The potential for remote ischemic conditioning to improve outcomes in heart failure

Abstract

Heart failure is the end-stage of a variety of underlying cardiovascular diseases and carries a poor prognosis. The condition is caused by a complex interaction between many pathophysiological processes including ischemia, fibrosis, ventricular remodeling, abnormal neurohumoral balance and inflammation. While traditional pharmacological treatment of heart failure often targets only one pathophysiological mechanism, remote ischemic conditioning induces a multitude of cardioprotective effects. In particular, the anti-ischemic, anti-remodeling and anti-inflammatory properties of remote ischemic conditioning may be of relevance. We propose that remote ischemic conditioning may offer a novel strategy to improve outcomes in heart failure.

Keywords:

• chronic ischemic heart disease
• heart failure
• ischemia
• myocardial infarction
• remote ischemic conditioning

The global burden of heart failure is vast and worsening. An estimated 38 million people worldwide suffer from heart failure most frequently as a consequence of ischemic heart disease, although hypertension, cardiomyopathy, valvular heart disease, congenital heart disease and arrhythmias are also important contributors. While the incidence of acute coronary syndromes has decreased and the short-term prognosis has improved [1], the number of patients with chronic ischemic heart disease is growing globally. Combined with aging populations, increasing lifestyle-induced obesity, diabetes and hypertension, the result is a growing prevalence of chronic heart disease involving heart failure. Pharmacological and device treatments have improved survival and decreased morbidity among patients with heart failure with reduced ejection fraction. Still, treatment options for patients with heart failure and preserved ejection, constituting almost half of the patients, are limited and with questionable effects. Collectively, patients with heart failure have a poorer 5-year survival rate than patients with most types of cancer. The 30-day mortality risk among patients admitted to the hospital due to heart failure exceeds 10%, and the prognosis in low- and middle-income countries is even worse [2]. The expected growth of the elderly population is estimated to be paralleled by a significant increase (50% in the USA over the next 15 years) in the number patients diagnosed with heart failure every year. The grave prognosis and expected future surge in the incidence and prevalence call for a response and recently, Eugene Braunwald declared war on heart failure in The Lancet [3]. We would like to propose a supplementary strategy to fight and win this battle.

Heart failure is the end-stage of a variety of underlying cardiovascular diseases and is defined as impairment of the heart as a pump to support physiological circulation, leading to insufficient delivery of oxygen to the metabolizing tissues. The pathophysiological mechanisms behind heart failure are complex and heterogeneous, including hemodynamic overload, ischemia, fibrosis, ventricular remodeling, abnormal neurohumoral balance, inflammation, gene mutations, abnormal calcium cycling and augmented apoptosis, all acting in a complex interplay. The activation of neurohormonal and inflammatory compensatory mechanisms [4] leads to a vicious circle through adaptive metabolic and remodeling processes, eventually resulting in a progressive decline of cardiac function with significant morbidity and mortality [5]. Many of these mechanisms appear to be regulated by circulating small noncoding RNAs (micro-RNAs or miRs). Thus, modulation of miR signaling has become a major focus of pharmacological research [3] and may represent a way forward to improve individualized treatment.

Frequent diseases underlying heart failure may illustrate the interaction and the complexity of the disarray: ischemic heart disease is frequently accompanied by hypertension and may lead to myocardial infarction. Each constituent contributes to remodeling, fibrosis and inflammation, ultimately resulting in clinical manifestation such as congestive heart failure and arrhythmia. In addition to pharmacological therapy a novel therapeutic modality – remote ischemic conditioning (RIC) – appears to have the capability to modulate chronic and acute ischemia and its inherent components including inflammation and remodeling. RIC may be used as an acute as well as a chronic repetitive therapy and possesses the potential to modify the natural course of heart failure.

Ischemia is the most frequent cause of heart failure; either through acute coronary syndromes or by chronic myocardial ischemia causing impaired myocardial function that may commence as reversibly reduced contractile function (stunning or hibernation) but eventually progresses into persistent injury and loss of function due to scar tissue with fibrosis and thinning. Coronary heart disease is often accompanied by endothelial dysfunction, which also compromises myocardial perfusion and reduces cardiac function. While targeting ischemia by revascularization and pharmacological approaches improves myocardial perfusion and function, many patients with ischemic heart disease are left with myocardial territories not amenable to revascularization and not effectively treated with pharmacological therapy. Whether described as small-vessel disease or subclinical ischemia, these patients frequently suffer from impaired ventricular function.

Hypertension induces myocardial hypertrophy, accelerated coronary atherosclerosis, remodeling, inflammation and fibrosis, all leading to impaired systolic and diastolic function of the left ventricle.

Inflammation in heart failure is considered a marker. While elevated CRP levels (particularly in high-sensitive CRP assays) are associated with manifest or developing heart failure, TNF-α and IL-6 appear to be actively involved in processes leading to fibrosis and increased apoptosis. A number of more recently identified molecules, including copeptin, natriuretic peptides and adrenomedullin, are also increased in patients with heart failure, and their levels reflect the severity of the condition. Successful pharmacological treatment of heart failure is mirrored by normalization of inflammatory markers.

Despite the fact that activation of the inflammatory system contributes significantly to the remodeling process through initiation of myocardial fibrosis and hypertrophy, most clinical studies targeting inflammatory components with, for example, TNF-α antagonists or glucocorticoids have been discouraging [4]. This might indicate that inflammation itself is not a dominant cause of heart failure. However, many statins and anticongestive compounds frequently used in this patients group have intrinsic anti-inflammatory effects that may blur the effect of on-top specific immunomodulatory treatment. Furthermore, the majority of investigated drugs target single pathways in a complex inflammatory condition.

Remote ischemic conditioning (RIC) by brief non-lethal episodes of ischemia in a remote organ or tissue (e.g., a limb) has recently emerged as a novel therapeutic method to achieve protection against ischemia-reperfusion injury in the target organ, for example, the heart [6]. In the clinical setting, RIC is most often performed by repeated episodes of limb ischemia achieved by intermittent inflation of a blood pressure cuff placed around the upper arm. In clinical randomized trials, RIC has been shown to reduce myocardial injury and improve long-term outcome in patients admitted with STEMI for primary percutaneous coronary intervention [7] and patients undergoing elective coronary intervention [8]. It deserves mentioning, however, that the translation of RIC to clinical use has yielded ambiguous results. While the use of RIC in acute ischemic events largely shown beneficial effect, the benefit of RIC treatment prior to cardiovascular surgery is controversial, which may be due to interaction with comorbidities and comedications [9].

Interestingly, RIC shares physiologic properties with vigorous exercise. In a study performed on young healthy volunteers, dialyzed blood from RIC-treated individuals protected isolated rabbit hearts against ischemia-reperfusion injury to a similar degree as dialyzed from the same individuals after intensive exercise [10]. Moreover, RIC has been shown to improve maximal performance in highly trained athletes [11].

The mechanisms underlying RIC are not yet completely understood, but increasing evidence indicates that RIC triggers complex humoral and neuronal signaling cascades leading not only to a cytoprotective state with improved resistance to ischemia-reperfusion injury in most organs but also to anti-inflammatory effects and endothelial protection [12]. Humoral signaling depends on the activation of the reperfusion injury salvage kinase (RISK) and survival activating factor enhancement (SAFE) pathways. Humoral protection by not yet identified factors is cross-species transferable and seems to activate same protective signal transduction pathways as local ischemic postconditioning [13]. Furthermore, recent evidence suggests that the protective effects are regulated by miRs [14], and several miRs have been identified as important triggers effectuating the cardioprotection afforded by RIC.

Chronic RIC treatment

The majority of experimental and clinical studies have used RIC as single-occasion treatment (i.e., three or four bouts of short limb ischemia conducted once). Recent experimental studies, however, suggest that repeated RIC treatment may infer further benficial effects.

In a rat model of myocardial infarction, RIC repeated daily for 28 days after infarction reduced adverse ventricular remodeling and improved survival [15]. These findings were recently supported by another rat study showing similar beneficial effect even when RIC treatment was not commenced before 4 weeks after myocardial infarction [16]. In humans, repeated RIC modifies human inflammatory response and leukocyte adhesion [17] and improves coronary microcirculation in healthy volunteers and patients with heart failure [18–20].

Of note, acute ischemia per se seems not a prerequisite for eliciting the cardioprotective response. A RIC analog in the heart, intermittent coronary sinus occlusion, shares organ protective effects with low-intensity occlusion-based resistance exercise by adding a low occlusion pressure stimulus to an exercising limb and is referred to as blood-flow-restricted exercise. This alternative conditioning modality seems capable of mobilizing endogenous protective mechanisms resembling RIC by yet unidentified similar mechanisms, which may include muscle stem cells, secretion of cytokines or growth factors, and, not least, miRNA delivered to remote locations by exosome transport. The potential of adding long-term benefits by RIC or blood-flow-restricted exercise in patients with heart failure is not yet known.

Perspective

The novelty and possible advantage of RIC compared with conventional treatment of heart failure lies in the multiple pathways and systems activated by RIC. The observations that RIC induces cytoprotection, improves endothelial function and microcirculation and modifies inflammation – all three key players in the pathology behind heart failure – suggest a potentially powerful tool to simultaneously counteract detrimental biological processes involved in the development of heart failure. Moreover, RIC increases plasma levels miRs that seem to act as triggers cardioprotection.

The effect of RIC on heart failure in humans is unknown, but animal studies strongly suggest beneficial effect of repeated RIC, which seems to reduce adverse remodeling. The combination of antiremodeling and anti-inflammatory properties, and improved endothelial function from repetitive RIC treatment, may translate into improved left ventricular function and better physical performance in patients suffering from heart failure. Currently, two ongoing clinical trials (clinicaltrials.gov: DREAM study [21] and CRIC-RCT study [22]) are investigating the effect of repeated RIC on ventricular function in patients with reduced ventricular function after an acute coronary event. Another recently launched trial is investigating the effect of repeated RIC as add-on treatment to the standard anticongestive treatment in patients with chronic heart failure (CONDI-HF, NCT02248441). Changes in ejection fraction or end-diastolic volume are used as primary outcome measures. If these trials yield beneficial results, larger clinical studies with hard clinical endpoints are warranted. Furthermore, RIC may also prove beneficial in patients with heart failure with preserved ejection fraction, which remains to be investigated.

Financial & competing interests disclosure

HE Botker and MR Schmidt are shareholders in CellAegis Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.