Person:

Neilan, Tomas

Background: Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR). Methods and Results: Mice were randomized to l‐nitro‐ω‐methyl ester (l‐NAME, 3 mg/mL in water; n=22), or l‐NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l‐NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo‐treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l‐NAME (“l‐NAME+S”) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43±0.09 for l‐NAME versus 0.25±0.03 for l‐NAME+S, P<0.001; τic: 0.42±0.11 for l‐NAME groups versus 0.12±0.05 for l‐NAME+S group). Mice treated with a combination of l‐NAME and spironolactone were similar to placebo‐treated controls at 7 weeks. Conclusions: Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure‐overload, furthering our understanding of HF progression.

Background

A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease (CAD). Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes.

Methods and Results

In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal MI (MACE) incremental to clinical risk models, using guideline–based low (<1%), moderate (1–3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated strong association with MACE (hazard ratio 14.66, P<0.0001) with low negative event rates of MACE and cardiac death (0.6% and 0.4%). This prognostic robustness maintained in patients with prior CAD (hazard ratio 8.17, P<0.0001, and 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (age and prior CAD adjusted) improved discrimination of MACE (C-statistic 0.81 to 0.86, P=0.04; Adjusted hazard ratio 7.37, P<0.0001) and reclassified 91.5% of patients at moderate pre-test risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/year and 4.9%/year, for low and high risk post-test, respectively). Categorical net reclassification index was 0.229 (95% CI 0.063–0.391). Continuous NRI was 1.11 (95% CI 0.81–1.39).

Conclusions

Stress CMR effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pre-test clinical risk and in patients with prior CAD.