Daily Cardiology Research Analysis
Across cardiology, a randomized trial shows dapagliflozin reduces myocardial fibrosis and improves structure and function in HFpEF with type 2 diabetes. A mechanistic JCI study reveals weight loss induces Fcgr4+ macrophages that help resolve atherosclerosis, while weight regain accelerates disease via immune progenitor reprogramming. A large propensity-matched analysis reports higher 5-year mortality after TAVR versus SAVR, informing long-term valve strategy.
Summary
Across cardiology, a randomized trial shows dapagliflozin reduces myocardial fibrosis and improves structure and function in HFpEF with type 2 diabetes. A mechanistic JCI study reveals weight loss induces Fcgr4+ macrophages that help resolve atherosclerosis, while weight regain accelerates disease via immune progenitor reprogramming. A large propensity-matched analysis reports higher 5-year mortality after TAVR versus SAVR, informing long-term valve strategy.
Research Themes
- Disease-modifying therapies and fibrosis regression in HFpEF
- Immunometabolic mechanisms driving atherosclerosis progression and resolution
- Long-term outcomes after transcatheter versus surgical aortic valve replacement
Selected Articles
1. Impact of SGLT2 inhibitors on myocardial fibrosis in diabetic HFpEF: a longitudinal study.
In a multicenter double-blind RCT (n=100) of HFpEF with type 2 diabetes, dapagliflozin reduced myocardial extracellular volume by 3.5% versus 0.8% with placebo over 12 months, indicating antifibrotic effects. Dapagliflozin also lowered LV mass, improved glycemia, and increased 6-minute walk distance.
Impact: Provides randomized evidence that SGLT2 inhibition may directly regress myocardial fibrosis in HFpEF with diabetes, suggesting disease-modifying potential beyond hemodynamic effects.
Clinical Implications: Supports use of dapagliflozin in diabetic HFpEF not only for symptom and hospitalization benefits but also for fibrosis regression. Cardiac MRI-derived ECV could serve as a surrogate to track disease modification.
Key Findings
- Dapagliflozin reduced myocardial ECV by −3.5% vs −0.8% with placebo (p<0.001).
- Left ventricular mass index decreased more with dapagliflozin.
- Functional improvements included greater 6-minute walk distance and better glycemic control.
Methodological Strengths
- Multicenter, double-blind, placebo-controlled randomized design
- Use of quantitative cardiac MRI (ECV) to assess fibrosis longitudinally
Limitations
- Modest sample size with imaging surrogate endpoints rather than hard outcomes
- HFpEF phenotype heterogeneity may limit generalizability
Future Directions: Larger outcome-driven RCTs should test whether fibrosis regression translates into reduced HF hospitalizations and mortality, and whether ECV-guided therapy personalization improves outcomes.
BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors offer cardiovascular benefits in patients with heart failure, yet their direct effects on myocardial fibrosis—particularly in heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D)—remain underexplored. This study investigates the antifibrotic impact of dapagliflozin in diabetic HFpEF patients, with a focus on its potential as a disease-modifying therapy. METHODS: In a multicenter, double-blind, placebo-controlled trial, 100 patients with HFpEF and T2D were randomized (1:1) to receive dapagliflozin 10 mg daily or placebo for 12 months. Stratification was performed by baseline extracellular volume fraction (ECV). Myocardial fibrosis was assessed using cardiac MRI-derived ECV at baseline, 6 months, and 12 months. Secondary endpoints included changes in left ventricular mass index (LVMI), HbA1c, and 6-min walk test (6MWT) distance. RESULTS: Dapagliflozin significantly reduced myocardial fibrosis (mean ΔECV: - 3.5% [95% CI - 4.2 to - 2.8]) compared to placebo (- 0.8% [95% CI - 1.3 to - 0.4]; p < 0.001). Additional benefits included greater reductions in LVMI (- 8.2 g/m
2. Caloric restriction promotes resolution of atherosclerosis in obese mice, while weight regain accelerates its progression.
In obese hypercholesterolemic mice, short-term caloric restriction promoted atherosclerosis resolution via expansion of Fcgr4+ macrophages in adipose tissue and plaques, clearing necrotic cores independently of plasma cholesterol. Weight regain eliminated these cells and reprogrammed immune progenitors, driving hyperinflammatory responses and accelerating atherosclerosis.
Impact: Reveals a previously unrecognized macrophage subset and bone marrow programming axis that mechanistically links weight cycling to atherosclerosis outcomes, opening translational targets.
Clinical Implications: Suggests potential therapeutic strategies in obesity and weight cycling: inducing Fcgr4+ macrophages and preventing progenitor hyperinflammatory programming may promote plaque stabilization and regression.
Key Findings
- Short-term caloric restriction resolved atherosclerosis independent of plasma cholesterol levels.
- Fcgr4+ macrophages accumulated in adipose tissue and plaques during restriction and cleared necrotic cores.
- Weight regain removed Fcgr4+ macrophages and reprogrammed immune progenitors to sustain hyperinflammation, accelerating atherosclerosis.
Methodological Strengths
- Integrated in vivo model isolating caloric restriction and weight regain effects without diet composition confounding
- Single-cell RNA sequencing with mechanistic validation across adipose tissue, bone marrow, and plaques
Limitations
- Preclinical murine model; human translatability remains to be established
- Short-term interventions; durability of macrophage and progenitor changes over time is unknown
Future Directions: Validate Fcgr4+ macrophage signatures and progenitor programming in humans with weight loss/regain; test pharmacologic or lifestyle interventions that sustain pro-resolving macrophages and prevent hyperinflammatory reprogramming.
While weight loss is highly recommended for those with obesity, >60% regain their lost weight. This weight cycling is associated with an elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss and regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss promoted atherosclerosis resolution independent of plasma cholesterol. Single-cell RNA sequencing and subsequent mechanistic studies indicated that this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fc γ receptor 4 (Fcgr4), helped to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyperinflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
3. Five-year outcomes after surgical versus transcatheter aortic valve replacement with new generation devices from the prospective OBSERVANT studies.
In propensity-matched cohorts from prospective registries, new-generation TAVR showed higher 5-year all-cause mortality (44.4% vs 33.2%, HR 1.36) and MACCE versus SAVR, with increased pacemaker and PCI rates. The signal persisted across LVEF strata and in younger, lower-risk subgroups.
Impact: Provides large-scale, long-term comparative effectiveness data questioning TAVR durability and outcomes versus SAVR, informing shared decision-making beyond short-term RCT results.
Clinical Implications: For patients eligible for both TAVR and SAVR, especially younger or lower-risk profiles, surgical replacement may confer better 5-year survival; pacemaker risk should be factored into valve strategy.
Key Findings
- After propensity matching (1008 pairs), TAVR had higher 5-year mortality than SAVR (HR 1.36, 95% CI 1.18–1.57).
- TAVR increased 5-year MACCE, pacemaker implantation (23.1% vs 9.3%), and PCI rates.
- Higher relative mortality with TAVR was observed in age ≤80, lower EuroSCORE II, and regardless of LVEF.
Methodological Strengths
- Large prospective registry datasets with propensity score matching
- Evaluation of new-generation TAVR devices with 5-year follow-up
Limitations
- Non-randomized design with potential residual confounding and era effects
- Differences in treatment periods (SAVR earlier vs TAVR later) may bias comparison
Future Directions: Head-to-head randomized trials with extended follow-up and attention to pacemaker risk, coronary access, and structural valve deterioration are needed, particularly in younger, lower-risk patients.
The efficacy and durability of transcatheter (TAVR) over surgical aortic valve replacement (SAVR) for severe aortic stenosis (AS) has been demonstrated in randomized studies, but these findings were not confirmed in several observational studies. This is an analysis of 5706 AS patients who underwent SAVR from 2010 and 2012, and 2989 AS patients who underwent TAVR from 2017 and 2018 from the prospective OBSERVANT I and II studies. TAVR procedures were performed with new-generation devices. Five-year all-cause mortality was the primary outcome of this analysis. Propensity score matching yielded 1008 pairs of TAVR and SAVR patients. The mean EuroSCORE II was comparable between the study cohorts (TAVR 4.7 ± 4.0% and SAVR 4.5 ± 5.7%, p = 0.419). At 5 years, TAVR was associated with higher mortality (44.4% vs. 33.2%, HR 1.36, 95%CI 1.18-1.57, Log-rank test p < 0.001), major adverse cardiac and cerebrovascular events (MACCEs) (49.3% vs. 37.9%, HR 1.32, 95%CI 1.15-1.51, Log-rank test p < 0.001), permanent pacemaker implantation (23.1% vs. 9.3%, HR 2.72, 95%CI 2.14-3.45, Log-rank test p < 0.001) and percutaneous coronary intervention rates (3.7% vs. 1.2%, HR 3.44, 95%CI 1.76-6.71, Log-rank test p < 0.001) compared to SAVR. Age ≤ 80 years, male gender, EuroSCORE II ≤ 4.0%, absence of coronary artery disease and absence of diabetes were associated with higher 5-year mortality after TAVR compared to SAVR. TAVR had a significantly higher 5-year mortality than SAVR both in patients with left ventricular ejection fraction ≤ 50% and > 50%. This observational study from prospective data showed that TAVR using new-generation devices was associated with increased rates of all-cause mortality compared to SAVR at 5 years. These findings should be viewed considering the non-randomized nature of this study and may be attributable to the characteristics of patients selected for TAVR, rather than the procedure itself.