IMPORTANCE Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known. OBJECTIVE To determine the long-term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI). DESIGN, SETTING, AND PARTICIPANTS Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67–93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure). RESULTS Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%).At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P <.001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27–2.04), MACE (HR, 1.56; 95% CI, 1.26–1.93), MI (HR, 2.09; 95% CI, 1.45–3.03), and heart failure (HR, 1.52; 95% CI, 1.09–2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71–1.38) and MACE (HR, 1.23; 95% CI, 0.91–1.66) vs RMI. CONCLUSIONS AND RELEVANCE In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing.

Patients with CAD and high plasma tHcy levels had elevated plasma levels of Iso-P. The increase remained unaffected by plasma tHcy-lowering therapy, suggesting that homocysteine per se does not cause increased lipid peroxidation. Levels of plasma ICAM-1 and S-AA were increased in patients with high plasma tHcy, suggesting an association between homocysteinemia and low-grade inflammation.

A nonsignificant trend to increased plasma levels of asymmetric dimethylarginine in patients with high plasma total homocysteine levels may be explained by concomitant subtle renal dysfunction. Substantial reduction of plasma total homocysteine did not affect the level of plasma asymmetric dimethylarginine.

It has been suggested that hyperhomocysteinemia observed in patients with occlusive vascular disease is caused by reduced renal function secondary to renovascular disease. We have therefore used serum cystatin C, a new sensitive marker for glomerular filtration, in 59 patients with acute coronary syndromes and high plasma homocysteine (tHcy) concentration to measure renal function. Samples were also obtained from 34 patients with low-normal plasma tHcy and 50 control subjects. The patients with low-normal plasma tHcy concentration showed decreased concentrations of serum cystatin C and serum creatinine and increased concentrations of blood folate and serum cobalamin compared to the controls and to the patients with high plasma tHcy. There was a large overlap in cystatin C concentrations between patients with high and low-normal plasma tHcy. None of the parameters investigated except plasma tHcy were significantly different in the group of patients with high plasma tHcy concentration compared to the control group. In order to further demonstrate the importance of renal impairment, a subgroup of the patients with high plasma tHcy was supplemented daily with folic acid 5 mg, pyridoxine 40 mg and cyancobalamin 1 mg for 3 months. Vitamin therapy reduced plasma tHcy from 18.3+/-4.6 pmol/l to 9.6+/-2.2 pmol/l (p<0.0001). However, vitamin treatment did not strengthen the correlation between cystatin C and plasma tHcy concentrations. These findings do not support the hypothesis that subtle renal dysfunction is an important cause of high plasma tHcy concentration in patients with acute coronary syndromes.

Despite the growing evidence that elevated total homocysteine (tHcy) in plasma is a cardiovascular risk factor, the mechanism underlying the vascular injury is still unknown. Studies are difficult due to the fact that little is known about the formation of different homocysteine species in vivo. In the present study we have investigated the different fractions of tHcy in 21 patients with acute coronary syndromes and elevated concentration of plasma tHcy. A subgroup of the patients (n=16) was investigated before and after a 3 months study period with or without vitamin supplementation (folic acid 5 mg, pyridoxine 40 mg and cyanocobalamin 1 mg once daily). A major finding is that these patients had a lowered ratio (0.95%) between the concentration of reduced homocysteine (HcyH) and tHcy compared to controls (1.38%). A low ratio HcyH/tHcy in plasma in combination with elevated plasma tHcy concentrations might reflect increased oxidative activity or decreased reducing capacity in plasma from the patients. Another main finding in the present study is that, although vitamin supplementation of these patients normalized plasma tHcy, the ratio between HcyH and tHcy did not normalize. Since substantial evidence indicates that progression of arteriosclerosis is related to enhanced oxidant activity, the premature vascular disease associated with increased plasma tHcy concentration might be due to increased oxidative activity and the elevated plasma tHcy concentration may only reflect the increased oxidative stress.