A new article reports interim findings from the BioVAT-HF phase 1–2 clinical trial, which investigated a novel regenerative treatment for advanced heart failure using stem-cell-derived biologic ventricular assist tissue (BioVAT). The study addressed a major unmet need in cardiology: patients with heart failure and reduced left ventricular ejection fraction (HFrEF) often experience progressive deterioration despite guideline-directed medical therapy, while heart transplantation and mechanical assist devices remain available to only a limited number of patients worldwide.
The authors explain that the principal pathological feature of HFrEF is the large-scale loss of cardiomyocytes, with approximately one billion cells estimated to be lost in each patient with symptomatic disease. BioVAT was developed as a tissue-engineered strategy to restore damaged myocardium through cardiac remuscularisation. The BioVAT construct consists of engineered heart-muscle units made from cardiomyocytes and stromal cells derived from allogeneic induced pluripotent stem cells. These units are assembled into grafts and surgically transplanted onto the epicardial surface of the failing heart.
The study was conducted at two German medical centres and involved patients aged 18 to 80 years with symptomatic heart failure, a left ventricular ejection fraction of 35% or less, and resistance to standard medical therapy. Patients also had at least one hypokinetic or dyskinetic segment of the left ventricular wall. Most participants had severe disease, with New York Heart Association (NYHA) class III heart failure at enrolment. All patients were receiving extensive guideline-directed therapy, including beta-blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, sodium–glucose cotransporter 2 inhibitors, and implantable cardioverter-defibrillator or cardiac resynchronisation devices.
The trial was divided into two parts. Part A focused on dose finding and assessed BioVAT grafts containing 5, 10, or 20 engineered-heart-muscle units to determine the safe maximal dose. Part B aimed to evaluate proof of concept after a safe dose had been identified. The interim analysis was conducted after 16 patients had received the maximal safe dose and completed three months of follow-up.
The BioVAT grafts were surgically implanted through a minimally invasive left lateral thoracotomy. Individual engineered-heart-muscle units were attached to the heart using sutures and supported by a TachoSil membrane. All patients received immunosuppressive therapy beginning several days before surgery in order to prevent rejection of the allogeneic tissue.
The primary objectives of the study were to determine the safety of BioVAT transplantation and assess preliminary efficacy. Safety outcomes included adverse events, arrhythmias, and worsening heart failure. Efficacy was assessed by measuring changes in target heart-wall thickness, left ventricular ejection fraction, and patient-reported quality of life using the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score (KCCQ-OSS).
Twenty patients received BioVAT treatment. Two received the low dose, two received the intermediate dose, and sixteen received the maximal safe dose of 20 engineered-heart-muscle units. The patients had lived with heart failure for an average of 4.6 years before enrolment.
All treated patients experienced at least one adverse event, with 196 adverse events and 57 serious adverse events reported overall. The most common complications involved renal or urinary disorders, infections, and cardiac disorders. Three patients died during the study period. One death occurred shortly after surgery due to systemic inflammatory response syndrome with vasoplegia. A second patient died following cardiopulmonary decompensation associated with COVID-19 infection after immunosuppression had been discontinued. A third patient died from type A aortic dissection after episodes of ventricular tachycardia and subsequent intensive cardiovascular interventions. The investigators and safety monitoring board concluded that these deaths were not directly related to BioVAT transplantation.
Arrhythmias represented an important concern because previous preclinical studies had shown the possibility of engraftment-related ventricular tachycardia after cardiomyocyte transplantation. In this study, three patients experienced ventricular tachycardia after transplantation, although electrophysiological mapping suggested these events were unrelated to the BioVAT graft itself. No patients developed ventricular fibrillation following transplantation.
Immunosuppression also produced complications. In one patient, treatment had to be stopped because of worsening chronic kidney disease, after which donor-specific antibodies developed and cardiac function deteriorated. Another patient discontinued immunosuppression after being diagnosed with urothelial carcinoma and later died from the malignancy.
Despite these safety concerns, the interim efficacy findings were encouraging. Among patients treated with the maximal safe dose, the mean increase in target heart-wall thickness at three months was 4.5 mm. Left ventricular ejection fraction improved by an average of 3.9 percentage points, while KCCQ-OSS quality-of-life scores increased by 6.7 points. Statistical significance was achieved for all three primary efficacy endpoints according to the study’s predefined criteria.
Longer-term follow-up also suggested sustained benefits in some patients. At twelve months, several participants maintained increased heart-wall thickness and improved quality-of-life scores. Among patients with available long-term data, left ventricular ejection fraction improved by an average of 6.9 percentage points over a mean follow-up period of 17 months. Hospitalisations for heart failure were relatively limited, with three hospitalisations occurring in two patients who had received the maximal dose.
The authors interpret these findings as evidence supporting the feasibility of tissue-engineered heart repair in advanced heart failure. They propose that the transplanted cardiomyocytes may improve cardiac performance by increasing contractile tissue mass, thickening weakened ventricular walls, and reducing wall stress according to Laplace’s law. However, they acknowledge that successful remuscularisation may depend on factors such as the extent of myocardial scarring and the degree of graft integration and synchronisation with the host myocardium.
The investigators conclude that although all patients experienced adverse events, the observed improvements in cardiac structure, function, and quality of life justify further investigation of BioVAT therapy in larger and more definitive clinical trials.
Source: NEJM
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