TY - JOUR

T1 - Hypoxia Attenuates Pressure Overload-Induced Heart Failure

AU - Froese, Natali

AU - Szaroszyk, Malgorzata

AU - Galuppo, Paolo

AU - Visker, Joseph R.

AU - Werlein, Christopher

AU - Korf-Klingebiel, Mortimer

AU - Berliner, Dominik

AU - Reboll, Marc R.

AU - Hamouche, Rana

AU - Gegel, Simona

AU - Wang, Yong

AU - Hofmann, Winfried

AU - Tang, Ming

AU - Geffers, Robert

AU - Wende, Adam R.

AU - Kühnel, Mark P.

AU - Jonigk, Danny D.

AU - Hansmann, Georg

AU - Wollert, Kai C.

AU - Abel, E. Dale

AU - Drakos, Stavros G.

AU - Bauersachs, Johann

AU - Riehle, Christian

N1 - Funding Information: This work was supported by a research grant of the German Heart Foundation to C.R. (F/32/18); the German Research Foundation (DFG) and the Clinical Research Unit (KFO) 311 to D.D.J., G.H., K.C.W., and J.B.; American Heart Association Heart Failure Strategically Focused Research Network 16SFRN29020000 to S.G.D.; National Heart, Lung, and Blood Institute R01 HL135121-01 and R01 HL132067-01A1 to S.G.D.; and Nora Eccles Treadwell Foundation Grant to S.G.D.

PY - 2024/2/6

Y1 - 2024/2/6

N2 - Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.

AB - Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.

KW - cardiac hypertrophy

KW - cardiac remodeling

KW - hypoxia

KW - left ventricular assist device

KW - pressure overload

UR - http://www.scopus.com/inward/record.url?scp=85184305061&partnerID=8YFLogxK

U2 - 10.1161/JAHA.123.033553

DO - 10.1161/JAHA.123.033553

M3 - Article

C2 - 38293923

AN - SCOPUS:85184305061

VL - 13

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 3

M1 - e033553

ER -