Version July 2025
INTRODUCTION —
The treatment of heart failure (HF) is designed to prolong survival, reduce morbidity, slow the progression of disease, and improve symptoms [1]. While conclusive trials established the efficacy of many HF therapies, other plausibly effective therapies remain investigational due to inconclusive evidence.
Investigational therapies for HF are reviewed here.
Standard therapies for HF are discussed elsewhere:
●(See "Overview of the management of heart failure with reduced ejection fraction in adults".)
●(See "Treatment and prognosis of heart failure with preserved ejection fraction".)
DEVICE-BASED THERAPIES —
Two device-based therapies, baroreflex activation therapy (BAT) and cardiac contractility modulation (CCM), are approved by the US Food and Drug Administration (FDA) for use in patients with HF with reduced ejection fraction (HFrEF). Controlled clinical trials have demonstrated that both therapies are safe and lead to improvements in exercise capacity and quality of life, but neither has been shown to cause significant improvements in morbidity or mortality. Due to the lack of effect on morbidity or mortality, these devices have not been addressed in society guidelines. However, a scientific statement from the Heart Failure Society of America has suggested that consideration of these devices may follow the persistence of New York Heart Association (NYHA) II symptoms three to six months after initiation of pharmacologic guideline-directed medical therapy (GDMT), including cardiac resynchronization therapy (CRT) where applicable [2]. We believe it is important to optimize GDMT before embarking on additional therapies and, therefore, recommend that consideration of BAT or CCM be reserved for patients who have received optimal GDMT and CRT (where applicable) for at least four months.
Baroreflex activation/parasympathetic stimulation — In patients with HF, the decrease in parasympathetic nervous system (PNS) activity may contribute to the pathophysiology of HF [3]. One mechanism for increasing PNS activity is by vagus nerve stimulation, which activates the baroreflex, and is referred to as "baroreflex activation therapy" (BAT). Implantation of a baroreflex activation device is approved by the FDA, but there are no data to suggest that mortality or rehospitalization rates improve with such therapy.
Clinical trials of BAT have shown improvements in exercise (six-minute walk distance) and quality of life (Minnesota Living with Heart Failure Questionnaire) but not mortality or hospitalization. BeAT-HF (Baroreflex Activation Therapy for Heart Failure) randomized 408 patients with current or recent NYHA class III, ejection fraction ≤35 percent, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) <1600 pg/mL [4]. BAT had a low rate of complications and significant improvements in exercise (six-minute walk distance), quality of life, and NT-proBNP levels. This trial led to FDA approval for patients with HF who met the entry criteria for BeAT-HF. An extension of this trial showed no significant effect on cardiovascular mortality or HF morbidity, and a meta-analysis reported similar findings [5,6]. Another trial, ANTHEM-HFrEF, was prematurely discontinued after enrollment of 532 patients with HFrEF [7].
Cardiac contractility modulation — Cardiac contractility modulation (CCM) involves applying biphasic electric stimulation to the right ventricular septum during the absolute refractory period to induce a mild augmentation of left ventricular (LV) contraction [8]. The role of CCM is uncertain. CCM does not clearly improve long-term HF outcomes, may improve functional measures by a small amount, and is associated with a relatively high risk of serious complications of approximately 10 percent. CCM is approved for use by the FDA.
A randomized trial (FIX-HF-5C) enrolled 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and LV ejection fraction (LVEF) between 25 and 45 percent [9]. Overall survival and survival free of hospitalization were similar in the CCM and usual care groups. Combined data from FIX-HF-5C and FIX-HF-5 trials showed improvements in peak oxygen consumption (mean difference +0.84 mL/kg/min, 95% CI 0.12-1.55), NYHA class (improved at least one class 60 versus 35 percent in controls), and six-minute walk distance (28 versus 6 meters). There was a 10.3 percent rate of device- or procedure-related complications with CCM that included five lead dislodgements, one deep vein thrombosis, and one generator with pocket erosion. A meta-analysis found similar results [10].
There are several ongoing trials of CCM in patients with HF.
Enhanced external counterpulsation — Enhanced external counterpulsation (EECP) is a technique that increases arterial blood pressure and retrograde aortic blood flow during diastole (diastolic augmentation). EECP is applied by wrapping cuffs around the patient's legs and applying sequential air pressure (300 mmHg) from the lower legs to the thighs in early diastole, which propels blood back to the heart.
In patients with HF, EECP is an unproven therapy; there are only limited data from subgroup analyses of trials and registries that show variable effects on exercise tolerance.
As an example, the PEECH trial directly evaluated the possible benefit of EECP in 187 patients with mild to moderate HF [11]. Patients were randomly assigned to standard medical therapy with seven to eight weeks of EECP or standard medical therapy alone. Patients assigned to EECP were slightly more likely to increase their total exercise time by more than 60 seconds (35 versus 25 percent with standard medical therapy). However, EECP did not have any effect on peak oxygen consumption (VO2). Thus, this study did not achieve positive results for one of its two primary endpoints. In addition, the results of this single-blind trial are subject to the placebo effect. Further research will be necessary to define the impact of EECP in the treatment of HF. There are no ongoing trials of EECP in HF. Based on the currently available data, we do not recommend the use of EECP to treat HFrEF.
The use of EECP to treat angina is discussed elsewhere. (See "New therapies for angina pectoris", section on 'External counterpulsation'.)
STEM CELL THERAPY —
Cell therapy involves transfer of less-differentiated cells (eg, cardiac stem cells, skeletal myoblasts) to the myocardium to induce therapeutic myocardial regeneration and/or improvement in cardiac function. Preclinical studies in animal models have shown promise. However, the benefit of cell therapy in patients with HF is uncertain, and cell-based therapies for HF remain investigational [12,13].
●Theoretical basis – The most likely mechanism of benefit is a paracrine effect in which transplanted cells produce growth factors, cytokines, and other signaling molecules that may improve myocardial function via mechanisms such as increased myocardial perfusion due to angiogenesis or prolongation of the survival of myocytes or other cells [14,15]. It is unclear if cell therapies can incorporate into the myocardium and differentiate into functional myocardial tissue; some studies have demonstrated that hematopoietic stem cells do not transdifferentiate into cardiac myocytes [16,17], while autologous skeletal myoblasts can contract but do not transdifferentiate into cardiomyocytes [14,18]. Studies in animal models found that endogenous cardiac progenitor cells contribute minimal or no cardiomyocytes to the heart [19,20].
●Efficacy – Several clinical studies have investigated the efficacy of skeletal myoblasts, bone marrow mononuclear cells, bone marrow progenitor cells, mesenchymal stem cells, and cardiac stem cells to treat patients with chronic HF due to both ischemic and nonischemic cardiomyopathy [12,13]. A systematic review and meta-analysis evaluated 38 randomized controlled trials that included 1907 participants with chronic ischemic heart disease and HF and that compared autologous adult stem/progenitor cells with no stem/progenitor cells . The meta-analysis ultimately included nine trials with 491 participants and found low-quality evidence of mortality benefit at ≥12 months (risk ratio [RR] 0.42, 95% CI 0.21-0.87). Based on data from six trials with 375 participants, there was no significant reduction in the risk of hospitalization for HF (RR 0.63; 95% CI 0.36-1.09). Adverse events were infrequent, and no long-term adverse events were reported.
A meta-analysis of cell therapy for nonischemic dilated cardiomyopathy evaluated 11 randomized controlled trials with 574 subjects [21]. LVEF was increased both at <1 year and ≥1 year. However, there were no effects on major adverse events or measures of quality of life, and changes in six-minute walk distance were inconclusive.
●Safety – The delivery of cell therapies via cellular cardiomyoplasty (ie, direct injection or implantation of cells into the myocardium) raises concerns for safety, though data are limited. Three concerns are ventricular arrhythmias (particularly after myoblast injection), myocardial ischemia, and undesired cell differentiation (eg, intramyocardial bone formation or perivascular fibrosis). Meta-analyses have not shown issues with the safety of cell therapy for HF [22].
GENE THERAPY —
Gene therapy for HF is based upon advances in appropriate gene targets and in gene transfer technology, which include development of safe and efficient vectors and delivery methods [23,24]. Potential targets for gene therapy include cardiomyocyte calcium cycling (eg, through restoring activity of the sarcoplasmic reticulum calcium ATPase pump [SERCA2a] or improving S100A1 activity) and altering beta adrenergic system activity (eg, through inhibition of G-protein-couple receptor kinase 2 or improving adenylyl cyclase 6 activity).
Gene therapy for the treatment of systolic dysfunction of multiple causes is under investigation, but published studies have not established the clinical value of this approach. Gene therapy for specific diseases is discussed separately. (See "Cardiac amyloidosis: Treatment and prognosis", section on 'Disease-specific therapy for ATTR amyloidosis'.)
NUTRITIONAL SUPPLEMENTS
Hawthorn extract — Hawthorn extract is an herbal agent derived from species of the hawthorn plant (Crataegus monogyna or Crataegus laevigata). Proposed mechanisms of action include vasodilation, as well as antioxidant activity, inotropy, and lipid effects [25].
The efficacy of hawthorn extract in the treatment of HF is uncertain; randomized trials have yielded mixed results. Although a meta-analysis found that hawthorn extract produced symptomatic and functional benefit in patients with chronic HF, two subsequently published randomized trials in patients with HF with reduced ejection fraction (HFrEF) found no benefit. It is unclear whether the difference in results is related to differences in patient populations (eg, the meta-analysis was not limited to HFrEF while the two later trials were limited to patients with HFrEF), differences in treatment regimens, or the effect of chance.
●A meta-analysis included 10 randomized trials enrolling a total of 855 patients with chronic HF (New York Heart Association [NYHA] class I to III); most of the trials did not require systolic dysfunction [26]. Treatment with hawthorn was associated with greater exercise tolerance and maximal achieved workload as well as reductions in pressure-heart rate product and symptoms of dyspnea and fatigue. Dosing varied widely (160 to 1800 mg), and the trials did not report data on mortality or HF hospitalization.
●Two trials published after the meta-analysis found similar rates of death, hospitalization, and symptom improvement in the hawthorn and placebo groups:
•The SPICE trial randomly assigned 2681 patients with NYHA class II to III HF and LVEF ≤35 percent to hawthorn extract or placebo. No effect of hawthorn was observed on the primary outcome of time until first cardiac event (cardiac death, nonfatal myocardial infarction, and hospitalization due to progressive HF) [27]. Adverse events were comparable in the two groups.
•The HERB CHF trial randomly assigned 120 adults with NYHA class II to III chronic HF and LVEF ≤40 percent to hawthorn extract or placebo. There was no symptomatic or functional benefit from hawthorn extract compared with placebo at six-month follow-up [28]. Adverse events (most noncardiac) were significantly more frequent in the hawthorn group (60 versus 38 percent).
Coenzyme Q10 — Coenzyme Q10 is a vitamin-like, fat soluble quinone found in high concentrations in the mitochondria of the heart, liver, and kidney, where it is involved in electron and proton transfer during oxidative phosphorylation. It is also an antioxidant and free radical scavenger with membrane-stabilizing properties. Myocardial biopsies from patients with HF have demonstrated coenzyme Q10 depletion.
The role of coenzyme Q10 as a treatment for HF is unclear. The trials of coenzyme Q10 are small, subject to bias, and, in aggregate, suggest a wide range of efficacy that includes no effect:
●A systematic review and meta-analysis of randomized trials concluded that trials of coenzyme Q10 were subject to substantial bias and that there was an uncertain benefit of coenzyme Q10 when compared with placebo for the outcome of mortality (relative risk 0.68, 95% CI 0.45-1.03) and unclear or minimal effect on HF symptoms [29].
●One of the randomized trials included in the meta-analysis provided evidence of clinical benefit from coenzyme Q10. In the Q-SYMBIO trial, 420 patients with chronic NYHA functional class III or IV HF were randomly assigned to either coenzyme Q10 100 mg three times daily or placebo, in addition to standard therapy [30]. Patients assigned to coenzyme Q10 had lower rates of cardiovascular mortality (9 versus 16 percent), all-cause mortality (10 versus 18 percent), and incidence of hospitalization for HF at two years. In addition, NYHA class improved in the coenzyme Q10 group. The rates of adverse events were similar in the two treatment groups (13 and 19 percent).
Qiliqiangxin — Qiliqiangxin is a Chinese traditional medicine with multiple components [31]. While a randomized trial suggested a benefit with qiliqiangxin, the population treated was not fully treated with a modern regimen of HF medications. Until further data are available in the presence of such therapy, the role of qiliqiangxin is unclear.
In a trial of 3110 patients with HFrEF, N-terminal pro-B-type natriuretic peptide levels ≥450 pg/mL, and an LVEF ≤40 percent [31], patients randomized to qiliqiangxin capsules had a nonsignificantly lower rate of cardiovascular mortality (13.3 versus 16 percent; hazard ratio [HR] 0.83, 95% CI 0.68-1.00) and a lower rate of HF hospitalization (15.6 versus 19.2 percent; HR 0.76, 95% CI 0.64-0.90) compared with placebo [31]. However, the trial participants did not receive an optimal HF regimen, as only approximately 61 percent of patients were on triple therapy with a renin-angiotensin inhibitor, beta blocker, and mineralocorticoid receptor antagonist, and only approximately 8 percent were receiving a sodium-glucose co-transporter 2 inhibitor. The medicine was well tolerated with similar rates of adverse side effects compared with placebo.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults".)
SUMMARY
●Investigational therapies – The treatment of heart failure (HF) is designed to prolong survival, reduce morbidity, slow the progression of disease, and improve symptoms [1]. While the efficacy of many HF therapies has been established by conclusive trials, other plausibly effective therapies remain investigational due to inconclusive evidence.
This topic reviews the following investigational therapies:
•Parasympathetic simulation. (See 'Baroreflex activation/parasympathetic stimulation' above.)
•Cardiac contractility modulation (CCM). (See 'Cardiac contractility modulation' above.)
•Enhanced external counterpulsation (EEC). (See 'Enhanced external counterpulsation' above.)
•Stem cell therapies. (See 'Stem cell therapy' above.)
•Gene therapy. (See 'Gene therapy' above.)
•Nutritional supplements, including hawthorn extract and coenzyme Q10. (See 'Hawthorn extract' above and 'Coenzyme Q10' above and 'Qiliqiangxin' above.)
●Standard therapies for heart failure – Standard therapies for HF with reduced ejection fraction (HFrEF) and the management of HF with preserved ejection fraction are discussed elsewhere. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
