Sudden cardiac death after early-onset myocardial infarction. A multicentre longitudinal cohort study with 20 years' follow-up.

BACKGROUND: Sudden cardiac death (SCD) is a serious consequence of a myocardial infarction (MI), but identifying patients at risk of developing SCD remains a major clinical challenge especially in the case of juvenile MI. The aim of this study was to identify predictors of SCD after early-onset MI using long-term follow-up data relating to a large nationwide patient cohort. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2,000 patients experiencing a first MI before the age of 45 years, who were followed up for a median of 19.9 years. Fine-Gray proportional hazard models were used to assess the associations between their clinical, demographic and index event data and the occurrence of SCD. RESULTS: SCD occurred in 195 patients, who were more frequently males, hypertensive and/or diabetic; had a history of previous thromboembolic events with a greater atherosclerotic burden; and had a lower left ventricular ejection fraction (LVEF) after the index event. Multivariable analysis showed that the independent predictors of SCD were diabetes, hypertension, previous thromboembolic events, higher Syntax score, and a lower LVEF. There was no clear evidence of the clustering of SCD events during follow-up. SCD was the first post-MI clinical event in 101 patients; the remaining 94 experienced SCD after a non-fatal MI or hospitalisation for coronary revascularisation. CONCLUSIONS: SCD frequently occurs during the 20 years after early-onset MI. The nature of the identified predictors and the absence of clustering suggests that the pathophysiological basis of SCD may be related to progressive coronary atherosclerosis.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).

BACKGROUND: Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. RESULTS: MINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57-1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08-0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52-1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87-3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43-1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15-0.47;p < 0.001). CONCLUSIONS: MINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure. Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1-22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52-0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up. Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes. Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Myocardial infarction in the young: a sex-based comparison.

A relative paucity of information concerns the natural history, clinical features and coronary anatomy in young patients with acute myocardial infarction. In particular, there is a dearth of data relating to sex differences in young patients. The objective was to evaluate whether or not there are correlations between the clinical characteristics and the extent and localization of coronary artery lesions in young men compared with young women. The study population consisted of 1646 young patients (87% men, 13% women; mean age 39+/-5 years) with a first acute myocardial infarction admitted to one of the 125 coronary care units of Italy in a period of 3 years. Clinical data were collected. All patients underwent coronary angiography during hospitalization. Smoking, hypercholesterolemia and obesity were significantly more prevalent in men than in women; physical inactivity was significantly more prevalent among women. Hemodynamically significant coronary stenosis occurred in 82% of patients and were more frequent in men than in women (P<0.05). Women more frequently had single-vessel disease and no coronary lesions at all (58 vs. 47% and 24 vs. 9% women vs. men respectively, both P<0.05). Men more frequently had multivessel disease (38 vs. 13%, P<0.05). Significant stenosis mainly affected the left anterior descending artery (52%) with no gender-related difference; men more likely had lesions of the left circumflex or right coronary artery (P<0.05). In conclusion, young patients with a first acute myocardial infarction risk factors profile and extent of coronary artery lesions were significantly different between sexes.

Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction.

OBJECTIVES: The purpose of this study was to test whether the 9p21.3 variant rs1333040 influences the occurrence of new cardiovascular events and coronary atherosclerosis progression after early-onset myocardial infarction. BACKGROUND: 9p21.3 genetic variants are associated with ischemic heart disease, but it is not known whether they influence prognosis after an acute coronary event. METHODS: Within the Italian Genetic Study of Early-onset Myocardial Infarction, we genotyped rs1333040 in 1,508 patients hospitalized for a first myocardial infarction before the age of 45 years who underwent coronary angiography without index event coronary revascularization. They were followed up for major cardiovascular events and angiographic coronary atherosclerosis progression. RESULTS: Over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 cardiovascular deaths, 223 reoccurrences of myocardial infarction, and 383 coronary artery revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI]: 1.08 to 1.37) for heterozygous carriers and 1.41 (95% CI: 1.06 to 1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of cardiovascular death (p = 0.24) or the reoccurrence of myocardial infarction (p = 0.57), but did provide significant evidence that it influenced on the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI: 1.17 to 1.63) and 1.90 (95% CI: 1.36 to 2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002). CONCLUSIONS: In early-onset myocardial infarction, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.