A mechanical bridge-to-recovery as a bridge-to-discovery: learning from few and applying to many

The unprecedented medical and public health burden of heart failure (HF) combined with the scientific bravado to defy biological limits, has spurred interest in clinicians and scientists to restore the function of a failing heart. Long-lasting conventional wisdom that chronic HF is unidirectional and progressive inevitably leading to end-stage disease, has been challenged by both spontaneous and facilitated cardiac function improvement in a variety of clinical scenarios. Stress-induced cardiomyopathy and chronic advanced HF with left ventricular assist devices (LVAD) ¹ are examples of myocardial recovery that provide unique opportunities to consider both the forward and reverse remodeling processes, as they relate to myocardial remission and recovery.

LVAD-mediated recovery offers access to human tissue, providing an unparalleled opportunity to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures ^{2, 3}. But how can we capitalize on this concept? Herein, we highlight the importance of understanding this unique phenomenon to provide insights into more common conditions directly related to broader patient populations. The impact of the innovations emerging from the mechanical circulatory support (MCS) recovery field in the advanced HF population can be conceptualized as the “tip of the iceberg”, that is providing via follow-up investigational steps critical insights into the broader HF field, i.e., the “main body of the iceberg” (Figure).

Figure. Learning from few and applying to many: extrapolating the lessons learned from the VAD patients to the broader HF population.

Implementation of clinical studies promoting ventricular assist device (VAD)-mediated cardiac recovery and translational and basic science studies leveraging human tissue to unveil mechanistic pathways involved in such response ^{2, 3}, will pave the way for future successes in this field. Human cardiac tissue findings in heart failure (HF) patients with VADs indicated that myocardial mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) may play a pivotal role in heart failure and reverse cardiac remodeling ⁴. Following a similar approach and guided by myocardial tissue findings in LVAD-supported patients and in non-failing donors, VDAC2 (voltage-dependent anion channel 2), and the VDAC2 agonist efsevin, were also identified as novel HF therapeutic targets ⁵. In both examples, hypothesis-generating findings emerged from human myocardial tissue and were further investigated in the laboratory using a variety of knockout, inhibition and overexpression strategies in vitro and in vivo to discover the underlying mechanism, and identify plausible therapeutic targets. This line of research emulates previous successful investigational settings, such as the study of the lipid clearance role of the low-density lipoprotein receptors in familial hypercholesterolemia, which opened the door to further translational research, leading to the advent of statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, impacting the broader preventive cardiology field. In these examples, the innovative insights and knowledge were extrapolated from a well-controlled, tractable, and well-studied sub-population to larger patient populations. In a similar fashion, the ongoing clinical and translational research to improve our understanding of myocardial recovery and resilience in VAD patients could be transformational for the greater HF population.

VAD: Ventricular assist device; HF: Heart failure; Mitochondrial pyruvate carrier (MPC); Monocarboxylate transporter 4 (MCT4); Voltage-dependent anion channel 2 (VDAC2); Proprotein convertase subtilisin/kexin type 9 (PCSK9)

Despite advances in the pharmacologic and device-based treatments for HF with reduced ejection fraction, the disease often progresses to end-stage with persistence of symptoms. In this context, LVADs have provided a viable and valuable option for select patients, particularly since heart transplantation is limited by organ availability. The fortuitous observation of significant myocardial improvement during LVAD support, occasionally leading to successful device weaning, opened up new horizons where a LVAD could serve as potential bridge-to-recovery (BTR). Such a strategy has practical benefits including primarily the avoidance of transplantation. This facilitates the precious organ allocation to those without alternative definitive options, and minimizes the time-dependent risks of life-threatening complications of prolonged LVAD support without sacrificing survival relative to a bridge-to-transplant or destination therapy approach ^1–3. The expansion of the field is currently limited by the lack of protocolized post-implant pharmacologic management, cardiac monitoring surveillance and the uncertainty regarding the sustainability of the favorable myocardial response. Importantly, an established clinical and/or biological signature synonymous to sustained recovery (or remission from HF events) is currently lacking ³.

Multiple BTR studies have confirmed that patients with recovery potential (i.e. “responders”) are more likely to have non-ischemic cardiomyopathy, shorter duration of HF history and less-dilated LV ². Direct tissue examination revealed that an intact transverse tubular system at LVAD implantation, may constitute a precondition and predictor for functional recovery following MCS ². Metabolic studies demonstrated that responders direct glycolytic metabolites into the cardioprotective pentose-phosphate and one-carbon metabolism pathways, likely contributing to recovery by enhancing biosynthesis and reducing oxidative stress ². Human myocardial tissue examination from responders and non-responders provides us with the opportunity and the specific findings to fuel subsequent in vitro and in vivo studies to establish causality, and understand the mechanisms driving this phenomenon. Human tissues have long been prized by pathologists and others in furthering our understanding of disease processes. Importantly, there is a growing appreciation of their value at the late pre-clinical stage of drug discovery, as challenges in translating pre-clinical studies to clinical trials include the inability of small animal models to fully recapitulate human disease. Human tissue-based assays could play a key role in improving the translation process and the effectiveness of disease model research on developing novel therapeutics.

On this basis, tissue from LVAD patients could potentially contribute to earlier phases of the discovery process. In a recent example of such a bedside-to-bench mechanistic study, the myocardial mitochondrial pyruvate carrier (MPC) appeared to play a pivotal role in LVAD-mediated cardiac recovery. Specifically, responders were found to overexpress MPC, fueling a series of in vitro and in vivo studies highlighting the importance of the pyruvate-lactate axis in cardiac hypertrophy and failure ⁴. These findings led to the emergence of monocarboxylate transporter 4 (MCT4), a cellular lactate exporter, as a novel myocardial recovery therapeutic target ⁴ (Figure). Following a similar approach and using myocardial tissue data from LVAD-supported patients and from non-failing donors, VDAC2 (voltage-dependent anion channel 2), a mitochondrial membrane protein which imports cytosolic calcium into the mitochondria, was shown to play a role in cardiac recovery ⁵. These hypothesis-generating findings were further investigated in mice to discover the underlying mechanism, and identify potential therapeutic targets. These mice studies ⁵ showed that the loss of VDAC2 in myocardium causes excitation-contraction coupling impairment by altering both intracellular and mitochondrial calcium signaling, progression to severe cardiomyopathy and death. Vice versa, treating HF mice with the VDAC2 agonist, efsevin, improved cardiac contractility and relaxation, and re-introduction of VDAC2 in knock-out mice improved cardiac function and prevented mortality. Altogether these findings demonstrated the crucial role of VDAC2 in calcium cycling and cardiac function, and its emergence as a new therapeutic target for HF and myocardial recovery (Figure). In a third example, the recovering heart in chronic advanced HF patients directs glycolytic metabolites into accessory glucose metabolism pathways such as pentose-phosphate and one-carbon metabolism ². By generating reduced NADP, enhancing biosynthesis and reducing oxidative stress, these pathways may have contributed to myocardial recovery and could be targeted therapeutically in chronic HF ² (Figure). The above-mentioned approach parallels other examples of accelerated tissue-to-discovery, i.e., the lipid clearance role of the low-density lipoprotein receptors in familial hypercholesterolemia, which opened the door to further translational research leading to statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors discoveries, impacting the broader preventive cardiology field.

Implementation of clinical studies promoting LVAD-mediated cardiac recovery and translational and basic science studies leveraging human tissue findings to unveil mechanistic myocardial recovery pathways, will pave the way for future successes and have the potential to revise the dogma that HF will eventually lead to end-stage, nonreversible disease. Extending the lessons learned from the LVAD investigational setting to the broader HF population is a major undertaking that deserves further investment. With the precedents set by trailblazers before us, we hope that the tip of the iceberg is only the beginning.