Role of Angiotensin II in Cardiogenic Shock Pathophysiology and Outcomes

This proposal describes a 5-year intensive mentoring program and research plan with the goal of developing the principal investigator into an independent, patient-oriented clinical researcher focusing on the pathophysiology of cardiogenic shock (CS) and its overlap with the cardiorenal syndrome. The applicant is an advanced heart failure cardiologist with formal training through a Master of Science in Clinical Epidemiology and is currently an Assistant Professor at the University of Utah. CS is a life-threatening complication of myocardial infarction or heart failure with a rising incidence but persistent 30-40% in-hospital mortality. Acute kidney injury (AKI) and pathophysiologic vasodilation are strong and consistent risk factors for CS death, but the mechanisms linking these risk factors with CS death and with each other are poorly understood. The central hypothesis of this proposal is that Angiotensin II (Ang II) becomes deficient in a subset of patients with CS resulting in AKI, vasodilation, and death. This is supported by our preliminary data showing diminished Ang II levels in CS despite excess renin and Ang I. A similar mechanism has been observed in sepsis, leading to approval of synthetic Ang II as a treatment for vasodilatory shock, but its role in mixed CS and vasodilatory shock is unknown. This model challenges the paradigm that RAAS activity is always increased and always detrimental in heart failure patients, even when it is required for the regulation of peripheral vascular resistance and maintenance of glomerular filtration in states of reduced renal blood flow, and it provides a novel and potentially druggable pathway for the treatment of CS. The goal of this K23 is to initiate a mentored research project and training plan to a) establish a body of evidence for Ang II deficiency as a contributor to CS death, vasodilation, and cardiorenal pathophysiology and b) obtain training, education, experience, and data needed to transition to independence as a patient-oriented clinical researcher. The aims of this proposal are to i) use advanced longitudinal data analysis techniques to evaluate the dynamic association of pathophysiologic vasodilation in CS with AKI and death, ii) show, in a prospective CS cohort study, that Ang II deficiency is associated with CS vasodilation independent of the systemic inflammatory response, and iii) estimate the causal effects of vasopressors on AKI and death in CS after accounting for time-varying confounding from circulating Ang II levels using marginal structural models. A comprehensive training plan is developed to integrate with these aims to 1) master new skills in causal inference and longitudinal data analysis, 2) gain robust experience leading prospective multicenter research in a critical care setting, and 3) learn to analyze cardiorenal outcomes and measure and interpret key cardiorenal biomarkers, under the guidance of mentors expert in these methods. This K23 award will provide the resources necessary to support the Candidate’s transition to an independent research career in an area of growing public health importance.