James C Moon

Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy

Fast breath-hold cardiovascular magnetic resonance (CMR) shows excellent results for interstudy reproducibility of left ventricular (LV) volumes, ejection fraction, and mass, which are thought to be superior to results of 2-dimensional echocardiography. However, there is no direct comparison of the interstudy reproducibility of both methods in the same subjects. A total of 60 subjects (normal volunteers [n = 20], or patients with heart failure [n = 20] or LV hypertrophy [n = 20]) underwent 2 CMRs and 2 echocardiographic studies for assessment of LV volumes, function, and mass. The interstudy reproducibility coefficient of variability was superior for CMR in all groups for all parameters. Statistical significance was reached for end-systolic volume (4.4% to 9.2% vs 13.7% to 20.3%, p <0.001), ejection fraction (2.4% to 7.3% vs 8.6% to 19.4%, p <0.001), and mass (2.8% to 4.8% vs 11.6% to 15.7% p <0.001), with a trend for end-diastolic volume (2.9% to 4.9% vs 5.5% to 10.5%, p = 0.17). The superior interstudy reproducibility resulted in considerably lower calculated sample sizes (reductions of 55% to 93%) required by CMR compared with echocardiography to show clinically relevant changes in LV dimensions and function. Thus, CMR has excellent interstudy reproducibility in normal, dilated, and hypertrophic hearts, and is superior to 2-dimensional echocardiography.

Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?

The last two decades have seen major advances in the treatment of chronic heart failure, primarily as a result of therapeutic manipulation of activated neurohormonal systems. Despite this progress, many patients still suffer significant morbidity and premature death. Antagonism of the biological effects of endothelin, a potent vasoconstrictor, represents a further potential target. To date, positive results from animal models of heart failure have not been translated into clinical practice, perhaps as a consequence of the high doses of drug used. The ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study evaluated the effects of low dose bosentan, a non-selective endothelin receptor antagonist, in patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association class IIIb-IV). A total of 1,613 patients were randomized to receive either bosentan (125 mg twice a day) or placebo. The preliminary results were presented at the 51st Annual Scientific Session of the American College of Cardiology (17-20 March 2002, Atlanta, GA, USA). The primary endpoint of all-cause mortality or hospitalization for heart failure was reached in 321/808 patients on placebo and 312/805 receiving bosentan. Treatment with bosentan appeared to confer an early risk of worsening heart failure necessitating hospitalization, as a consequence of fluid retention. It has been suggested that further studies using even lower doses of bosentan or more aggressive concomitant diuretic therapy may avoid this adverse effect. The results from the ENABLE study have, however, thrown further doubt on the potential benefits of non-specific endothelin receptor blockade in heart failure.

Lamin mutation location predicts cardiac phenotype severity: combined analysis of the published literature

Objective Two LMNA genotype–phenotype cardiac correlations are reported: first, that cardiac involvement in multisystem laminopathies prevails with mutations upstream of the nuclear localisation signal (NLS); second, that worse outcomes occur with non-missense (compared with missense) mutations. We tested whether LMNA mutation DNA location and mutation subtype can predict phenotype severity in patients with lamin heart disease. Methods We used a semantic workflow platform and manual electronic literature search to identify published LMNA mutations with cardiac-predominant phenotype. Hierarchical cluster analysis (HCA) assembled lamin heart disease into classes based on phenotype severity. 176 reported causative mutations were classified and any relationships to mutation location/subtype assessed by contingency analysis. Results More adverse phenotype was associated with mutation location upstream of the NLS (p=0.014, OR 2.38, 95% CI 1.19 to 4.80) but not with non-missense mutations (p=0.337, OR 1.36, 95% CI 0.72 to 2.57), although an association with non-missense mutations was identified in a subcluster with malignant ventricular arrhythmia (p=0.005, OR 2.64, 95% CI 0.76 to 9.21). HCA limited to the 65 mutations described on ClinVar as pathogenic/likely pathogenic showed similar findings (upstream of NLS, p=0.030, OR 4.78, 95% CI 1.28 to 17.83; non-missense, p=0.121, OR 2.64, 95% CI 0.76 to 9.21) as did analysis limited to pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics standards. Conclusion Cardiac patients with an LMNA mutation located upstream versus downstream of the NLS have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones.