Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy.

AIMS: Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. METHODS AND RESULTS: We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. CONCLUSIONS: We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.

Permanent work disability in patients ≤50 years old after percutaneous coronary intervention and coronary artery bypass grafting (the CRAGS study).

Background: The aim of this study was to investigate the incidence of permanent working disability (PWD) in young patients after percutaneous or surgical coronary revascularization. Methods and Results: The study included 1035 consecutive patients ≤50 years old who underwent coronary revascularization [910 and 125 patients in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) groups, respectively] between 2002 and 2012 at 4 Finnish hospitals. The median follow-up time was 41 months. The overall incidence of PWD was higher after CABG compared to PCI (at 5 years, 34.8 vs. 14.7%, P < 0.001). Freedom from PWD in the general population aged 45 was 97.2% at 4 years follow-up. Median time to grant disability pension was 11.6 months after CABG and 24.4 months after PCI (P = 0.018). Reasons for PWD were classified as cardiac (35.3 vs. 36.9%), psychiatric (14.7 vs. 14.6%), and musculoskeletal (14.7 vs. 15.5%) in patients undergoing CABG vs. PCI. Overall freedom from PWD was higher in patients without major adverse cardiac and cerebrovascular event (MACCE) (at 5 years, 85.6 vs. 71.9%, P < 0.001). Nevertheless, rate of PWD was high also in patients without MACCE and patients with preserved ejection fraction during follow-up. Conclusions: Although coronary revascularization confers good overall survival in young patients, PWD is common especially after CABG and mostly for cardiac reasons even without occurrence of MACCE. Supportive measures to preserve occupational health are warranted concomitantly with coronary revascularization at all levels of health care.

[Percutaneous treatment of coronary chronic total occlusions]. / Sepelvaltimon kroonisen totaalitukoksen perkutaaninen hoito.

Chronic total occlusions (CTOs) are frequently detected on diagnostic coronary angiograms. For the selection of patients for CTO percutaneous coronary intervention, factors such as the level of symptoms, level of myocardial viability and extent of ischemia must be taken into account. Remarkable progress has been achieved in the success of complex CTO procedures during the past decade. In addition to antegrade wire escalation strategy, subintimal passage of the guidewire with or without dissection and re-entry techniques and retrograde techniques can be utilized. After successful wiring of the lesion, balloon angioplasty and stenting comparable to a non-CTO lesion are performed.

[Update on Current Care Guidelines. Current Care Guideline: Stable Coronary Artery Disease]. / Kaypa Hoite-Suosituksen Paivitystiivistelma. Stabiili sepelvaltimotauti.

This guideline covers coronary heart disease symptoms, diagnosis and treatment. Stable coronary heart disease refers to a disease in, which patients have stable symptoms and evidence of ischemia or significant stenosis of coronary artery. Diagnosis is based on medical history and exercise test, which is the primary diagnostic test. Coronary angiography is in selected cases necessary to confirm the diagnosis and assess invasive treatment. Pharmacotherapy aims to improve the survival of the patient, relieve symptoms and improve quality of life. The guideline also deals with invasive treatment either with PCI or CABG.

Predictors of permanent work disability among ≤50-year-old patients undergoing percutaneous coronary intervention.

OBJECTIVES: This study aimed to describe the incidence and periprocedural predictors of permanent work disability (PWD) pension among patients ≤50 years old who underwent percutaneous coronary intervention (PCI). METHODS: Patient records of 910 consecutive patients undergoing PCI at four Finnish hospitals in 2002-2012 were reviewed for baseline and procedural data and late adverse events. Data on permanent work disability (PWD) pension allocation were acquired from the Finnish Centre for Pensions, which governs the statutory pension security in Finland. RESULTS: Mean follow-up was 41 [standard deviation (SD) 31] months. Altogether 103/910 (11.3%) of patients were on PWD by the end of follow-up, 60 (58.3%) for cardiac diagnoses (cumulative freedom from PWD 81% at 7 years). Independent predictors of PWD were post procedural stroke [hazard ratio (HR) 4.7, 95% confidence interval (95% CI) 1.8-11.9], post procedural myocardial infarction (MI) (HR 3.3, 95% CI 1.8-6.0), diabetes (HR 2.0, 95% CI 1.1-3.7), discharge diuretics (HR 3.5, 95% CI 2.1-5.9), and increasing age (HR 1.2, 95% CI 1.1-1.3). Predictors of PWD for cardiac diagnoses were post procedural stroke and MI, discharge diuretics, and use of calcium-channel blockers, diabetes and older age. CONCLUSIONS: Patients ≤50 years old undergoing PCI are at a high risk for subsequent permanent disability for cardiac diagnoses. This finding underscores the need for reinforcing adherence to secondary prevention by cardiac rehabilitation and early collaboration with occupational health care professionals.

Prognosis and disease progression in patients under 50 years old undergoing PCI: the CRAGS (Coronary aRtery diseAse in younG adultS) study.

OBJECTIVE: Young patients undergoing percutaneous coronary intervention (PCI) are generally considered at low procedural risk, but the potentially aggressive nature of coronary artery disease and long expectancy of life expose them to a high risk of recurrent coronary events. The extent and determinants of disease progression in this patient subset remain largely unknown. The aim of the present study was to evaluate general risk factors for late outcomes among patients ≤50 years old who underwent PCI. METHODS: Coronary aRtery diseAse in younG adults (CRAGS) is a multicenter European retrospective registry that enrolled 1617 patients (age ≤50 years) who underwent PCI over the years 2002-2012. The median follow-up was 3.0 years. RESULTS: The majority of patients were smokers who were nevertheless prescribed adequate secondary prevention medication, including statins, aspirin, beta blockers and/or ACE inhibitors/AT blockers. At 5 years, survival was 97.8%, while freedom from major adverse cardiac and cerebrovascular events was 74.1%, from repeat revascularization 77.8% and from myocardial infarction 89.9%. Altogether 13.5% of patients exhibited disease progression that indicated a need for repeat revascularization. Other indications for repeat revascularization were restenosis (7.1%) and stent thrombosis (2.1%) at the 5-year follow-up. Independent post-PCI predictors of disease progression were multivessel disease, diabetes and hypertension. CONCLUSION: PCI is associated with excellent survival in patients ≤50 years old. Nevertheless, despite guideline-adherent medication, every eighth patient underwent repeat revascularization due to disease progression diagnosed at the median follow-up of three years, underscoring the need for more effective secondary prevention than currently available.

Comparison of 30-day and 5-year outcomes of percutaneous coronary intervention versus coronary artery bypass grafting in patients aged≤50 years (the Coronary aRtery diseAse in younG adultS Study).

Data on the outcome of young patients after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are scarce. Data on 2,209 consecutive patients aged≤50 years who underwent CABG or PCI were retrospectively collected from 15 European institutions. PCI and CABG had similar 30-day mortality rates (0.8% vs 1.4%, p=0.27), late survival (at 5 years, 97.8% vs 94.9%, p=0.082), and freedom from stroke (at 5 years, 98.0% and 98.0%, p=0.731). PCI was associated with significantly lower freedom from major adverse cardiac and cerebrovascular events (at 5 years, 73.9% vs 85.0%, p<0.0001), repeat revascularization (at 5 years, 77.6% vs 92.5%, p<0.0001), and myocardial infarction (at 5 years, 89.9% vs 96.6%, p<0.0001) compared with CABG. These findings were confirmed in propensity score-adjusted and matched analyses. Freedom from major adverse cardiac and cerebrovascular events after PCI was particularly low in diabetics (at 5 years, 58.0% vs 75.9%, p<0.0001) and in patients with multivessel disease (at 5 years, 63.6% vs 85.1%, p<0.0001). PCI in patients with ST elevation myocardial infarction was associated with significantly better 5-year survival (97.5% vs 88.8%, p=0.001), which was driven by its lower 30-day mortality rate (1.5% vs 6.0%, p=0.017). In conclusion, patients aged≤50 years have an excellent immediate outcome after either PCI or CABG with similar long-term survival when used according to the current clinical practice. PCI was associated with significantly lower freedom from myocardial infarction and repeat revascularization.

A new common mutation in the cardiac beta-myosin heavy chain gene in Finnish patients with hypertrophic cardiomyopathy.

BACKGROUND: In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. PATIENTS AND METHODS: Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. RESULTS: MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. CONCLUSION: Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland.

Association of resting heart rate with cardiovascular function: a cross-sectional study in 522 Finnish subjects.

BACKGROUND: High resting heart rate (HR) is associated with increased cardiovascular risk in general populations, possibly due to elevated blood pressure (BP) or sympathetic over-activity. We studied the association of resting HR with cardiovascular function, and examined whether the hemodynamics remained similar during passive head-up tilt. METHODS: Hemodynamics were recorded using whole-body impedance cardiography and continuous radial pulse wave analysis in 522 subjects (age 20-72 years, 261 males) without medication influencing HR or BP, or diagnosed diabetes, coronary artery, renal, peripheral arterial, or cerebrovascular disease. Correlations were calculated, and results analysed according to resting HR tertiles. RESULTS: Higher resting HR was associated with elevated systolic and diastolic BP, lower stroke volume but higher cardiac output and work, and lower systemic vascular resistance, both supine and upright (p < 0.05 for all). Subjects with higher HR also showed lower supine and upright aortic pulse pressure and augmentation index, and increased resting pulse wave velocity (p < 0.001). Upright stroke volume decreased less in subjects with highest resting HR (p < 0.05), and cardiac output decreased less in subjects with lowest resting HR (p < 0.009), but clear hemodynamic differences between the tertiles persisted both supine and upright. CONCLUSIONS: Supine and upright hemodynamic profile associated with higher resting HR is characterized by higher cardiac output and lower systemic vascular resistance. Higher resting HR was associated with reduced central wave reflection, in spite of elevated BP and arterial stiffness. The increased cardiac workload, higher BP and arterial stiffness, may explain why higher HR is associated with less favourable prognosis in populations.

Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. OBJECTIVE: To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. RESULTS: The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. CONCLUSION: The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM.

Age-dependent interaction of apolipoprotein E gene with eastern birthplace in Finland affects severity of coronary atherosclerosis and risk of fatal myocardial infarction--Helsinki Sudden Death Study.

BACKGROUND: Mortality from coronary heart disease (CHD) has been constantly higher in eastern late settlement regions compared to western early settlements in Finland, unrelated to classical risk factors. In line with this, eastern birthplace was an age-dependent predictor of severe coronary atherosclerosis and pre-hospital sudden coronary death among male residents of Helsinki. We investigated a possible interaction of apolipoprotein E (APOE) gene with birthplace on the risk of myocardial infarction (MI) and coronary atherosclerosis. METHOD: APOE genotypes were analyzed in the Helsinki Sudden Death Study series comprising out-of-hospital deaths among males aged 33-70 years (n = 577), who were born in high (east, n = 273) or low (west, n = 304) CHD mortality area. RESULTS: Eastern-born men ≤ 55 years carried 30% more often (P = 0.017) and older men 40% less often (P = 0.022) the APOE ϵ4 allele compared to western-born men (P = 0.003 for birthplace-by-age interaction). In multivariate analysis, the ϵ4 allele associated with the risk of out-of-hospital MI (odds ratio 2.58; 95% CI 1.20-5.55; P = 0.016) only in eastern-born men and with advanced atherosclerosis in both regions of origin, respectively. CONCLUSIONS: Birthplace-bound risk of CHD was age-dependently modified by APOE ϵ4 allele, suggesting genetic differences in CHD susceptibility between early and late settlement regions in Finland and providing one explanation for the eastern high mortality.

Severe hypocalcemia simulating ST-elevation myocardial infarction.

ST-elevation myocardial infarction (STEMI) is an emergency situation in which immediate measures for myocardial reperfusion are needed. The diagnosis is based on the recognition of ST-segment elevation in the electrocardiogram (ECG). In case of coronary artery occlusion, ST-segment elevation is caused by an injury current from the ischemic myocardium. Rarely, other mechanisms may lead to ECG changes mimicking STEMI. In our case, a 65-year-old man was presented to our institution with ECG abnormalities suggestive of STEMI. However, coronary angiography showed open arteries. Laboratory tests revealed severe hypocalcemia caused by a deficiency of vitamin D. After calcium replacement therapy, the ECG normalized, and the patient was discharged in good condition. Only a few case reports on hypocalcemia-induced ST-segment elevation exist, and the mechanism remains unknown.

Reduced systemic vascular resistance in healthy volunteers with presyncopal symptoms during a nitrate-stimulated tilt-table test.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Nitrates may facilitate syncope through various pathways, but the precise mechanism of nitrate-induced syncope is still under debate. The purpose of the present study was to compare the underlying haemodynamic mechanisms in subjects without and with presyncopal symptoms during a nitroglycerin-stimulated tilt-table test. WHAT THIS STUDY ADDS: A major decrease in systemic vascular resistance was documented in subjects with presyncope during 0.25 mg nitroglycerin-stimulated tilt-table test, in the absence of changes in cardiac output. These findings indicated that even a small dose of nitroglycerin significantly decreased arterial resistance and cardiac afterload. AIMS The mechanism of nitrate-induced syncope remains controversial. We examined the haemodynamic changes in healthy volunteers during nitroglycerin-stimulated tilt-table test. METHODS: Continuous radial pulse wave analysis, whole-body impedance cardiography and plethysmographic finger blood pressure were recorded in a supine position and during head-up tilt in 21 subjects with presyncopal symptoms (6 male/15 female, age 43 ± 3 years) after 0.25 mg sublingual nitroglycerin and 21 control subjects (6 male/15 female, age 43 ± 2 years). The drug was administered in the supine position and a passive head-up tilt followed 5 min later. Additionally, nitroglycerin was only administered during head-up tilt in 19 subjects and the haemodynamics were recorded. RESULTS: Supine and upright haemodynamics were similar before nitroglycerin administration in the two groups. During the nitroglycerin-stimulated tilt test, aortic and radial mean blood pressure decreased significantly more in the presyncope group when compared with the controls (P= 0.0006 and P= 0.0004, respectively). The decreases in systemic vascular resistance (P= 0.0008) and heart rate (P= 0.002), and increase in aortic reflection time (P= 0.0002) were greater in the presyncope group, while the change in cardiac index was not different between the groups (P= 0.14). If nitroglycerin was administered during the upright tilt and not in supine position, the haemodynamic changes were quite corresponding. CONCLUSIONS: Presyncopal symptoms during nitrate-stimulated tilt test were explained by decreased systemic vascular resistance and increased aortic reflection time, while cardiac output remained unchanged. These findings indicated reduced arterial resistance in nitroglycerin-induced presyncope.

Birthplace in area with high coronary heart disease mortality predicts the severity of coronary atherosclerosis among middle-aged Finnish men who had migrated to capital area: the Helsinki sudden death study.

BACKGROUND: Reasons why eastern-born male Finns have higher coronary heart disease (CHD) mortality than do western-born men are still unsettled. Recently, eastern birthplace was found to be an independent predictor of pre-hospital sudden cardiac death (SCD) in the new low-mortality area of residence. AIM: To investigate the association of birthplace with high CHD mortality attributes to more severe coronary atherosclerosis among men migrated to the low-mortality capital area. METHOD: Coronary atherosclerosis was measured in 373 western-born and 314 eastern-born out-of-hospital male deaths aged 33-70 years in Helsinki (The Helsinki Sudden Death Study), covering 24.6% of male deaths within this age-group. CHD risk factors were obtained from an interview of a next of kin. RESULTS: In multivariate analysis there was a strong birthplace-by-age interaction with atherosclerosis (P = 0.0005). Eastern-born men <54 years had larger areas of fatty streaks (P = 0.0195), fibrotic plaque (P = 0.0133), calcification (P = 0.0009), total plaque area (P = 0.0011), and greater stenosis (P = 0.0004) in the left coronary compared to western-born men, independent of CHD risk factors. Amongst older men (>or=54 years) such an association no longer appeared. CONCLUSION: Higher CHD mortality among eastern-born men may be due to more severe coronary atherosclerosis independently of CHD risk factors, reflecting Finns' two-phase settlement history.

Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

AIMS: The interleukin 18 (IL-18) gene has a single nucleotide promoter region (-137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors. METHODS AND RESULTS: TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78-7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39-29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-gamma mRNA (P = 0.004). CONCLUSION: Hypertension interacts with IL-18 gene promoter -137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.

Non-invasive measurement of the haemodynamic effects of inhaled salbutamol, intravenous L-arginine and sublingual nitroglycerin.

AIMS: To examine the effects of salbutamol and L-arginine, two compounds acting largely on the endothelium, and the endothelium-independent agent nitroglycerin on blood pressure, arterial compliance, cardiac function and vascular resistance. METHODS: Continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic blood pressure from fingers in the supine position and during head-up tilt were recorded in nine healthy subjects. Data were captured before and after L-arginine (10 mg mg(-1) min(-1)) or saline infusion, salbutamol (400 microg) or placebo inhalation, and sublingual nitroglycerin (0.25 mg) or placebo resoriblet. RESULTS: The results of all measurements were comparable before drug administration. The effects of inhaled salbutamol were apparent in the supine position: systemic vascular resistance (-9.2 +/- 2.6%) and augmentation index (-4.0 +/- 1.5%) decreased, and heart rate (8.6 +/- 2.5%) and cardiac output (8.8 +/- 3.1%) increased. L-arginine had no clear effects on supine haemodynamics, but during head-up tilt blood pressure was moderately decreased and reduction in aortic reflection time prevented, indicating improved large arterial compliance. Nitroglycerin reduced supine vascular resistance (-6.7 +/- 1.8%) and augmentation index (-7.4 +/- 1.6%), and increased cardiac output (+9.2 +/- 2.7%). During head-up tilt, nitroglycerin increased cardiac output (+10.6 +/- 5.6%) and heart rate (+40 +/- 7.5%), decreased vascular resistance (-7.8 +/- 5.8%) and augmentation index (-18.7 +/- 3.2%), and prevented the decrease in aortic reflection time. CONCLUSIONS: Inhaled salbutamol predominantly changed supine haemodynamics, whereas the moderate effects of L-arginine were observed during the head-up tilt. In contrast, small doses of nitroglycerin induced major changes in haemodynamics both supine and during the head-up tilt. Altogether, these results emphasize the importance of haemodynamic measurements in both the supine and upright positions.

ADAM8 and its single nucleotide polymorphism 2662 T/G are associated with advanced atherosclerosis and fatal myocardial infarction: Tampere vascular study.

OBJECTIVE: Previously, we scanned all 23,000 human genes for differential expression between normal and atherosclerotic tissues and found the involvement of ADAM8. METHODS: We investigated the expression of ADAM8 mRNA and protein level in human atherosclerotic tissues and non-atherosclerotic internal thoracic arteries as well as the association of ADAM8 2662 T/G single nucleotide polymorphism (SNP) with the extent of coronary atherosclerosis and with the risk of fatal myocardial infarction. RESULTS: ADAM8 mRNA was up-regulated in carotid, aortic, and femoral atherosclerotic plaques (n=24) when compared with non-atherosclerotic arteries. ADAM8 protein expression was increased in advanced atherosclerotic plaques as compared to control vessels wherein it was localized to macrophages and smooth muscle cells The G allele carriers of the ADAM8 2662 T/G SNP had significantly larger areas of fibrotic, calcified, and complicated plaques in coronary arteries (P=0.027, P=0.011, and P=0.011, respectively) and significantly higher occurrence of myocardial infarction (MI) (P=0.004) and fatal pre-hospital MI (P=0.003) than did the TT homozygotes. CONCLUSION: ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and MI.

Ageing and cardiovascular responses to head-up tilt in healthy subjects.

OBJECTIVE: Ageing is associated with increased postural blood pressure changes and attenuated cardiovascular reactivity. As the background of these changes remains uncertain, we examined arterial stiffness, cardiac function and vascular resistance in healthy subjects in supine position and during orthostatic challenge. METHODS: Haemodynamics of 179 normotensive subjects (109 female and 70 male, 21-59 years) were examined using continuous radial pulse wave analysis, whole-body impedance cardiography, and plethysmographic finger blood pressures. RESULTS: Both in supine position and during head-up tilt central and peripheral blood pressure and augmentation index (amplitude of the reflected pressure wave divided by pulse pressure) increased, and time of pulse wave reflection decreased with age. Supine pulse wave velocity progressively increased with age. There were only minor differences in supine and upright systemic vascular resistance, cardiac index, stroke index, and heart rate that were not systematically related to age. In regression analysis, the explanatory factors for a more pronounced decrease in central systolic blood pressure during the head-up tilt were in the age of 50-59 years, higher baseline pulse wave velocity and central systolic BP. None of the changes in other haemodynamic variables during tilt were related to age. CONCLUSION: As no systematic age-related differences were observed in cardiac function or vascular resistance, these results support the view that progressive reduction of large arterial compliance contributes to the exaggerated age-related decrease in central systolic blood pressure in response to head-up tilt.

[Coronary artery disease attack caused by cytotoxic chemotherapy]. / Solunsalpaajahoidon aiheuttama sepelvaltimotautikohtaus.

Capesitabine is a orally administered cytotoxic drug metabolized to 5-fluorouracil and is widely used in large intestine cancer and breast cancer therapy. Its adverse effects against the heart have been considered to be rare. We describe four patients, who were diagnosed with an attack of coronary artery disease during capesitabine therapy on the basis of coronary spasm. This adverse effect should be kept in mind as a cause of chest pain symptoms and the medication discontinued in a suspected case.

Birthplace predicts risk for prehospital sudden cardiac death in middle-aged men who migrated to metropolitan area: The Helsinki Sudden Death Study.

BACKGROUND: Eastern-born male Finns, irrespective of their place of residence, have high mortality from coronary heart disease (CHD), and half of such deaths are sudden. AIM: To study whether eastern birthplace alone or combined with life-style factors predicts risk for prehospital sudden cardiac death (SCD) in the new (west) low-mortality area of residence. METHOD: Prospective case-control autopsy study of all (700) out-of-hospital deaths of men aged 35-69 years in metropolitan Helsinki during 1981-82 and 1991-92. Data on CHD risk factors were obtained for 405, of whom 149 died of SCD (cases) and 256 of other causes (controls). RESULTS: A birthplace-by-age interaction with SCD (P=0.024) and with myocardial infarction (P=0.005) appeared. Men < or =54 years born in the east were more often victims of SCD (odds ratio 2.99, 95% confidence interval 1.38-6.49, P=0.006) than were men born in the west, independently of CHD risk factors. SCD was predicted also by alcohol consumption, age, smoking, and hypertension. Amongst older (>54 years) men no association with birthplace was any longer evident, but alcohol and socio-economic status predicted SCD. CONCLUSIONS: Birthplace-based risk for SCD suggests the contribution of early life environment or genetic east-west differences, reflecting Finns' two-phase settlement history.