A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

[1]  M. Lindsey,et al.  Guidelines for measuring cardiac physiology in mice , 2018, American journal of physiology. Heart and circulatory physiology.

[2]  G. Heusch,et al.  Translating Cardioprotection for Patient Benefit: The EU-CARDIOPROTECTION COST Action. , 2019, Journal of the American College of Cardiology.

[3]  Larisa H. Cavallari,et al.  Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine , 2013, Pharmacological Reviews.

[4]  Eloi Marijon,et al.  State-of-the-art Paper Prevalences, Patterns, and the Potential of Early Disease Detection , 2022 .

[5]  Shannon M. Dunlay,et al.  Epidemiology of heart failure with preserved ejection fraction , 2017, Nature Reviews Cardiology.

[6]  M. Ward,et al.  Increasing proportion of ST elevation myocardial infarction patients with coronary atherosclerosis poorly explained by standard modifiable risk factors , 2017, European journal of preventive cardiology.

[7]  A. Kesselheim,et al.  Temporal Trends and Factors Associated With Cardiovascular Drug Development, 1990 to 2012 , 2016, JACC. Basic to translational science.

[8]  J. Danesh,et al.  Large-scale association analysis identifies new risk loci for coronary artery disease , 2013 .

[9]  P. Hotez,et al.  Neglected Tropical Diseases as Hidden Causes of Cardiovascular Disease , 2012, PLoS neglected tropical diseases.

[10]  Sanjiv J Shah,et al.  Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview , 2017, Journal of Cardiovascular Translational Research.

[11]  G. Figtree,et al.  New opportunities for targeting redox dysregulation in cardiovascular disease. , 2020, Cardiovascular research.

[12]  D. Drucker,et al.  Never Waste a Good Crisis: Confronting Reproducibility in Translational Research. , 2016, Cell metabolism.

[13]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[14]  G. Figtree,et al.  Utilizing state‐of‐the‐art “omics” technology and bioinformatics to identify new biological mechanisms and biomarkers for coronary artery disease , 2018, Microcirculation.

[15]  Y. Rosenberg,et al.  Improving the Design of Future PCI Trials for Stable Coronary Artery Disease: JACC State-of-the-Art Review. , 2020, Journal of the American College of Cardiology.

[16]  Nima Milani-Nejad,et al.  Small and large animal models in cardiac contraction research: advantages and disadvantages. , 2014, Pharmacology & therapeutics.

[17]  G. Figtree,et al.  Cardiac spheroids as promising in vitro models to study the human heart microenvironment , 2017, Scientific Reports.

[18]  D. DeMets,et al.  Cardiovascular drug development: is it dead or just hibernating? , 2015, Journal of the American College of Cardiology.

[19]  M. Matsusaki,et al.  Development of In Vitro Drug-Induced Cardiotoxicity Assay by Using Three-Dimensional Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells , 2017, Tissue engineering. Part C, Methods.

[20]  J. Arnhold,et al.  Differences in innate immune response between man and mouse. , 2014, Critical reviews in immunology.

[21]  Sathish Kumar Jayapal,et al.  Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019 , 2020, Journal of the American College of Cardiology.

[22]  P. Libby,et al.  Acute Coronary Syndromes: The Way Forward From Mechanisms to Precision Treatment , 2017, Circulation.

[23]  P. Barter,et al.  Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. , 1982, Comparative biochemistry and physiology. B, Comparative biochemistry.

[24]  Joanna Coast,et al.  Guidelines for Inclusion of Patient-Reported Outcomes in Clinical Trial Protocols: The SPIRIT-PRO Extension , 2018, JAMA.

[25]  René M. Botnar,et al.  Society for Cardiovascular Magnetic Resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part I - analytical validation and clinical qualification , 2018, Journal of Cardiovascular Magnetic Resonance.

[26]  D. Celermajer,et al.  Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study. , 2017, JACC. Cardiovascular imaging.

[27]  G. Filippatos,et al.  Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial , 2019, European journal of heart failure.

[28]  R. Califf,et al.  Resourcing Drug Development Commensurate With its Public Health Importance , 2016, JACC: Basic to Translational Science.

[29]  Kevin C. Wang,et al.  Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy , 2020, Science Translational Medicine.

[30]  G. Iacobucci Inclisiran: UK to roll out new cholesterol lowering drug from next year , 2020, BMJ.

[31]  Somy Yoon,et al.  Heart failure with preserved ejection fraction: present status and future directions , 2019, Experimental & Molecular Medicine.

[32]  Esther J Pearl,et al.  The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research , 2020, PLoS biology.

[33]  F. Pammolli,et al.  The productivity crisis in pharmaceutical R&D , 2011, Nature Reviews Drug Discovery.

[34]  T. Lüscher,et al.  From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. , 2020, European heart journal.

[35]  Panos Vardas,et al.  European Society of Cardiology: Cardiovascular Disease Statistics 2019. , 2019, European heart journal.

[36]  S. Grieve,et al.  Biobanking for discovery of novel cardiovascular biomarkers using imaging-quantified disease burden: protocol for the longitudinal, prospective, BioHEART-CT cohort study , 2019, BMJ Open.

[37]  F. Schiele,et al.  Coronary artery disease: Risk stratification and patient selection for more aggressive secondary prevention , 2017, European journal of preventive cardiology.