New-onset atrial fibrillation is associated with cardiovascular events leading to death in a first time myocardial infarction population of 89,703 patients with long-term follow-up: a nationwide study.

BACKGROUND: New-onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients. METHODS AND RESULTS: All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new-onset AF on all-cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re-infarction and noncardiovascular death, were analyzed by multiple time-dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow-up of 5.0 ± 3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus-rhythm (n=78 992): all-cause mortality 173.9 versus 69.4 per 1000 person-years, cardiovascular death 137.2 versus 50.0 per 1000 person-years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person-years, fatal/nonfatal re-infarction 29.0/60.7 versus 14.2/37.9 per 1000 person-years. In time-dependent multiple Cox analyses, new-onset AF remained predictive of increased all-cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re-infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non- cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P<0.001). Propensity-score matched analyses yielded nearly identical results (all P<0.001). CONCLUSIONS: New-onset AF after first-time MI is associated with increased mortality, which is largely explained by more cardiovascular deaths. Focus on the prognostic impact of post-infarct AF is warranted.

A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic mice.

Chronic renal failure markedly accelerates atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice. To study the putative role of receptor for advanced glycation end products (RAGE) in development of uremic atherosclerosis, apoE(-/-) mice received intraperitoneal injections thrice weekly of a neutralizing murine RAGE-antibody (RAGE-ab) (n=21) or an isotype-matched control antibody (placebo-ab) (n=23). Treatment was started 4 weeks after surgical 5/6 nephrectomy in 16 weeks old mice and continued for 12 weeks. The RAGE-ab did not affect blood pressure, plasma cholesterol or measures of uremia. However, the aortic plaque area fraction was reduced by 59% in RAGE-ab compared with placebo-ab-treated mice (0.016 +/- 0.002 versus 0.039 +/- 0.005, P<0.001). In plasma, the RAGE-ab reduced concentrations of oxidized phospholipid neo-epitopes in plasma as detected by the specific monoclonal antibody EO6 (P<0.05) and titers of IgG antibodies against oxidized low-density lipoprotein (P<0.001). In the aorta of treated mice, the RAGE-ab did not affect the mRNA expression of eight selected genes associated with inflammation. The results suggest that blockade of RAGE reduces the proatherogenic effects of uremia, possibly through a systemic decrease in oxidative stress.

Effect of uremia on HDL composition, vascular inflammation, and atherosclerosis in wild-type mice.

Wild-type mice normally do not develop atherosclerosis, unless fed cholic acid. Uremia is proinflammatory and increases atherosclerosis 6- to 10-fold in apolipoprotein E-deficient mice. This study examined the effect of uremia on lipoproteins, vascular inflammation, and atherosclerosis in wild-type C57BL/6J mice. Uremia was induced by nephrectomy (NX) and increased plasma urea and creatinine concentrations 2.5- to 4.5-fold; control mice were sham operated. After NX, mice were fed a Western-type diet or the same diet with 0.5% cholic acid. Cholic acid-fed NX mice did not thrive and were killed. In NX mice fed the Western-type diet (n = 7), the total plasma cholesterol concentration was similar to that in sham mice (n = 11), but on gel filtration the LDL/HDL cholesterol ratio was increased. HDL from NX mice contained more serum amyloid A and triglycerides and less cholesterol than HDL from sham mice. Plasma concentrations of sICAM-1 and sVCAM-1 and aortic mRNA expression of ICAM-1 and VCAM-1 did not differ between NX and sham mice. Twenty-six weeks after NX, the average oil red O-stained area of the aortic root was similar in NX and sham mice fed the Western-type diet, while it was increased in cholic acid-fed sham mice. The results suggest that moderate uremia neither induces aortic inflammation nor atherosclerosis in C57BL/6J mice despite increased LDL/HDL cholesterol ratio and altered HDL composition.