Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 +/- 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/dtmax) and decrease (-dP/dtmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 +/- 6 vs. 51 +/- 35.3 mmHg (P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/dtmax 4,178 +/- 388 vs. 2,801 +/- 503 mmHg/s, LVP 115 +/- 11 vs. 83 +/- 14 mmHg, RPP 33,688 +/- 1,910 vs. 23,541 +/- 3,858 beats x min(-1) x mmHg(-1), -dP/dtmax -3,036 +/- 247 vs. -2,091 +/- 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.
Introduction Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) and T1 mapping techniques enable the quantification of focal and diffuse myocardial LGE, respectively. Studies have shown evidence of fibrosis in middle-age athletes, but not relative to physically active (PA) adults who perform recommended physical activity levels. Therefore, we examined cardiac remodeling and presence of left ventricular (LV) LGE and T1 values in both recreational middle-age endurance athletes (EA) and PA adults. Methods Healthy EA and PA adults (45–65 yr) completed a standardized 3-T CMR protocol with ventricular volumetry, LV LGE, and T1 mapping. Results Seventy-two EA and 20 PA participants (mean age, 53 ± 5 vs 56 ± 4 yr; P < 0.01; V˙O2peak = 50 ± 7 vs 37 ± 9 mL·kg−1·min−1, P < 0.0001) were examined, with CMR data available in 89/92 participants. Focal LV LGE was observed in 30% of participants (n = 27/89): 33% of EA (n = 23/69; 33%) and 20% of PA (n = 4/20; 20%). LGE was present at the right ventricular hinge point (n = 21/89; 23.5%) or identified as ischemic (n = 2/89; 2%) or nonischemic (n = 4/89; 4%). Focal LV LGE was observed similarly in both EA and PA (P = 0.25). EA had larger LV chamber sizes and T1 native values (1169 ± 35 vs 1190 ± 26, P = 0.02) compared with PA, with similar LV ejection fraction. Global extracellular volume (ECV) was similar in both EA and PA (22.6% ± 3.5% vs 21.5% ± 2.6%, P = 0.26), with no relationship between global ECV and LV mass (r = −0.16, P = 0.19). Conclusions Focal LGE at the right ventricular hinge point was detected at the same frequency in both groups, was unrelated to demographic or clinical indices, and was found without evidence of global ECV expansion in EA, suggesting a physiologic remodeling response. The long-term clinical implications of hinge-point LGE require clarification using prospective, long-term follow-up studies.
Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. Results: Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m 2 and 63.8 ± 14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m 2 ) (P=0.74). Median baseline (IQR) NT-proBNP was 51 pg/mL (20, 105 pg/mL) and 55 pg/mL (21, 132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=0.70) for systolic blood pressure, diastolic blood pressure and NT-proBNP, respectively. No clinically meaningful between group differences in LV volumes (diastolic and systolic indexed to baseline BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041
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