The grand challenge of discovering new cardiovascular drugs

Abstract

KEYWORDSdrug discovery, heart failure, human genetics, inherited cardiomyopathy, induced pluripotent stem cells, academia-biotech-pharma ecosystem, real world data, biobanking and biorepositories BackgroundHeart disease is the #1 killer worldwide, greater than all cancers combined. This is despite the fact that, in the developed world, there has been a substantial decline in cardiovascular mortality since the mid-20th century (Centers for Disease Control and Prevention (CDC), 1999), driven largely by a reduction in ischemic heart disease (Mensah et al., 2017;Nowbar et al., 2019). This decline is multifactorial, involving a reduction in tobacco use, changes in diet, treatment of hypertension, advances in rapid coronary revascularization, and the advent of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, and P2Y12 ADP receptor antagonists (Arnett et al., 2019). However, with the adoption of the Western diet and lifestyle in the developing world, and the rise in prevalence of cardiometabolic diseases and obesity, there has been an increase in the global burden of cardiovascular diseases (CVD) (Roth et al., 2020) and a stalling of improvements in the United States (Sinatra and Huston, 2020).Our collective success in treating cardiovascular diseases has been mixed. While the relative burden of ischemic heart disease (IHD) has decreased in the developed world, the burden of heart failure (HF) has increased in the past several decades (Virani et al., 2021). HF is now a global pandemic, afflicting 26 million people worldwide and 6 million in the United States alone (Savarese and Lund, 2017;Jackson et al., 2018). Despite advances in medical and surgical therapies, HF is associated with high mortality, having a lower 5years survival rate than most cancers (Virani et al., 2021). In fact, even as the mortality rate from IHD dropped 14.9% from 2011 to 2017, the HF mortality rate increased 20.7% during the same period (Sidney et al., 2019). Additionally, HF is associated with significant morbidity, reduced quality of life, and loss of earning potential due to diminished functional capacity. Moreover, advanced HF is frequently associated with anemia, sarcopenia, renal failure, depression, and cognitive decline (Lang and Mancini, 2007). Medical management is difficult and often complicated by volume overload and/or kidney injury. Consequently, HF is a leading diagnosis for hospitalizations and rehospitalization in the United States (McDermott and Roemer, 2021). Even as the advent of goal-directed medical therapy (GDMT) has substantially modified the rate of progression of HF, and internal cardiac defibrillators have reduced the risk of sudden cardiac death (van der Meer et al., 2019), HF remains a progressive disease, often

Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort

“…To our knowledge, our study is the first to show a human genetic association of PIM1 with PAH. Since pipeline drug targets with human genetic evidence of disease association are more likely to lead to approved drugs than those without such evidence (Nelson et al, 2015;Hong, 2022), our study lends important support for PIM1 inhibition as a promising therapeutic approach for PAH. Moreover, as plasma PIM1 levels have been associated with PAH disease severity, our findings further corroborate the role of PIM1 in the pathogenesis of PAH and as a potential therapeutic target (Renard et al, 2013;Zhu et al, 2019).…”

Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects

“…Preliminary Screening and SAR Study. An initial assessment of 23 synthesized derivatives (3,4, and 5a−u) alongside the starting material 1 was undertaken to evaluate their protective effects in a zebrafish model of DOX-induced cardiomyopathy. Levosimendan (LSD), recognized for its notable cardioprotective activity and clinical application in heart failure treatment, 61 served as the positive control.…”

“…2 Thus, a primary objective in medical research remains the development of innovative drugs capable of effectively protecting the heart from injury, preserving or restoring compromised cardiac function, ultimately contributing to the stabilization of CVDs, and thereby mitigating disability while enhancing overall survival. 3 Mitochondria, serving as the primary sites for eukaryotic energy production, play a vital role in meeting the heightened energy demands of the heart, constituting approximately 30% of cardiomyocyte volume. 4 While the intricate mechanisms underlying CVDs remain incompletely understood, mitochondrial dysfunction is recognized as a pivotal factor in their development.…”

“…The inherent challenge in CVDs management lies in the limited regenerative capacity of the human heart, where cardiomyocytes, as terminally differentiated cells, are scarcely replaced following damage . Thus, a primary objective in medical research remains the development of innovative drugs capable of effectively protecting the heart from injury, preserving or restoring compromised cardiac function, ultimately contributing to the stabilization of CVDs, and thereby mitigating disability while enhancing overall survival …”

Special Issue: “New Trends in Diabetes, Hypertension, and Cardiovascular Diseases”

“…Cardiovascular disease (CVD) encompasses a range of disorders affecting the heart and blood vessels, including coronary heart disease and cerebrovascular disease [ 1 ] and conditions such as aortic aneurysms and lower-extremity peripheral artery disease [ 2 ]. It remains the leading cause of death worldwide, claiming 17.9 million lives annually [ 3 ], despite the availability of numerous therapeutic drugs [ 4 ]. Thus, further research is warranted to enhance CVD treatment and reduce its morbidity and mortality [ 5 ].…”