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A canine model of chronic heart failure was produced by multiple sequential intracoronary embolizations with microspheres. Twenty closed-chest dogs underwent three to nine intracoronary embolizations performed 1-3 wk apart. Embolizations were discontinued when left ventricular (LV) ejection fraction was less than 35%. LV ejection fraction was 64 +/- 2% at baseline and decreased to 21 +/- 1% at 3 mo after the last embolization (P less than 0.001). During the same period, LV end-diastolic pressure increased from 6 +/- 1 to 22 +/- 3 mmHg (P less than 0.001); LV end-diastolic volume increased from 64 +/- 3 to 101 +/- 6 6 ml (P less than 0.001), and cardiac output decreased from 2.9 +/- 0.2 to 2.3 +/- 0.1 l/min (P less than 0.01). These changes were accompanied by significant increases of pulmonary artery wedge pressure and systemic vascular resistance. Plasma norepinephrine increased from 332 +/- 17 pg/ml at baseline to 791 +/- 131 pg/ml at 3 mo after the last embolization (P less than 0.01); plasma levels of atrial natriuretic factor increased from 12.7 +/- 10.0 to 28.8 +/- 8.6 pmol/l (P less than 0.01), whereas plasma renin activity remained unchanged. Gross and microscopic postmortem examination showed patchy myocardial fibrosis and LV hypertrophy. We conclude that multiple intracoronary embolizations with microspheres, separated in time, can lead to chronic heart failure in dogs. The preparation is stable and reproducible and manifests many of the sequelae of heart failure that result from loss of contractile myocardium.

In this study of patients with symptomatic heartfailure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.

These data indicate that transformation of left ventricular shape (increased chamber sphericity) is the most likely substrate for the development of functional mitral regurgitation.