Relationship Between Cardiac Structure and Function With Renal Function Trajectory and Outcomes in Patients With Heart Failure: Insights From the PARAGON-HF Trial.

Background: Renal dysfunction is common and associated with a poor prognosis in patients with heart failure. However, the association of cardiac structure and function with decline in kidney function in this population is unknown. We aimed to assess the association between individual measures of cardiac structure and function with changes in renal function and renal outcomes in patients with heart failure with preserved ejection fraction.
Methods: Patients enrolled in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) echocardiographic substudy were included. The association between each echocardiographic parameter (expressed in standardized units) and changes over time in estimated glomerular filtration rate was calculated with repeated-measures mixed-effect models. Multivariable Cox proportional hazards models were used to identify individual cardiac parameters associated with the composite renal outcome (≥50% decline in estimated glomerular filtration rate relative to baseline, development of end-stage renal disease, or death attributable to renal causes), after adjusting for covariates.
Results: Among 1097 patients (mean age 74±8 years and 53% women), over a median follow-up of 2.9 years, 28 composite renal events (0.9 per 100 person-years) occurred. Higher left ventricular (LV) mass index and higher E/average e' ratio were associated with significantly more profound annual decline in estimated glomerular filtration rate (for both, -0.4 [95% CI, -0.7 to -0.1] mL/min/1.73 m ² /y per 1 higher SD). Higher LV mass index, LV end-diastolic volume index, right ventricular end-diastolic area, and a lower right ventricular fractional area change were each associated with a significantly higher risk for the composite renal outcome.
Conclusions: In the PARAGON-HF echocardiographic substudy, higher LV mass and filling pressures were independently associated with more profound kidney function decline, and higher LV mass and volume, as well as impaired right ventricular structure and function, were each associated with renal events. Assessing these parameters may help identify patients with heart failure with preserved ejection fraction at higher risk for adverse renal events and indicate potential therapeutic targets.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
Competing Interests: Dr Lu received research funding from the Gottfried und Julia Bangerter-Rhyner Foundation, the SICPA (Société industrielle et commerciale de produits alimentaires) Foundation, and the Société Académique Vaudoise. Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Mc Causland reports grant funding from the National Institutes of Health (NIH), Satellite Healthcare, Fifth Eye, Lexicon, and Novartis paid directly to his institution; consulting fees from GlaxoSmithKline (GSK) and Zydus Therapeutics; and expert witness fees from Rubin-Anders Scientific. Dr Shah reports consulting fees from Philips Ultrasound and research funds from Novartis through Brigham and Women’s Hospital. He was supported by NIH/National Heart, Lung, and Blood Institute (NHLBI) grant K24HL152008. Dr Cikes reports Investigator-Initiated Research Grants to institution: Novartis, Abbott, and Pfizer; Clinical Study Contracts with institution: NovoNordisk and CorVia; advisory role and speaker honoraria, travel grants from Abbott, Abiomed, Amgen, Amicus Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Livanova, Krka Pharma, Novartis, NovoNordisk, Pfizer, Pulsify Medical, Roche, Swixx, Takeda, Teva Pharmaceutical Industries, and Viatris. Dr Claggett reports personal consulting from Alnylam, Cardurion, Corvia, Cytokinetics, CVRX, Intellia, and Rocket. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee (SC)/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr O’Meara reports grants/research support from the Montreal Heart Institute’s Carolyn & Richard J. Renaud Chair for Research in Heart Failure, with fees paid through her institution for this Chair and for the following: Canadian Heart Function Alliance (CHFA) Team Grant, funded by the Canadian Institutes of Health Research (SC member), and involvement in the following trials as a SC member for DAPA ACT HF-TIMI 68 (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure–Thrombolysis in Myocardial Infarction 68; TIMI [Thrombolysis in Myocardial Infarction] group and AZ) and GARDEN-HF (A Study of Ponsegromab in People With Heart Failure; TIMI group and Pfizer), for HEART-FID (Ferric Carboxymaltose in Heart Failure With Iron Deficiency; SC member, American Regent), CARDINAL-HF (Effectiveness of CRD-740 in Heart Failure; SC member, Cardurion), and HERMES (Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation; National Lead Investigator Novo Nordisk); reports consulting fees from Astra Zeneca, Boerhinger Ingelheim, GSK, Novartis, and Novo Nordisk; speaker fees from Astra Zeneca, Boerhinger Ingelheim, GSK, Novartis, Novo Nordisk, Pfizer, and other fees from Cytokinetics (Heart Failure Patient Steering Committee), industry partners for Canadian Heart Function Alliance Network. Dr Wang is supported by the Scott Schoen and Nancy Adams First.In.Women Cardiovascular Fellowship, Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and the American College of Cardiology/Association of Black Cardiologists Merck Research Fellowship Award. Dr McMurray reports payments through Glasgow University from work on clinical trials, consulting and other activities from: Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; personal consultancy fees from: Alnylam Pharma, Bayer, Bristol Myers Squibb (BMS), George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; reports the following lecture fees: Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of Continuing Medical Education, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. Dr Pfeffer reports research grant support (via institution): Lexicon and Novartis. He is a consultant to Alnylam, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Lexicon, NHLBI Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (Master Protocol Committee), Novartis, Novo Nordisk, and Sanofi, and has equity in DalCor. Dr Hegde reports fees paid to the institution for core laboratory services for BMS and Cytokinetics. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH/NHLBI, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.ai, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Skali reports research support or consulting fees from: ABT Associates, Astellas Pharma, Emmi Solutions, and Hikma Pharmaceuticals. The other authors report no conflicts.