss cardiomyopathy in the elderly through the lens of chronic inflammation, a hallmark of pathological cardiac aging. We also highlight the potential of key anti-inflammatory interventions, aiming to encourage further research and guide future directions in the treatment of cardiomyopathy and HF.

1. In older adults, cardiomyopathy is a significant risk factor for heart failure

A key perspective on cardiomyopathy in older adults is its strong causative association with HF regardless of a patient's ejection fraction (EF). HF is defined as a complex clinical syndrome in which the heart is unable to pump enough blood to meet the body's needs, and is characterized by severe clinical symptoms from pulmonary and peripheral edema, along with elevated plasma levels of natriuretic peptides [5]. Despite advancements in pharmacotherapy, advanced HF remains largely irreversible in the absence of heart transplantation or mechanical circulatory support [6].

In the older population, cardiomyopathy increases the risk in both HF with reduced EF (HFrEF) and preserved EF (HFpEF). Both conditions are increasingly prevalent with age, but HFpEF is particularly associated with older adults, especially with hypertension or diabetes, being more common in women, and exhibits distinct risk factors and outcomes [7]. HFpEF results from age-related structural changes, including increased left ventricular (LV) and left atrial (LA) stiffness, which leads to diastolic dysfunction.

Emerging evidence suggests overlapping features of cardiac aging and HF: 1) epidemiological evidence: Approximately one in four individuals is projected to develop HF in their lifetime [6]. 2) Shared pathophysiology: cardiac remodeling including hypertrophy, fibrosis, and amyloid deposition, increased myocardial stiffness, left atrial dilation, subclinical diastolic and systolic dysfunction, reduced cardiac reserve, and arrhythmias [8], also characterize HF. 3) Common molecular mechanisms: systemic inflammation, cellular senescence, dysregulated proteostasis, overactivation of the renin-angiotensin-aldosterone system (RAAS), as well as mitochondrial and endothelial dysfunction [8,9].

These overlapping features blur the distinction between normal and pathological cardiac aging, suggesting that therapeutic strategies targeting cardiac aging may also benefit HF and vice versa.

2. Chronic inflammation acts as a driver of cardiomyopathy in older adults

Aging is accompanied by a chronic, systemic, low-grade inflammatory state termed “inflammaging”, characterized by persistent activation of pro-inflammatory pathways and impaired anti-inflammatory responses. This state is characterized by elevated levels of circulating inflammatory mediators, including interleukin (IL)-1β, IL-6, TNF-α, and C-reactive protein.

Inflammaging directly contributes to myocardial dysfunction and structural remodeling and promotes HF, through mechanisms involving immune cell infiltration and activation of the systemic inflammatory cascade disorders [1,10]. It has been shown that aging hearts exhibit increased infiltration of pro-inflammatory M1 macrophages and T-cells. These immune cells disrupt homeostasis and contribute to adverse remodeling and diastolic dysfunction. Additionally, age-related dysbiosis alters microbial metabolites, which activate inflammatory cascades (e.g., caspase-1 activation and IL-1β/IL-18 secretion), thereby exacerbating myocardial inflammation and fibrosis.

Progression of cardiomyopathy to HF induces a state of sterile chronic inflammation when a cardiac mechanical stretch and impairment of systemic neurohormonal systems, particularly the RAAS, trigger the expression of inflammatory genes, including TNF-α, IL-6, IL-1β, and myostatin by cardiac myocytes and fibroblasts, contributing to cardiac and systemic inflammation, which promotes cardiac remodeling and dysfunction [11].

In addition to systemic inflammation driven by inflammaging, emerging evidence suggests that the intracellular inflammatory pathway within cardiac cells also plays a critical role in cardiac aging and contributes to cardiomyopathy in the elderly. Notably, two key mechanisms have garnered significant attention:

1. Senescence-Associated Secretory Phenotype (SASP): During cardiac aging and progression of cardiomyopathy in older adults, senescence occurs in key cardiac cell types, particularly cardiomyocytes and cardiac fibroblasts. These senescent cells adopt a SASP, characterized by the secretion of pro-inflammatory factors, including cytokines, chemokines, proteases, extracellular matrix components, and growth factors. This secretory profile promotes chronic inflammation, tissue remodeling, immune cell recruitment, and fibrosis, collectively contributing to impaired cardiac function [12]. The systemic RAAS significantly contributes to cardiac SASP by inducing and promoting senescence and inflammation in normal and pathological cardiac aging [9].

2. NLRP3 Inflammasome Activation: The NLRP3 inflammasome is a key component of the innate immune system, and its hyperactivation with age is closely linked to cardiac dysfunction. It can be triggered by mitochondrial dysfunction, reactive oxygen species, and damage-associated molecular patterns. Activation of the NLRP3 inflammasome in cardiomyocytes promotes the maturation of IL-1β and IL-18, contributing to a pro-inflammatory milieu within cardiac tissue. Conversely, inhibition of NLRP3 improves cardiac function and promotes longevity in animal models. These findings highlight the NLRP3 inflammasome as a potential therapeutic target in cardiomyopathy in older adults [13,14].

3. Perspectives on therapeutic strategies

Traditional therapies for cardiomyopathy and HF in the older population have primarily focused on symptom management and the treatment of comorbid conditions. However, current perspectives emphasize a more proactive, mechanistic approach aimed at targeting the root causes of cardiac aging combined with heart muscle pathologies [8,9].

Given the central role of inflammation in age-related cardiac dysfunction, anti-inflammatory therapies are emerging as a promising treatment strategy. In particular, advances in understanding the molecular pathways underlying systemic inflammaging and cardiac-cell-specific inflammatory mechanisms, such as SASP and NLRP3 inflammasome activation, have opened new possibilities for targeted treatment that have not yet been translated into clinical cardiology.

In parallel, insights into the hallmarks of cardiac aging have revealed novel therapeutic roles for existing drugs originally developed for other conditions. For example, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and colchicine have demonstrated significant anti-inflammatory effects and improved endothelial dysfunction, which contribute to their benefits in preclinical and clinical settings [15-17]. In addition, recent research has identified novel molecular targets, such as IGFBP7 and miR-34a, that may play critical roles in cardiac aging; however, their efficacy and safety require further validation in aging-specific models.

3.1. Traditional anti-inflammatory pharmacologic interventions

3.1.1. Pharmacologic strategies

Several drugs have been developed to target systemic inflammatory mediators. For example, Anakinra, an IL-1 receptor antagonist, has shown early clinical promise in HFpEF by improving exercise tolerance and reducing inflammation. Canakinumab, a monoclonal antibody targeting IL-1β, has been shown to reduce cardiovascular events in postmyocardial infarction patients and is currently being evaluated in aging-associated cardiovascular conditions. Although initial trials of TNF-α inhibitors, such as etanercept and infliximab, have not demonstrated a benefit in the treatment of HFrEF, these outcomes may stem from non-selective targeting and suboptimal patient selection. Future approaches focused on the precise mechanism of TNF-α may identify responsive subgroups among elderly patients with elevated TNF-α levels.

3.2. Repurposed drugs with anti-inflammatory effects

3.2.1. SGLT2i (e.g., empagliflozin, dapagliflozin)

Originally developed for glycemic control in type 2 diabetes, SGLT2i are now FDA-approved for HFrEF and HFpEF [15,16]. Clinical and preclinical studies demonstrate that in HF, SGLT2i reduce circulating biomarkers of chronic inflammation and cardiac transcripts expression of inflammatory cytokines, including TNF-α and IL-1β, suggesting that their anti-inflammatory effects contribute to their overall mechanism of action. In the context of cardiac aging, the clinical efficacy of SGLT2i may, in part, be attributed to their anti-inflammatory mechanisms, including the reduction of NLRP3 inflammasome activation, limitation of macrophage infiltration, and improvement of mitochondrial and endothelial function. Most recent multicenter clinical study demonstrated that SGLT2i are effective and safe for older adults with HF, reducing mortality and HF hospitalizations, despite age-related comorbidities [18].

3.2.2. Colchicine

Traditionally used in the treatment of gout and pericarditis, colchicine exerts anti-inflammatory effects by inhibiting microtubule polymerization and suppressing inflammasome activation. Colchicine is the first anti-inflammatory drug approved by the FDA for reducing cardiovascular risk. It is currently under clinical investigation for use in HF, where its potential to mitigate chronic inflammation could have therapeutic value [17]. Colchicine may directly reduce chronic inflammation in cardiomyopathy in older adults by disrupting microtubules, thereby impairing immune cell function, particularly neutrophils, and blocking their migration and activation. It also affects the NLRP3 inflammasome and the expression of inflammatory cytokines such as IL-1β and IL-18 by macrophages [19].

3.3. Anti-SASP therapy

Given the complexity of senescence signaling pathways, targeting either specific senescent cells or their secretory profile has emerged as a promising strategy to modulate age-associated inflammation, offering a safer and more refined alternative to global senolytic approaches.

3.3.1. Senolytic agents (e.g., dasatinib and quercetin)

These agents selectively eliminate senescent cells, resulting in reduced inflammation, myocardial fibrosis, and improved ventricular function in aged animal models [20].

3.3.2. JAK/STAT pathway inhibition

This pathway is a major regulator of SASP expression. Ruxolitinib, a JAK inhibitor, has shown efficacy in reducing systemic inflammation and may attenuate SASP-driven cardiac damage [21].

3.4. Non-pharmacologic strategies

Lifestyle interventions are also being extensively investigated for their anti-inflammatory and cardioprotective effects. Regular aerobic exercise has been shown to reduce systemic inflammation, enhance the expression of anti-inflammatory cytokines such as IL-10, reduce cardiac stiffness, and improve overall cardiac function [22,23]. Clinical and preclinical evidence support exercise as a targeted therapy for the age-related accumulation of senescent cells [24].

Anti-inflammatory diets, such as the Mediterranean diet, modulate inflammatory pathways through components like omega-3 fatty acids and polyphenols. Caloric restriction and intermittent fasting reduce oxidative stress and circulating levels of inflammatory cytokines, thereby conferring cardioprotective effects in preclinical models [25].

4. Challenges and future directions

Cardiac aging, accompanied or not by cardiomyopathy, is a complex, multifactorial process with profound implications for public health and age-related morbidity. Despite growing interest, several critical challenges remain:

4.1. Incomplete understanding

Human studies are often inconsistent, partly due to the difficulty in defining “normal” aging and assembling representative cohorts. Similarly, HF is a clinically heterogeneous syndrome, with evolving diagnostic criteria, especially for HFpEF, complicating both clinical and research efforts.

4.2. Context-specific effects

The effects of aging and the therapeutic efficacy are highly dependent on cell type, and individual variability (e.g., comorbidities, biological age). This underscores the need for context-specific and personalized therapeutic approaches.

4.3. Translational limitations

Research on normal and pathological cardiac aging using animal models has revealed several age-related cardiac changes that resemble those observed in humans. However, while there are notable similarities, differences must be acknowledged. The manifestations and progression of cardiomyopathy in older adults can vary across and within species [26,27]. Clinical trials must better reflect the biological and clinical complexity of aging populations.

Looking forward, multimodal strategies that combine senolytic agents, anti-cytokine therapies, and metabolic modulators, with or without conventional therapies, may offer synergistic benefits.

5. Conclusion

Understanding the molecular drivers and mechanisms of natural cardiac aging and their integration with pre-existing cardiomyopathy in older adults opens the door to mechanism-based, disease-modifying treatments. Therapeutic approaches that precisely target systemic and/or cardiac chronic inflammation may slow the progression of cardiomyopathy (Fig. 1), improving quality and duration of life. Future advancements will rely on early detection, risk assessment, and personalized, multi-targeted therapies.

Fig. 1.

Schematic summary of the proposed mechanisms by which chronic inflammation contributes to cardiomyopathy and heart failure (HF) in older adults and the potential therapeutic framework. The solid arrows represent a strong connection, and the dashed arrows represent an association with a higher risk or predisposition.

Data availability

No data was used for the research described in the article.