Younger age of patients with myocardial infarction correlates with higher number of relatives with history of premature atherosclerosis

Background. Premature coronary artery disease belongs to the most pressing global issues in a modern cardiology. Family history appears to be one of the most important and signi�cant risk factors in young patients with myocardial infarction (MI). The aim of the study was to investigate the role of family history of premature cardiovascular disease (CVD) in patients <50 years with myocardial infarction (MI) compared to patients ≥ 50 years with MI and to young healthy people. Methods. The studied group (MI<50) consisted of 240 patients aged 26-49 years with MI. The control groups consisted of 240 patients (MI ≥ 50) with MI aged 50-92 years and 240 healthy people aged 30-49 years. Results. There were statistically signi�cant differences between the MI<50 and MI ≥ 50 and young healthy groups regarding family history of premature MI/ischaemic stroke and percent of patients with of ≥ 2 relatives affected including parents, children, siblings, siblings of parents and grandparents (10.8%, 2.9%, 3.7%, respectively; p<0.0001). There was a statistically signi�cant negative correlation between the age of the �rst episode of MI and the number of relatives with a history of premature MI/stroke (r=0.249, p<0.05) within all MI patients. Statistically signi�cant differences between MI<50 and MI ≥ 50 groups as well as young healthy control group were revealed regarding prevalence of smoking, body mass index (BMI), LDL, HDL, triglycerides (TG) and glucose levels. Conclusions. Younger age of patients with myocardial infarction correlates with a higher number of relatives with a history of premature MI/ischemic


Background
Coronary artery disease (CAD), according to the report of the American Heart Association, remains the leading cause of cardiovascular diseases (CVD) deaths [1].Regarding this, premature CAD seems to be one of the most pressing global issues in this area.
Data regarding the prevalence of myocardial infarction (MI) in young people differ according to assumptive cut-off age and study population.The percent of patients aged < 35 years who underwent cardiac catheterization due to MI was determined to be 2% [2].Recently published data reported 10% of patients with MI, ST-elevation MI (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA) were ≤ 40 years of age [3].Patients aged < 40 years represented 1.2% of all patients with MI in a Polish study [4].When a cut-off age of 45 was established, the percent of patients increased to 3.2% [5].The percent of adults aged < 55 years with MI within participants of the Global Registry of Acute Coronary Events (GRACE) was 23 [6].In one of the recently published meta-analysis the cut-off age for young age of acute coronary syndrome (ACS) has been set down on the level of 50 [7].
Family history appears to be one of the most important and signi cant risk factors in young patients with MI.It covers inherited genetic as well as environmental risk factors (diet, lifestyle, smoking).A recently published Polish study (the MAGNETIC Project) revealed that young adults with a family history of premature CAD presented unfavourable dietary patterns, which suggested the possible continuity of familial lifestyle across generations [8].
A family history of premature CV events is de ned as MI or ischaemic stroke in the-rst degree relatives at age < 55 years in men and < 65 years in women [9,10].The INTERHEART study indicated that parental history of CAD was a risk factor independent of environmental, cultural, behavioural, classical, and genetic conditions [11].Furthermore, the age of onset of disease in parents and whether one or both parents are affected is valuable information providing an assessment of individual risk of MI.
Nevertheless, the data regarding the role of a history of premature CV events in family members other than parents are scarce.
The aim of the study was to analyse risk factors for MI at young age, particularly the role of a family history of CVD.Regarding the plenty of cut-off ages for young MI among the literature, we assumed this limit on the level of 50 years.We investigated the family history of premature MI/ischaemic stroke in patients with MI at age < 50 compared to patients with MI at age ≥ 50 and to healthy young people.We assessed correlations between the number of relatives affected and the age of MI patients, including not only parents but also other family members such as siblings, grandmothers, grandfathers, children and siblings of parents.

Patients
The investigated population included 720 people, partly participants of the previously published study [12].The data from studied group have been compared to the control group (MI ≥ 50 group) including also 240 patients admitted to our department due to the rst episode of MI, aged ≥ 50 years, range 50-92 (mean 65.9 years, SD ± 12.6), including 152 men and 88 women (63.3% and 36.7%,respectively).
The another control group consisted of healthy young people, aged, similarly to the studied group < 50 years (mean 43.2 years, SD ± 5.0, range from 30 to 49 years), without history of CAD.This group (young healthy controls) included 137 men and 103 women (57.1% and 42.9%, respectively).These participants were recruited in the Regional Blood Centre and a general practitioner outpatient clinic.
We collected from all participants of the study (together 720 people) detailed information regarding family history of premature CVD (MI/ischaemic stroke in men aged < 55 and in women aged < 65), body mass index (BMI), smoking, hypertension, diabetes mellitus (DM) and depression.Hypertension was de ned, according to ESH/ESC (European Society of Hypertension, European Society of Cardiology) guidelines as values ≥ 140 mmHg of systolic blood pressure (SBP) and/or ≥ 90 mmHg of diastolic blood pressure (DBP), based on blood pressure measurement, medical history and ongoing blood pressurelowering treatment [13].DM was assessed accordingly to WHO and ADA (American Diabetes Association) guidelines based on a fasting plasma glucose ≥ 126 mg/dl or ≥ 200 mg/dl in an oral glucose tolerance test measurements, based on medical history and hypoglycaemic ongoing treatment [14].
The investigation conforms to the principles outlined in the Declaration of Helsinki.The study protocol was approved by the Ethical Committee of the Centre of Postgraduate Medical Education.The participants gave written informed consent for participation in the study.

Biochemical analyses
The blood for all biochemical analyses, including glucose, total cholesterol, HDL and LDL cholesterol and triglyceride (TG) plasma concentrations was taken in the rst morning after admission to the hospital.
Analyses were determined from fasting blood samples by standard enzymatic methods using COBAS INTEGRA 800 reagents and equipment (Roche Diagnostics Gmbh, Manheim, GE).

Statistical analysis
The comparison of the studied groups was performed using the U Mann-Whitney test, p values were corrected for multiple comparisons, and the level of signi cance was established at 0.05.Correlations were assessed using Spearman's test for abnormal data distribution.Statistical analyses were performed using the Statistica software package (StatSoft Inc., Tulsa, USA).

Socio-economic characteristics of the studied groups
There were no signi cant differences between MI < 50 and MI ≥ 50 in the level of education (primary, vocation, secondary or university) or the type of job (unemployed, blue collar, white collar or pensioners).
There was a statistically signi cant difference in a marital status (percent of married people: 74.9% in MI < 50 vs 64.1% in MI ≥ 50 group, p = 0.04) between these groups (Table 2).
Comparing the MI < 50 group and the young healthy control group, there was a statistically signi cant difference in the level of education (percent of people with university degree: 22.1% vs 41.4%, respectively, p < 0.0001).Although, patients with premature MI were less commonly employed as white collars compared with young healthy people, there were no differences between these groups in the type of job as well as in a marital status.

Family history
There were statistically signi cant differences between MI < 50, MI ≥ 50, and the young healthy group in the presence of a family history of premature CVD in the rst-degree relatives: 32.9% vs 9.6% (p < 0.0001) and 32.9% vs 11.7% (p < 0.0001), respectively (Table 3).There were also statistically signi cant differences between MI < 50, MI ≥ 50 and the young healthy group in the presence of a family history of premature CVD age involving the rst-and the second-degree relatives: 35.9% in MI < 50 group vs 15.6% in MI ≥ 50 (p < 0.0001) and 14.2% in young healthy controls (p < 0.0001).Moreover, there were statistically signi cant differences between studied groups in the family history of CVD events within family members (the rst-and the second-degree relatives) for each age category -65.4% in MI < 50 group vs 47.6% in MI ≥ 50 (p < 0.0001) and 41.7% in young healthy controls (p < 0.0001).
There was a statistically signi cant negative correlation between the age of the rst episode of MI and the number of the rst-degree relatives with a history of premature MI/stroke (r = 0.249, p < 0.05) within all MI patients (Fig. 2).There was also a clear correlation between the age of MI and the number of affected the rst-and the second-degree relatives with premature CVD events (r = 0.208, p < 0.05), the number of the rst-degree relatives with CVD event in each age category (r = 0.235, p < 0.05) and the number of the rst-and the-second degree relatives with CVD events at every age (r = 0.193, p < 0.05).

Discussion
In our study there was a signi cantly higher incidence of a family history of premature CVD events in patients with MI age < 50 in comparison to patients with MI at age ≥ 50 and to healthy young people.
Family history is a CAD risk factor independent from other risk factors.In the Malmo Diet and Cancer Study, family history of coronary heart disease (CHD) was associated with an incidence of CHD with a hazard ratio of 1.52 (95%CI: 1.39-1.65),and only a small proportion of the family history effect was mediated by hypertension, hyperlipidaemia and diabetes [15].
Although the highest cardiovascular risk was associated with a maternal history at age < 50 years and a paternal history at age < 55 years, no substantial differences were seen between maternal and paternal positive CVD history [16].In a Dutch Cohort study a particularly high incidence of CVD has been revealed in people with parental onset of MI before age 70, with maternal history of MI before age 60 being the strongest predictor of CVD incidence [17].
Offspring age of onset of CVD is signi cantly associated with both maternal and paternal age of CVD onset [18].Nevertheless, data regarding the role of a family history of CVD that includes relatives other than parents or the number of affected family members are scarce.
In our study, there were signi cant differences between MI < 50, MI ≥ 50 group and young healthy controls in positive family history of CVD involving not only the prevalence of premature CVD events restricted to parents but also such events in other the rst-and the second-degree relatives.Moreover, there were statistically signi cant differences between the studied groups in the prevalence of CVD events at every age in family members (the rst-and the second-degree relatives).A higher number of relatives with a positive history of CAD, including parents, children, siblings, siblings of parents and grandparents, was associated with a younger age of MI.
Interestingly, there was a clear negative correlation between the age of the rst MI and the number of relatives with premature CVD events, and this relationship was particularly evident in the analysis involving the rst-degree relatives, but not exclusively.An Italian study revealed that being a relative (including parents, siblings and siblings of parents) of an early-onset MI case confers an adjusted hazard ratio of 2.7 for such events [19].There are also data indicating that early-onset hypertension in grandparents raises the risk for hypertension in grandchildren, even after adjusting for early-onset hypertension in parents and for lifestyle factors [20].
Among other risk factors, the prevalence of smoking, BMI, HDL, LDL, TG and glucose levels differs signi cantly between the MI < 50 group and both control groups (MI ≥ 50 and healthy controls aged < 50) in our study.Such ndings are independent of region and patient ethnicity across the literature [21,22].For instance, our data are in concordance with recently published data from New Zealand, conducted in a more complex population, including Caucasians, Maori and Paci c islanders [23].Although, among the risk factors for MI at a young age, smoking, hyperlipidaemia and obesity are crucial, there are some differences in their distribution between particular groups of patients [24,25].For example, the strongest predictor of ACS in women ≤ 45 years of age was diabetes, with a 6-fold increase in risk [26].Our study con rmed the signi cance of smoking, dyslipidaemia, obesity and carbohydrates metabolism disturbances as CAD risk factors.
The major limitation of our study is a relatively small number of patients, thus the ndings are di cult to apply to a larger, more diverse population.On the other hand, the high homogeneity of the groups, limited to Polish population of a Caucasian race, could be of value regarding the potential population and racial differences in the pathogenesis of CAD, particularly taking into account heritable risk factors.The control group of young healthy blood donors, usually more educated and more conscious of lifestyle than general population, may not represent the community at large.On the other hand, the fact that donors stay free from CAD until the age of 50, whereas our young patients suffer from MI before this age, enhances the role of lifestyle in CAD prevention.

Conclusions
This study revealed that the number of family members with premature CAD correlated with the age of the rst episode of ACS.The utility of this ndings seems to be important for an individual life-style changes interventions as a rational CVD prevention.Once a positive family history, particularly strengthened by such data, has been established, the health care provider can emphasise the increased likelihood of MI at a young age as a strong incentive for patient-dedicated improvement in adherence to healthy life style and medical regimen.
In conclusion, family history of an early MI or stroke is one of the most evident risk factors for MI at a young age apart from smoking, BMI, lipid and glucose levels.Younger age of MI is associated with a higher number of relatives with a history of premature atherosclerosis.Thus, the family history of premature atherosclerosis involving not only the rst-, but also the second-degree relatives, seems to be valuable and could be considered in an individual CAD risk evaluation in young people.Differences between the MI<50, MI≥50 and young healthy control groups in the percent of cases with 0, 1 or ≥2 the rst-and the second-degree relatives with the history of CVD events including: a. family history of premature CVD events: 11.1% MI<50 group vs 3% in MI ≥50 (p<0.0001) and 11.1% vs 3.7% in healthy young controls (p<0.0001);b. family history of CVD events at every age: 21.4% in MI<50 group vs 12.7% in MI ≥50 (p<0.0001) and 10.8% in healthy young controls (p<0.0001).

Abbreviations
Correlations between the age of the patient rst MI and the number of relatives with a history of CVD events: a. correlation between the age at the rst MI and the number of the rst-degree relatives with premature CVD events (r=0.249,p<0.05); b. correlation between the age at the rst MI and the number of the rst-and the second-degree relatives with premature CVD events (r=0.208,p<0.05); c. correlation between the number of the rst-degree relatives and the number of relatives with CVD events at every age (r=0.235,p<0.05); d. correlation between the number of the rst-and the second-degree relatives and the number of relatives with CVD events at every age (r=0.193,p<0.05).
The studied group consisted of 240 young patients aged < 50 years (mean age 43.5, SD ± 5.0; range 26-49) admitted to the Department of Cardiology, Centre of Postgraduate Medical Education, Grochowski Hospital (Warsaw) with the rst episode of MI diagnosed based on ST changes in ECG including STEMI (ST elevation MI) as well as NSTEMI (non-ST elevation MI), serum troponin levels and clinical manifestation.The group (MI < 50 group) consisted of 188 men and 52 women (78.3% and 21.7%, respectively).

Figures
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Figure 1
Figure 1 The participants gave written informed consent for participation in the study.The investigation conforms to the principles outlined in the Declaration of Helsinki and the study protocol was approved by the Ethical Committee of the Centre of Postgraduate Medical Education.