The importance of whether atrial fibrillation or heart failure develops first.

AIMS: Atrial fibrillation (AF) and heart failure often co-exist. It is unknown whether the sequence in which AF and heart failure develop is of significance regarding prognosis. We assessed the prognosis of AF patients hospitalized for heart failure based on the timing of AF and heart failure development. METHODS AND RESULTS: Consecutive AF patients hospitalized for heart failure were included. Patients who had developed AF before or consecutively with heart failure ('AF first') were compared with patients who had developed heart failure before AF ('heart failure first'). The primary endpoint was a composite of cardiovascular hospitalization or all-cause mortality. The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first (137 of 182 patients, 75%, vs. 45 of 182 patients, 25%). The two groups were similar regarding age and gender, but patients with AF first less often had coronary artery disease and had higher ejection fractions than patients with heart failure first (39 ± 14% vs. 32 ± 13%, P = 0.004). During 16 ± 11 months follow-up, the primary composite endpoint occurred less often in patients with AF first than in patients with heart failure first (49.6% vs. 77.7% of patients, P = 0.001). Development of AF first remained beneficial regarding the primary endpoint on multivariable analysis (adjusted hazard ratio 0.50, 95% confidence interval 0.29-0.86, P = 0.01). CONCLUSION: The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first. Prognosis in these patients was relatively benign as compared with those who had developed heart failure first.

Acute myocardial ischemia in a patient with heterozygous alpha-2-plasmin inhibitor deficiency.

In this brief report we present a patient with heterozygous alpha2 plasmin inhibitor (alpha2PI) deficiency who developed atherosclerosis and myocardial ischemia in the presence of multiple classical risk factors. Management was complicated by fear of bleeding complications with the use of antiplatelet agents and serious comorbidity.The role of alpha2PI in atherosclerosis and pathological clot formation is still not clear. This case shows, however, that atherosclerosis and acute cardiovascular events can develop in patients with reduced alpha2PI levels.

Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2/3.

BACKGROUND: Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two. METHODS AND RESULTS: We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, P<0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo. CONCLUSIONS: Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-beta signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

Vascular effects of quinapril completely depend on ACE insertion/deletion polymorphism.

INTRODUCTION: The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described. MATERIALS AND METHODS: In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries. RESULTS: In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2+/-5.11% [n=13] vs. 55.6+/-4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar between DD- and ID/II-genotype (59.6+/-9.19% [n=8] vs. 57.7+/-4.07% [n=35]; p=0.85). CONCLUSIONS: DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.

Efficacy of angiotensin II type 1 receptor blockade on reperfusion-induced arrhythmias and mortality early after myocardial infarction is increased in transgenic rats with cardiac angiotensin II type 1 overexpression.

Angiotensin II induces ischemia/reperfusion (I/R)-induced arrhythmias and blockade of the angiotensin II type 1 receptor (AT1R) may therefore be beneficial in preventing arrhythmias and decreasing mortality after myocardial infarction (MI). Because the AT1R is upregulated after myocardial ischemia, it was hypothesized that the level of AT1R expression would mediate the response to AT1R blockade. Transgenic (TGR) rats that overexpress the human AT1R and Sprague-Dawley rats were used as controls. Total duration of arrhythmia (seconds) after I/R injury was similar in TGR and SD rats (433 +/- 109 vs. 376 +/- 117, p = n.s.). AT1R blockade with losartan decreased total duration of arrhythmia in the TGR rats (433 +/- 110 s-164 +/- 48 s; p < 0.05), whereas it caused a nonsignificant increase in the SD rats (376 +/- 117 s-497 +/- 97). In vivo, survival in the first 24 hours after MI was impaired in TGR rats (39%; SD, 63%). Losartan improved survival significantly in TGR rats (from 39% to 80%, p < 0.05). A smaller, nonsignificant effect was observed in SD rats (63% to 81%). AT1R blockade is beneficial only when the AT1R was overexpressed, both in reducing the reperfusion-induced arrhythmias and mortality early after MI.