Phase 1 Feasibility and Safety of Whole Heart Radiotherapy for End-stage Heart Failure: First In-human Treatments

HEART FAILURE Heart Failure (HF) is a heterogeneous syndrome manifested by vascular congestion and/or peripheral hypoperfusion in the setting of structural and/or functional cardiac abnormalities. Congestion commonly presents with dyspnea, reduced exercise tolerance, and edema while hypoperfusion results in end-organ dysfunction. HF is a major public health problem and because of its age-dependent increase in incidence and prevalence, it's one of the leading causes of death and hospitalization among the elderly. As a consequence of the worldwide increase in life expectancy, and due to improvements in the treatment of HF in recent years, the proportion of participants that reach an advanced phase of the disease, so-called ESHF, is steadily growing.

HF is characterized by impairment in cardiac structure and function which, in its advanced phases, results in decreased cardiac output (hypoperfusion) and/or fluid buildup (congestion). Initially cardiac output (CO) is maintained through the Frank-Starling mechanism with LV dilation and wall thickening. Eventually myocardial contractility declines and stroke volume (SV) decreases . A compensatory increase in heart rate (HR) may initially help maintain cardiac output, but this too will ultimately fail to preserve output. Currently, patients with HF are most often categorized as having heart failure with reduced (HFrEF; LVEF <40%), mid-range (HFmrEF; LVEF 40-49%) or preserved ejection fraction (HFpEF; LVEF ≥50%). The four classical hemodynamic profiles of heart failure can be categorized in a two-by-two matrix based on filling pressures (presence or absence of congestion) and perfusion status (adequate/inadequate). Furthermore, patients are classified by the New York Heart Association (NYHA) based on the presence or absence of symptoms during rest and physical activity (Figure 2). Patients with ESHF typically live in the NYHA Class III-IV and in a fine balance between the "wet and warm" (i.e. relatively preserved perfusion but congested) and "wet and cold" (i.e. low perfusion and congested) categories.

The two principal pathways mediating the pathophysiology of heart failure are the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). These systems are innately related, having the ability to further activate each other and ultimately resulting in a chronic state of increased effective circulating volume. Over time, myocardial alterations result in reduced responsiveness to these adaptive mechanisms, and thus a drop in cardiac output ensues. Not surprisingly the principal HF therapies target these pathways. The primary therapies have been comprised of the triad of ACE inhibitors (or angiotensin receptor blockers [ARB] if intolerant), beta-adrenoreceptor antagonists (beta-blockers), and mineralocorticoid receptor antagonists (MRAs) titrated to target doses. Unfortunately, in ESHF, medical optimization is often not tolerated because of worsening hypotension, hyperkalemia, and renal dysfunction. There is often a need to reduce the dose or eliminate these therapies which is a well-established marker of poor prognosis. Once diagnosed with ESHF focus turns towards defining the optimal therapeutic approach with options including orthotopic heart transplant (OHT), left ventricular assist device (LVAD) and/or palliation. Ultimately, a combination of these three strategies is often required.

Left ventricular ejection fraction (LVEF) is generally viewed as a clinically useful phenotypic marker indicative of underlying pathophysiological mechanisms and sensitivity to therapy.

End-stage heart failure (ESHF) manifests as severe and often relentless symptoms of dyspnea, fatigue, abdominal discomfort and ultimately cardiac cachexia with renal and hepatic dysfunction frequently further complicating the process. Recurrent hospitalizations, cardiac arrhythmias, and intolerance to standard HF therapies are common as the disease progresses. Management focuses on controlling symptoms, correcting precipitants, avoiding triggers, and improving quality-of-life (QOL).