Innovation and Discovery in Cardiovascular Biology

The ACS journal Pharmacology and Translational Science is pleased to be publishing a Special Issue focused on Innovations and Discovery in Cardiovascular Biology. Despite tremendous advances in the detection and treatment of cardiovascular diseases, as a group these pathologies remain the number one cause of global death, accounting for approximately 17.9 million deaths in 2016; nearly one-third of all deaths worldwide.¹ Idiopathic and resistant hypertension remain significant underlying origins of cardiovascular disease and stroke, and yet the genetic, environmental, and pathophysiological underpinnings of dysfunctional blood pressure regulation remain murky. Large-scale clinical studies have made some progress toward revealing common predictive biomarkers or genetic variants associated with cardiovascular disease, so that clinical care and management of at-risk individuals is occurring earlier in life. However, our therapeutic arsenals have not expanded in a way that enables us to achieve our vision of personalized or bench-to-bedside medicine. In addition, there remains broad sex bias toward adult males in clinical studies and genome-wide association studies, thereby undermining the ultimate success of putative diagnostics and therapeutics for the general population.²

Therefore, we focus this issue of Pharmacology and Translational Science on the publication of primary research discoveries in areas broadly related to cardiovascular disease. We specifically solicited submissions that used innovative technological approaches and interdisciplinary methodologies to elucidate mechanistic pathways underlying cardiovascular pathophysiology. In keeping with the scope of the journal, we were excited to receive submissions that focus on therapeutic strategies and targets. Collectively, this special issue on Innovations and Discovery in Cardiovascular Biology has been successful in coalescing reviews and primary research articles that pave the way toward new diagnostics and therapeutics as well as an improved understanding of the integrative physiology that underlies the world’s most common and deadly disease.

Two separate articles are focused on revealing novel molecular pathways associated with cardiac dysfunction. The irreversible death of cardiomyocytes following an ischemic event is mediated through both apoptosis and necrosis, but recent studies suggest that necrosis may be a reversible event. Therefore, Cheng et al.³ used a genome-wide RNAi screen in human muscle cells to identify key pathways involved in calcium-induced necrosis. They discovered multiple molecular pathways, encompassing several druggable enzymes, that either enhance or inhibit cardiomyocyte necrosis, thereby offering a rich data set of clinically relevant targets for cardiac ischemia. Zhang et al.⁴ tackled the complex problem of cardiotoxicity and cardiac failure following chemotherapy by performing a small-scale clinical study aimed at discovering better predictive markers of cardiotoxicity in patients treated with chemotherapy. Using nanotrap fractionation and mass spectometry of plasma, the group was able to enrich for plasma peptides produced by cathepsin B cleavage. They discovered a plasma peptide fragment from serum amyloid A1 which could effectively serve as a sensitive, precise, and minimally invasive biomarker to detect chemotherapy-induced cardiotoxicity. Together, these studies exemplify how sophisticated biochemical technologies (nanotrap fractionation) and innovative screening approaches (RNAi screens) can be harnessed to reveal previously unrecognized paths for precision diagnosis of cardiotoxicity or new molecular targets for treatment of cardiac ischemia.

The study by Igreja and colleagues⁵ uses the preclinical, aged spontaneously hypertensive rat (SHR) model to explore the therapeutic potential of a relatively new dopamine β-hydroxylase inhibitor, zamicastat, as a possible therapeutic strategy to reduce overactivity of the sympathetic nervous system—a clinical condition that is commonly associated with essential hypertension and congestive heart failure. Consistent with early stage clinical trials, the authors found that a daily dosage of zamicastat for 9 weeks significantly decreased norepinephrine levels and improved overall cardiometabolic health in the aged SHR rats compared to nonhypertensive controls. These positive outcomes should bolster current efforts at therapeutically targeting sympathetic overactivity in order to alleviate hypertension and its many cardiovascular comorbidities.

Two exciting research articles focus their efforts on therapeutically targeting the vascular system. Kofler et al.⁶ capitalize on the robust physiological angiogenesis associated with corpus luteal formation following ovulation to test and characterize the effects of Jagged-specific Notch inhibition on vascular growth and pericyte recruitment. Their studies reveal remarkable differences between the vascular effects of Notch inhibition during normal ovulation compared to hyperstimulated ovulation—a condition that is present in women undergoing assisted reproductive technologies. Overall, the study highlights the inherent heterogeneity of the vasculature, and the variability that this heterogeneity imparts on therapeutic compounds and their anticipated actions. Tacconi et al.⁷ used a mouse model of colitis to test the efficacy of a novel form of vascular endothelial growth factor C (VEGFC) that is fused to the F8 antibody, thereby delivering a potent lymphangiogenic signal to sites of inflammation. Systemic treatment with this new therapeutic tool expectedly stimulated profound lymphangiogenesis and further culminated in a significant reduction in inflammation and associated inflammatory cells and markers. These studies serve to underscore the strong interdependence of peripheral organ function on its invested vasculature, while also providing deeper mechanistic insights and novel therapeutic strategies into two of the most studied and therapeutically tractable vascular signaling pathways: VEGF and NOTCH signaling.

The special issue also includes two lymphatic-themed review articles, representing a largely understudied vascular system compared to the blood vasculature. Indeed, authors Sestito and Thomas⁸ bring forth a highly innovative and comprehensive review to introduce readers to the unique properties of lymphatic vessels which render them desirable to modulate therapeutically, but at the same time, present distinct challenges for targeted drug delivery. The authors expand on the potential of biomaterials for enhancing lymphangiogenesis in the periphery as well as in lymph nodes. Ultimately, given the predominate immunomodulatory functions of the lymphatic vasculature, their specific targeting with biomaterials and nanoparticles could significantly expand the clinical value of this vascular highway beyond the cardiovascular system and into a myriad of disease conditions that require the fine-tuning of immune regulation.

The review article by Trincot and Caron⁹ also addresses the lymphatic system, but draws special attention to our lack of appreciation for the fundamental differences in lymphatic vascular biology that are imparted by biological sex. Indeed, the prevalence of biomedical knowledge, from basic foundational studies to large scale clinical trials, is largely biased toward the male sex. Studies in the lymphatic vascular system are no exception, but considering the preponderance of women affected by lymphatic disorders compared to men, a focused attention to sex differences in lymphatic vascular biology, as summarized in the review, is certainly an area of cardiovascular biology worth pursuing on a large scale.

We hope that readers of ACS Pharmacology and Translational Science will enjoy learning about these remarkable and insightful discoveries in the field of cardiovascular biology. The special issue provides the full spectrum of bench-to-bedside translational research: from the discovery of predictive biomarkers of disease to target discovery and mechanistic preclinical validation and culminating in drug delivery modalities and drug launches. There remains much work to be done to combat cardiovascular disease, and the articles in this special issue are certain to make impactful and lasting contributions to our worldwide scientific efforts.

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.