Cardiac and Paracardiac Structure in the SUMMIT Trial
March 15, 2025
By Michael H. Crawford, MD
Synopsis: A cardiac magnetic resonance imaging study in a subgroup of the patients in the SUMMIT trial of tirzepatide in patients with heart failure with preserved ejection fraction has demonstrated that patients treated with tirzepatide had reduced left ventricular mass and paracardiac adipose tissue compared to placebo-treated patients, which may partially explain the reduction in heart failure events observed in the main SUMMIT trial.
Source: Kramer CM, Borlaug BA, Zile MR, et al. Tirzepatide reduces LV mass and paracardiac adipose tissue in obesity-related heart failure: SUMMIT CMR substudy. J Am Coll Cardiol. 2024; Nov 5. doi: 10.1016/j.jacc.2024:11.001. [Online ahead of print].
This cardiac magnetic resonance (CMR) substudy of SUMMIT was designed to elucidate any cardiac structural changes caused by tirzepatide (TZ) therapy in patients with heart failure with preserved ejection fraction (HFpEF). Such patients have been shown to have increased left ventricular (LV) mass and epicardial adipose tissue. Thus, CMR studies at baseline and at the 52-week final visit were included in the SUMMIT trial.
Epicardial adipose tissue was defined as the volume of adipose tissue between the visceral pericardium and the LV epicardium. Pericardial adipose tissue was defined as the adipose tissue beyond the parietal pericardium. There was almost four times the amount of pericardial adipose tissue compared to epicardial. The combination of pericardial and epicardial adipose tissue was considered the paracardiac adipose tissue (PAT). LV mass and volumes and left atrial (LA) volumes and strain also were measured.
Baseline CMR was performed in 175 patients (24% of the SUMMIT population). Of these patients, 52 had inadequate CMR images, six died, and five dropped out for other reasons, leaving 106 patients (15% of the SUMMIT population) who had baseline and 52-week CMR images of adequate quality for analysis. The baseline characteristics of these 106 patients were not different from the total SUMMIT population.
Baseline CMR showed that LV mass and LA volume were higher than reported normal values. At 52 weeks, placebo-corrected LV mass had decreased by a mean of 11 g in the TZ group (P = 0.004) and LV stroke volume by -8 mL (P = 0.011). Changes in LV end diastolic and end systolic volumes and EF were not significant. PAT was significantly reduced in the TZ group (-45 mL, P < 0.001), which was mainly the result of a decrease in pericardial adipose tissue (-43 mL, P < 0.001).
The decrease in LV mass with TZ was correlated with weight loss (r = 0.34, P < 0.02). The authors concluded that TZ therapy in patients with obesity and HFpEF decreases LV mass and PAT compared to placebo, and these observations may partially explain the reductions in HF events observed in the main SUMMIT trial.
Commentary
An increase in visceral adipose tissue has several potential adverse effects on the heart. It can increase plasma volume and result in LV hypertrophy. Also, visceral adipose tissue may act locally by secreting proinflammatory and profibrotic adipocytokines and excess free fatty acids into the myocardium. These effects could lead to lipid accumulation, myocardial inflammation, and fibrosis. In addition, PAT may result in cardiac compression and impair LV filling. Thus, this CMR substudy of SUMMIT is of interest.
Compared to placebo, TZ reduced LV mass and PAT, but there was no effect on LV volumes or function, nor were there any changes in LA volume, function, or strain. Thus, TZ may predominately act at the tissue and cellular levels to reduce filling pressures, which are the hallmark of HFpEF.
There are limitations to SUMMIT-CMR. CMR determination of LV mass includes extracellular and myocardial volume. Thus, it is unknown whether TZ is decreasing cardiomyocyte hypertrophy or fibrosis or both. There was no late gadolinium enhancement imaging performed, which would have distinguished between myocyte and extracellular volume. Also, one-third of CMR images were inadequate for analysis, which reduced the power of the substudy.
In addition, LV and LA volumes were measured in biplane long-axis views rather than using Simpson’s rule with stacked short-axis views, which is considered superior. Finally, no analysis of the right ventricle was performed.
Despite these limitations, SUMMIT-CMR supports the concept that GLP-1 receptor agonists, in addition to promoting weight loss, cause structural changes in the heart that facilitate diastolic function and reduce visceral adiposity, which ameliorates the proinflammatory effects of excess adipose tissue.
Michael H. Crawford, MD, is Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.
A cardiac magnetic resonance imaging study in a subgroup of the patients in the SUMMIT trial of tirzepatide in patients with heart failure with preserved ejection fraction has demonstrated that patients treated with tirzepatide had reduced left ventricular mass and paracardiac adipose tissue compared to placebo-treated patients, which may partially explain the reduction in heart failure events observed in the main SUMMIT trial.
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