Pharmacological interventions to enhance exercise capacity in patients with heart failure

Abstract

Heart failure (HF) is characterized by unbalanced oxygen demand and supply and impaired exercise capacity, which substantially affects the quality of life and prognosis of patients with HF. Cardiac rehabilitation is an effective intervention for improving exercise intolerance in patients with cardiovascular diseases, including HF. However, cardiac rehabilitation is not always accessible to these patients because a restricted number of hospitals offer cardiac rehabilitation, and access to these hospitals is limited to those who require rehabilitation. Although pharmacological interventions may help improve exercise capacity in patients with HF, evidence for this intervention is scarce. This mini-review summarizes the available research on the effects of pharmacological therapies on improving exercise capacity.

Key Words: Heart failure; Exercise capacity; Pharmacological therapy; Rehabilitation; Mini-review

Core Tip: Heart failure (HF) affects quality of life and prognosis in patients with HF. Although cardiac rehabilitation is an effective intervention to improve exercise intolerance in patients with HF. Cardiac rehabilitation is not always accessible because of restricted access for those who need rehabilitation. Evidence on pharmacological interventions to improve exercise capacity in patients with HF is scarce. This mini-review summarizes available evidence on the effects of pharmacological therapy for HF on improving exercise capacity.

INTRODUCTION

Heart failure (HF) is accompanied by exercise intolerance owing to impaired cardiac function, limited pulmonary reserve, and comorbidities, such as anemia, diabetes mellitus, impaired kidney function, and frailty[1,2]. Regardless of the etiology of HF, dyspnea and fatigue are the leading limiting symptoms that may impair exercise capacity and quality of life. Exercise intolerance and impaired cardiac reserve in patients with HF may further limit exercise capacity and cause pulmonary congestion and systemic edema, thereby creating a continuous vicious cycle of decompensation, hospitalization for worsening HF, and exercise intolerance. Exercise intolerance occurs in patients with HF through impaired left ventricular contractility, reduced β-adrenergic responsiveness to workload, elevated systemic vascular resistance, and insufficient peripheral arterial vasodilator response to exercise[2,3].

Exercise capacity can be assessed both subjectively and objectively. Subjective assessment includes symptoms such as dyspnea on exertion and the patients perceived exertion (i.e., the Borg scale)[4]. Objective measurements include peak oxygen consumption or oxygen consumption at the anaerobic threshold, exercise duration, and metabolic equivalents obtained by exercise testing. The standard exercise testing to evaluate exercise capacity is cardiopulmonary exercise testing with respiratory gas analysis, and alternative methods are the 6-minute walking distance (6MWD) test and exercise stress tests using an ergometer or treadmill[5,6]. Multiple factors determine the peak oxygen consumption, which represents exercise capacity. As shown in the following equation: (1) Oxygen consumption = cardiac output multiplied by the oxygen content difference between arterial oxygen content and mixed venous oxygen content; (2) Cardiac output; (3) Pulmonary diffusing capacity; (4) Oxygen-carrying capacity of the blood; and (5) Skeletal muscle characteristics affect peak oxygen consumption[7].

Recent advances in medical therapy for HF have had a prognostic impact in patients with HF[8]. Specifically, the combination of sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors), angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), and beta-blockers are essential HF medications. Evidence for each drug has accumulated, and the international guidelines for HF management recommend the use of these drugs in patients with HF, especially those with reduced left ventricular ejection fraction (EF)[9,10].

Although extending longevity has been a major issue in medicine, ways of improving the quality of life should also be sought for patient satisfaction and healthy societies[11,12]. Several factors affect the quality of life, such as health literacy, socioeconomic status, multimorbidity, social support, and access to healthcare in patients with non-communicable diseases such as HF[13,14]. A vicious cycle of limited functional reserve, exercise intolerance, and impaired quality of life in patients with HF makes it difficult to intervene appropriately to combat deteriorating exercise capacity.

In the general population, exercise is the only established effective method to improve exercise tolerance and simultaneously yield beneficial effects in patients with HF[15,16]. Cardiac rehabilitation is available in some countries, including Japan, for patients with cardiovascular disease, including HF, but it is not widely available owing to limited access to cardiac rehabilitation facilities. Moreover, patients with HF may not necessarily be grateful to perform physical activities or exercises. Nutritional interventions and medical therapy may be alternative approaches for improving exercise tolerance. However, there is currently no drug of choice for this purpose. In this review, the literature and clinical studies on pharmacological approaches to improve exercise capacity in patients with HF are surveyed.

EFFECTS OF GUIDELINE-DIRECTED MEDICAL THERAPY ON EXERCISE CAPACITY

A summary of a systematic review and meta-analysis of guideline-directed medical therapy for HF in relation to exercise capacity in patients with HF is provided in Table 1[17-19].

Table 1 Summary results of systematic review and meta-analysis of guideline directed medical therapy for heart failure in relation to exercise capacity in individuals with heart failure.

Ref.	Agent used	Inclusion criteria	Number of clinical trials	Number of participants	Duration of follow-up	Outcomes	Results	Quality assessment tool
Gao et al[17], 2024	SGLT2i	RCTs published up to July 31, 2023	4	250	3-12 months	Peak VO2	Significant improvement for SGLT2i	The risk of bias 2 for the included RCTs
			7	1457	3-9 months	6MWD	Significant improvement
Fukuta et al[18], 2019	Mineralocorticoid receptor antagonist	RCTs published up to December 31, 2017	3	633	6-12 months	Peak VO2	No significant difference	The Jadad quality scale for the included RCTs
			4	594	6-12 months	6MWD	No significant difference
Bhattacharjee et al[19], 2023	Angiotensin receptor neprilysin inhibitor	RCT published from January 1, 2010 to January 1, 2023	1	52	12-24 weeks	Peak VO2	No significant difference	The risk of bias for the included RCTs and the Grading of Recommendations, Assessment, Development, and Evaluations framework for the quality of evidence for the primary outcome
			2	673	12-24 weeks	6MWD	No significant difference

RCT: Randomized controlled trial; SGLT2i: Sodium glucose co-transporter 2 inhibitor; VO₂: Peak oxygen consumption; 6MWD: 6-minute walking distance.

SGLT2 inhibitor

SGLT2 inhibitors reduce cardiovascular events such as incident cardiovascular death and HF hospitalization[20-22]. Because SGLT2 inhibitors promote urinary glucose excretion, sodium excretion, and water diuresis, they may reduce cardiac workload by decreasing the circulating plasma volume through diuresis, which can also reduce blood pressure and peripheral vascular resistance. The beneficial effects of SGLT2 inhibitors, other than diuresis, include increased cardiac energy production through increased cardiac ketone utilization, glucose oxidation, and fatty acid oxidation, which may be exerted by increasing the efficiency of energy utilization in the heart. SGLT2 inhibitors may improve exercise tolerance through cardiac energy utilization. A systematic review and meta-analysis of 17 studies, including 23523 patients with HF, reported that patients receiving SGLT2 inhibitors experienced significant increases in peak oxygen consumption compared to the control group[17]. In the meta-analysis, four studies included peak oxygen consumption as an outcome, and seven studies assessed the 6MWD. SGLT2 inhibitor therapy was associated with significant improvement in peak oxygen consumption [mean difference (MD): 1.61 mL/kg/minute; 95%CI: 0.59-2.63, P = 0.002] and 6MWD (MD: 13.09 m; 95%CI: 1.20-24.97, P = 0.03). This finding is of interest in that it shows that pharmacological therapy may improve exercise tolerance in patients with HF.

MRA

MRAs have both favorable prognostic and preventive effects on myocardial hypertrophy and fibrosis, which can cause left ventricular diastolic dysfunction[23,24]. The improvement in left ventricular diastolic function provided by MRAs potentially enhances exercise capacity in patients with HF. A meta-analysis of six clinical trials including 755 patients with HF with preserved left ventricular EF examined the effects of MRAs on left ventricular diastolic function, exercise capacity, and quality of life in HF with preserved EF[18]. In the meta-analysis, three trials reported the results on peak oxygen consumption, and four trials reported on the 6MWD. Although MRAs improve left ventricular diastolic function and decrease left ventricular mass, changes in exercise capacity assessed by peak oxygen consumption [weighted MD (WMD) (95%CI): 0.866 (-0.744 to 2.477), P = 0.29] and 6MWD also do not significantly differ between MRAs and the control group [WMD (95%CI): -11.9 (-26.2 to 2.26), P = 0.1].

ARNI

Clinical trials of ARNI have shown prognostic benefits in individuals with HF and reduced EF. The drug increases the left ventricular EF[25,26] and could potentially improve peripheral vasodilation and blood flow to the skeletal muscle through its inhibitory effect on neprilysin, which potentially improves exercise capacity in patients with HF. A systematic review of eight randomized clinical trials of ARNI in HF with reduced EF reported the results of descriptive analysis of exercise capacity, because the included trials had disparities in reporting the effects of ARNI on peak oxygen consumption and 6MWD[19]. The review reported that ARNI, compared to enalapril, did not improve exercise capacity, expressed as peak oxygen consumption or 6MWD.

Beta-blockers

Beta-blockers are essential HF medications with mortality benefits through the reduction in heart rate, systolic blood pressure, and myocardial contractility, resulting in a decrease in myocardial oxygen consumption, whereas the negative chronotropic effects of the agents can impair exercise tolerance. The withdrawal of beta-blockers is associated with an increase in peak oxygen consumption in patients with HF and a preserved EF[27,28]. A systematic review and meta-analysis of the effects of beta-blocker withdrawal on exercise capacity in patients with HF and preserved EF is ongoing[29].

Ivabradine

Ivabradine is a unique pharmacological agent that specifically reduces heart rate and potentially improves cardiac overload in patients with HF[30]. The findings on the effects of ivabradine treatment on exercise capacity in patients with HF are inconsistent. Although a meta-analysis of four randomized controlled trials shows that ivabradine did not significantly change exercise capacity expressed by peak oxygen consumption (three trials included the MD of 1.02 and the 95%CI of -2.51 to 4.56) and 6MWD (only one trial included the MD of -3.80 and the 95%CI of -22.03 to 14.43) in individuals with HF and preserved EF[31], the meta-analysis of six other randomized controlled trials and one subgroup analysis shows that addition of ivabradine to standard HF therapy increased exercise capacity measured by exercise duration (MD of 8.52 and the 95%CI of 0.09-16.94) in patients with HF and reduced EF, although the results were from two trials of the six trials[32]. The inconsistent results of the two meta-analyses can be explained by different populations with different types of HF (reduced or preserved left ventricular EF). The measurements of exercise capacity also differed between the two meta-analyses, which may have undermined the validity of the findings.

A NOVEL ANTI-DIABETIC AGENT THAT POTENTIALLY AFFECTS EXERCISE CAPACITY

A clinical trial focusing on the effect of imeglimin on exercise capacity is ongoing[33]. Imeglimin, a novel antidiabetic agent, lowers blood glucose by suppressing gluconeogenesis in the liver, increasing glucose utilization in skeletal muscles, and stimulating insulin secretion in pancreatic beta cells in a glucose concentration-dependent manner[34]. It is approved and marketed in Japan for the treatment of type 2 diabetes. Imeglimin reduces reactive oxygen species production via competitive inhibition of mitochondrial respiratory chain complex I and improves mitochondrial function by enhancing nitric oxide utilization. A previous study reported that imeglimin improved left ventricular diastolic dysfunction when administered for 90 days in a basic experiment using a mouse model of metabolic syndrome. Therefore, it is highly significant to conduct a placebo-controlled intervention study on the effect of imeglimin on exercise tolerance in patients with diabetic HF to improve their prognosis and quality of life. Given that imeglimin improves exercise capacity, basic research is required to verify the effects of the drug and its pathophysiological mechanisms.

CONCLUSION

This article summarized the available evidence on HF medications for the enhancement of exercise capacity and described other candidate drugs that may positively affect exercise capacity in patients with HF. An alternative approach to physical activity and exercise to improve exercise tolerance is desired for a subset of patients and the general population who are unwilling to engage in physical activity. However, I believe no approach is able to replace physical activity because it yields multi-dimensional effects from the prevention of both communicable and non-communicable diseases, reinforcement of physical activity levels, and beneficial psychological effects. Exercise-mimicking pills may function as part of the physical activity of the human body, and nutrition may work to build an ideal body composition and muscle strength. However, these approaches for enhancing exercise capacity work only in combination with exercise. Hopefully, pharmacological therapy, including available HF medications and exercise-mimicking drugs, can add color to the fundamentals of exercise and nutrition to improve quality of life and extend healthy longevity in the general population and patients with specific diseases, including HF, in a new era (Figure 1).

Figure 1  Pharmacological therapy may add color to fundamental of exercise and nutrition in order to improve quality of life and extend healthy longevity.