Juha S. Perkiömäki

Heart Rate Variability and Non-Linear Dynamics in Risk Stratification

The time-domain measures and power–spectral analysis of heart rate variability (HRV) are classic conventional methods to assess the complex regulatory system between autonomic nervous system and heart rate and are most widely used. There are abundant scientific data about the prognostic significance of the conventional measurements of HRV in patients with various conditions, particularly with myocardial infarction. Some studies have suggested that some newer measures describing non-linear dynamics of heart rate, such as fractal measures, may reveal prognostic information beyond that obtained by the conventional measures of HRV. An ideal risk indicator could specifically predict sudden arrhythmic death as the implantable cardioverter-defibrillator (ICD) therapy can prevent such events. There are numerically more sudden deaths among post-infarction patients with better preserved left ventricular function than in those with severe left ventricular dysfunction. Recent data support the concept that HRV measurements, when analyzed several weeks after acute myocardial infarction, predict life-threatening ventricular tachyarrhythmias in patients with moderately depressed left ventricular function. However, well-designed prospective randomized studies are needed to evaluate whether the ICD therapy based on the assessment of HRV alone or with other risk indicators improves the patients’ prognosis. Several issues, such as the optimal target population, optimal timing of HRV measurements, optimal methods of HRV analysis, and optimal cutpoints for different HRV parameters, need clarification before the HRV analysis can be a widespread clinical tool in risk stratification.

The prognostic accuracy of different QT interval measures.

Background: The QT intervals accuracy for predicting arrhvthmic death varies between studies, possibly due to differences in the selection of the lead used for measurement of the QT interval. The purpose of this study was to analyze the prognostic accuracy of all known ways to select the lead.

Prognostic Significance of Impaired Baroreflex Sensitivity Assessed from Phase IV of the Valsalva Maneuver in a Population-Based Sample of Middle-Aged Subjects

Depressed baroreflex sensitivity (BRS) is associated with an increased risk of mortality in patients with a known cardiac disease. The prognostic significance of BRS in subjects without history of major cardiovascular (CV) events is unknown. The present study tested the hypothesis that impaired BRS predicts the CV mortality in a population-based sample of middle-aged subjects. The present study is a part of the Oulu Project Elucidating Risk of Atherosclerosis study, where middle-aged hypertensive and age- and gender-matched control subjects were randomly selected. Along with clinical and laboratory assessments, BRS was measured from the blood pressure overshoot of Valsalva maneuver in 559 subjects (age 51 ± 6xa0years; 300 men). The causes of death (nxa0= 72) were registered during a follow-up of up to 19xa0years. CV death (nxa0= 23) was defined as the primary end point. CV death was predicted by smoking status, alcohol consumption, high-sensitivity C-reactive protein, use of diuretics, waist circumference, and fasting glucose. Among all measured risk factors, impaired Valsalva BRS (<3xa0ms/mm Hg) was the most potent predictor of CV death (hazard ratio 9.1, 95% confidence interval 3.8 to 21.7, p <0.001) and remained so after adjustments for the other significant predictors (hazard ratio 5.3, 95% confidence interval 2.1 to 13.3, pxa0<0.001). In conclusion, impaired Valsalva BRS is a potent and independent predictor of CV death in a population-based sample of middle-aged subjects without history of major CV complications and may have important clinical implications in early risk stratification.

Non-alcoholic fatty liver disease with and without metabolic syndrome: Different long-term outcomes.

BACKGROUNDnNon-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are both shown to increase the risk of cardiovascular diseases and type 2 diabetes. However, there is a great overlap between these two diseases. The present study was aimed to examine the cardiovascular and metabolic prognosis of non-alcoholic fatty liver disease with and without metabolic syndrome.nnnMETHODSnMiddle-aged subjects (n=958) were divided into four subgroups, those with NAFLD and MetS, those with NAFLD or MetS, and healthy controls. The baseline characteristics of the subgroups were analyzed. The follow-up time for cardiovascular events was about 16years. After approximately 21years the cardiac ultrasound and laboratory parameters were re-analyzed and new type 2 diabetes cases were recorded.nnnRESULTSnThose with both diseases were at the greatest risk for cardiovascular events (p<0.001). Compared to healthy controls, only those with MetS, with or without NAFLD, were at increased risk for the development of type 2 diabetes (p<0.001) and for an increase in left ventricular mass index (p=0.001 and p=0.005, respectively). The cardiovascular and metabolic risk in subjects with NAFLD only was quite similar to that in healthy controls. The I148M variant of the patatin-like phospholipase domain-containing 3 gene (PNPLA3 polymorphism) was most present in those with NAFLD only (p=0.008).nnnCONCLUSIONSnNAFLD with MetS implies a considerable risk for cardiovascular diseases, type 2 diabetes and the increase of left ventricular mass index whereas NAFLD without MetS does not.

Sudden cardiac death during physical exercise: Characteristics of victims and autopsy findings

Abstract Objective. To provide data on the risk factors and characteristics of subjects who experience sudden cardiac death (SCD) during physical exercise. Methods and results. We assessed the characteristics and the medico-legal autopsy findings of SCD victims who had experienced a witnessed fatal cardiac arrest at rest (n = 876) or in relation to physical exercise (n = 328) in the Finnish Study of Genotype and Phenotype Characteristics of SCD (FinGesture). A total of 876 (73%) witnessed SCDs occurred at rest (R group) and 328 (27%) during or immediately after physical exercise (PE group). Male gender was more common in the PE group compared to the R group (309/328, 94% versus 678/876, 77%, P < 0.001). Coronary artery disease was a more common structural heart disease than non-ischemic disease at autopsy when SCD was exercise-triggered (299/328, 91% versus 657/876, 75%, P < 0.001). Myocardial scarring and cardiac hypertrophy were more commonly found at autopsy in the PE group (194/328, 59% versus 370/876, 42%, P < 0.001; 243/328, 74% versus 585/876, 67%, P = 0.012, respectively). Skiing, cycling, and snow shoveling were the most common modes of exercise at the time of SCD. Conclusions. SCD during or immediately after exercise is related to male gender, ischemic heart disease, cardiac hypertrophy, and myocardial scarring.

Predictors of Development of Echocardiographic Left Ventricular Diastolic Dysfunction in the Subjects Aged 40 to 59 Years (from the Oulu Project Elucidating Risk of Atherosclerosis Study)

Factors in the middle age that are associated with the risk for development of diastolic dysfunction in long term are not fully established. The Oulu Project Elucidating Risk of Atherosclerosis OPERA study randomly selected middle-aged subjects with hypertension and age- and gender-matched control subjects (nxa0= 1,045, age 51 ± 6xa0years, men 49.8%). After >20xa0years of follow-up, majority of the subjects still alive were available for reexaminations (nxa0= 600). After excluding the subjects with mitral regurgitation, left ventricular ejection fraction <50%, and those from whom echocardiographic septal E/E could not be reliably measured, the present analysis included 460 subjects. E/E was divided into 3xa0subgroups (subgroup 1: E/E ≤8, subgroup 2: 8 < E/E < 15, subgroup 3: E/E ≥15), subgroup 3 suggesting a significant diastolic dysfunction. Several baseline variables were associated with diastolic dysfunction: greater age (pxa0= 0.001), female gender (pxa0= 0.001), shorter height (p <0.001), larger body mass index (pxa0= 0.008), greater systolic blood pressure (pxa0= 0.001), greater pulse pressure (p <0.001), lower baroreflex sensitivity (pxa0=xa00.007), lower estimated glomerular filtration rate (pxa0= 0.02), greater atrial natriuretic peptide (pxa0= 0.001), greater fasting plasma glucose (pxa0= 0.001), more common occurrence of diabetes (pxa0= 0.011), and more common usage of antihypertensive medication (pxa0=xa00.001). After adjustments in the multivariate model, only systolic blood pressurexa0(pxa0=xa00.001), shorter height (pxa0= 0.002), and estimated glomerular filtration rate (pxa0=xa00.006) retained a significant association with the risk of developing diastolic dysfunction. In conclusion, greater systolic blood pressure, short height, and lower estimated glomerular filtration rate of the middle-aged subjects were the main determinants of development of diastolic dysfunction during a 20-year follow-up.

Exercise Capacity and Heart Rate Responses to Exercise as Predictors of Short-Term Outcome Among Patients With Stable Coronary Artery Disease

Although exercise capacity (EC) and autonomic responses to exercise predict clinical outcomes in various populations, they are not routinely applied in patients with coronary artery disease (CAD). We hypothesized that the composite index of EC and exercise heart rate responses would be a powerful determinant of short-term risk in CAD. Patients with angiographically documented stable CAD and treated with β blockers (n = 1,531) underwent exercise testing to allow the calculation of age- and gender-adjusted EC, maximal chronotropic response index (CRI), and 2-minute postexercise heart rate recovery (HRR, percentage of maximal heart rate). Cardiovascular deaths and hospitalization due to heart failure, registered during a 2-year follow-up (n = 39, 2.5%), were defined as the composite primary end point. An exercise test risk score was calculated as the sum of hazard ratios related to abnormal (lowest tertile) EC, CRI, and HRR. Abnormal EC, CRI, and HRR predicted the primary end point, involving 4.5-, 2.2-, and 6.2-fold risk, respectively, independently of each other. The patients with intermediate and high exercise test risk score had 11.1-fold (95% confidence interval 2.4 to 51.1, p = 0.002) and 25.4-fold (95% confidence interval 5.5 to 116.8, p <0.001) adjusted risk for the primary end point in comparison with the low-risk group, respectively. The addition of this risk score to the established risk model enhanced discrimination by integrated discrimination index and reclassification by categorical and continuous net reclassification index (p <0.001 for all). In conclusion, the composite index of EC and heart rate responses to exercise and recovery is a powerful predictor of short-term outcome in patients with stable CAD.

Association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease

BACKGROUNDnThe data on biomarkers as predictors of atrial fibrillation (AF) in patients with coronary artery disease (CAD) are limited.nnnMETHODSnA total of 1946 patients with CAD were recruited to the ARTEMIS study. At baseline, the study patients underwent clinical and echocardiographic examinations and had laboratory tests. The patients (n=1710) with the information about the occurrence of new-onset AF during the follow-up were included in the present analysis.nnnRESULTSnDuring 5.7±1.5years of follow-up, 143 (8.4%) patients developed a new-onset AF. Higher values of soluble ST2 (sST2) (20.2±10.8 vs. 17.5±7.2ng/mL, p=0.005), high-sensitivity troponin T (hs-TnT) (11.9±10.2 vs. 10.3±8.3ng/L, p=0.005), high-sensitivity C-reactive protein (hs-CRP) (3.3±5.9 vs. 2.0±4.4mg/L, p<0.001) and brain natriuretic peptide (BNP) (85.6±77.5 vs. 64.9±73.5ng/L, p<0.001) had significant associations with the occurrence of new-onset AF. In the Cox clinical hazards model, higher age (p=0.004), greater weight (p=0.045), larger left atrial diameter (p=0.001), use of asthma/chronic obstructive pulmonary disease medication (p=0.001) and lack of cholesterol lowering medication (p=0.008) had a significant association with the increased risk of AF. When the biomarkers were tested in the Cox clinical hazards model, sST2 (HR=1.025, 95% CI=1.007-1.043, p=0.006) and hs-CRP (HR=1.027, 95% CI=1.008-1.047, p=0.006) retained their significant power in predicting AF.nnnCONCLUSIONnA biomarker of fibrosis, sST2, and a biomarker of inflammation, hs-CRP, predict the risk of occurrence of new-onset AF in patients with CAD. These biomarkers contributed to the discrimination of the AF risk model, but did not improve it markedly.

Bias of QT Dispersion

Background: Prolonged QT dispersion (QID) is associated with an increased risk of arrhythmic death but its accuracy varies substantially between otherwise similar studies. This study describes a new type of bias that can explain some of these differences.

Blood alcohol in victims of sudden cardiac death in northern Finland

AIMSnMomentary intake of large quantity of alcohol provokes ventricular ectopic activity increasing electrical instability. The present study was aimed to assess the prevalence of alcohol intake prior to a sudden cardiac death (SCD) event.nnnMETHODS AND RESULTSnVictims of unexpected SCD [n = 2363, age 61 ± 12 years, males 1940 (82%)] included in the Finnish study of genotype and phenotype profiles of SCD (FINGESTURE) had a thorough interview of family members, medico-legal autopsy, and determination of blood alcohol concentration. Because of the Finnish law, all unexpected deaths undergo medico-legal autopsy. Patients who were admitted to a hospital due to an acute myocardial infarction [n = 128, age 63 ± 10 years, males 100 (78%)] served as controls. Based on autopsy findings, 1691 of these victims had ischaemic heart disease (IHD) and were included in the present analysis. A total of 646 (38%) SCD victims with IHD had a blood ethanol concentration above 0‰. Of these victims with blood alcohol test positive, 41% (n = 264) had blood ethanol concentration ≥1.5‰ and 56% (n = 362) ≥1‰. Male SCD victims had more frequently alcohol in blood than the females (40 vs. 27%, P < 0.001, respectively). None of the controls, who gave a consent for the blood ethanol concentration determination (n = 88), had alcohol in blood. Of the controls, 40 (31%) declined to participate in the study and give the consent for blood alcohol testing.nnnCONCLUSIONnAlmost 4 of 10 of the victims of unexpected SCD have evidence of alcohol intake before the fatal event in the northern Finland autopsy population.