New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Association of genetic variants at 3q22 with nephropathy in patients with type 1 diabetes mellitus.

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) and affects about 30% of these patients. We have previously localized a DN locus on chromosome 3q with suggestive linkage in Finnish individuals. Linkage to this region has also been reported earlier by several other groups. To fine map this locus, we conducted a multistage case-control association study in T1DM patients, comprising 1822 cases with nephropathy and 1874 T1DM patients free of nephropathy, from Finland, Iceland, and the British Isles. At the screening stage, we genotyped 3072 tag SNPs, spanning a 28 Mb region, in 234 patients and 215 controls from Finland. SNPs that met the significance threshold of p < 0.01 at this stage were followed up by a series of sample sets. A genetic variant, rs1866813, in the noncoding region at 3q22 was associated with increased risk of DN (overall p = 7.07 x 10(-6), combined odds ratio [OR] of the allele = 1.33). The estimated genotypic ORs of this variant in all Finnish samples suggested a codominant effect, resulting in significant association, with a p value of 4.7 x 10(-5) (OR = 1.38; 95% confidence interval = 1.18-1.62). Additionally, an 11 kb segment flanked by rs62408925 and rs1866813, two strongly correlated variants (r(2) = 0.95), contains three elements highly conserved across multiple species. Independent replication will clarify the role of the associated variants at 3q22 in influencing the risk of DN.

Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects.

The onset of type 1 diabetes can occur at any age, with as many as half of all cases diagnosed after age 15. Despite this wide distribution in age at diagnosis, most genetic studies focus on cases diagnosed in childhood or during early adulthood. To better understand the genetics of late-onset type 1 diabetes, we collected a Finnish case/control cohort with all cases diagnosed between ages 15 and 40. We genotyped 591 probands and 1,538 control subjects at regions well established as susceptibility loci in early onset type 1 diabetes. These loci were then tested for disease association and age-at-diagnosis effects. Using logistic regression, we found that single-nucleotide polymorphisms (SNPs) at the INS, PTPN22, and IFIH1 loci were associated with late-onset disease (OR (95%CI) = 0.57(0.47-0.69), p = 2.77 x 10(-9); OR (95%CI) = 1.50 (1.27-1.78), p = 3.98 x 10(-6); and OR (95%CI) = 0.81(0.71-0.93), p = 0.0028, respectively). In contrast, a disease association was not detected for two SNPs at the IL2RA locus (rs11594656 and rs41295061). Despite this, we did find an independent age-at-diagnosis effect for each IL2RA SNP using a multivariate Cox proportional hazards model (p = 0.003, 0.002, respectively). Taken together, polymorphisms at the IL2RA locus were a major determinant of age at diagnosis in our cohort with an effect at par with the HLA-DQ2/DQ8 genotype as measured by hazard ratios. These findings suggest that the IL2RA locus controls both the susceptibility to disease and its time of occurrence. Thus, we believe the IL2/IL2R axis represents a potential therapeutic target for delaying the onset of disease.

Incidence of stroke in Europe at the beginning of the 21st century.

BACKGROUND AND PURPOSE: Comparable data on stroke incidence across European countries are lacking because previous studies have used different methods of case ascertainment, different periods of observation, and different age restrictions. METHODS: Population-based stroke registers were established in 6 European countries: France (Dijon); Italy (Sesto Fiorentino); Lithuania (Kaunas); the United Kingdom (London); Spain (Menorca); and Poland (Warsaw). Standardized criteria were used among these register including overlapping sources of notification. Overall, a source population of 1087048 inhabitants was observed, ranging from 47236 in Sesto Fiorentino to 365191 in Kaunas. All patients with first-ever stroke of all age groups from the source populations were included. Data collection took part between 2004 and 2006; 4 centers collected data for a 24-month and 2 for a 12-month time period. Crude annual incidence rates were age-adjusted to the European population. RESULTS: A total of 2129 patients with first stroke were registered. Median age was 73 years and 51% were female. Annual stroke incidence adjusted to the European population was found in men to be higher in Kaunas and lower in Sesto Fiorentino and Menorca and in women to be higher in Kaunas and Warsaw and lower in Sesto Fiorentino and Menorca compared with mean incidence rates. Total stroke incidence ranged in men from 101.2 per 100000 (95% CI, 82.5 to 123.0) in Sesto Fiorentino to 239.3 per 100000 (95% CI, 209.9 to 271.6) in Kaunas and in women from 63.0 per 100000 (95% CI, 48.5 to 80.7) in Sesto Fiorentino to 158.7 per 100000 (95% CI, 135.0 to 185.4) in Kaunas. Differences in prior-to-stroke risk factors were found among the populations with prevalence of hypertension highest in Warsaw and Kaunas (76% and 67%, respectively) and lowest in Menorca and Sesto Fiorentino (54% and 62%, respectively). CONCLUSIONS: The risk of stroke among European populations in our study varied more than 2-fold in men and women. On average, higher rates of stroke were observed in eastern and lower rates in southern European countries.

Quality Assurance and measurement errors in monitoring tree crown conditions in Italy.

The adoption of a comprehensive Quality Assurance (QA) programme for tree condition monitoring resulted in a rapid and steady improvement of data consistency in crown transparency assessment. On the other hand, the assessment of damage due to insects and fungi remains problematic and requires further training and control efforts. While our findings demonstrated the benefits arising from a QA programme and even the need to reinforce it, recent financial constrains have resulted in a severe reduction of the field checks. This will render it difficult to obtain a sound estimate of data quality and will jeopardize the results of any statistical analysis aimed at identifying status and trends of tree conditions in Italy.

Body mass index, waist circumference, and waist-hip ratio on the risk of total and type-specific stroke.

BACKGROUND: Adiposity is an established risk factor for cardiovascular disease, but the relationship of adiposity with the risk of cerebrovascular disease is still to some extent unclear. METHODS: We prospectively investigated the association of different indicators of adiposity (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], waist circumference, and waist-hip ratio) with total and type-specific stroke incidence among 49 996 Finnish participants who were aged 25 to 74 years and free of coronary heart disease and stroke at baseline. RESULTS: During a 19.5-year follow-up, 3228 people developed an incident stroke event (674 hemorrhagic and 2554 ischemic). Compared with normal-weight men (BMI, 18.5-24.9), the multivariate-adjusted (age, study year, smoking, physical activity, educational level, family history of stroke, and alcohol drinking) hazard ratios among lean (BMI, < 18.5), overweight (BMI, 25.0-29.9), and obese (BMI, > or = 30.0) men were 0.74 (95% confidence interval [CI], 0.18-2.96), 1.23 (95% CI, 1.10-1.37), and 1.59 (95% CI, 1.37-1.83) for total stroke, and 0.49 (95% CI, 0.07-3.50), 1.27 (95% CI, 1.12-1.44), and 1.70 (95% CI, 1.45-2.00) for ischemic stroke, respectively. Among women, the corresponding hazard ratios were 1.87 (95% CI, 1.12-3.14), 1.08 (95% CI, 0.95-1.22), and 1.30 (95% CI, 1.14-1.50) for total stroke, and 1.81 (95% CI, 0.97-3.41), 1.11 (95% CI, 0.96-1.28), and 1.41 (95% CI, 1.21-1.64) for ischemic stroke. Abdominal adiposity, defined as the highest quartile of waist circumference or waist-hip ratio, was associated with a greater risk of total and ischemic stroke in men but not in women. CONCLUSIONS: Body mass index was a risk factor for total and ischemic stroke in men and women. Abdominal adiposity was a risk factor for total and ischemic stroke only in men.

A genome-wide scan for type 1 diabetes susceptibility genes in nuclear families with multiple affected siblings in Finland.

BACKGROUND: A genome-wide search for genes that predispose to type 1 diabetes using linkage analysis was performed using 900 microsatellite markers in 70 nuclear families with affected siblings from Finland, a population expected to be more genetically homogeneous than others, and having the highest incidence of type 1 diabetes in the world and, yet, the highest proportion in Europe of cases (10%) carrying neither of the highest risk HLA haplotypes that include DR3 or DR4 alleles. RESULTS: In addition to the evidence of linkage to the HLA region on 6p21 (nominal p = 4.0 x 10-6), significant evidence of linkage in other chromosome regions was not detected with a single-locus analysis. The two-locus analysis conditional on the HLA gave a maximum lod score (MLS) of 3.1 (nominal p = 2 x 10-4) on chromosome 9p13 under an additive model; MLS of 2.1 (nominal p = 6.1 x 10-3) on chromosome 17p12 and MLS of 2.5 (nominal p = 2.9 x 10-3) on chromosome 18p11 under a general model. CONCLUSION: Our genome scan data confirmed the primary contribution of the HLA genes also in the high-risk Finnish population, and suggest that non-HLA genes also contribute to the familial clustering of type 1 diabetes in Finland.

The metabolic syndrome: prevalence, CHD risk, and treatment.

An increased risk of coronary heart disease (CHD) morbidity and mortality is associated with the metabolic syndrome, a condition characterized by the concomitant presence of several abnormalities, including abdominal obesity, dyslipidemia, hypertension, insulin resistance (with or without glucose intolerance or diabetes), microalbuminuria, prothrombotic, and proinflammatory states. Estimates of the prevalence of the metabolic syndrome indicate that this condition is now common and likely to increase dramatically over the coming decades, in parallel with greater rates of obesity and Type 2 diabetes. Risk factors for the metabolic syndrome are already present in obese children and adolescents. Thus, identifying and treating all affected individuals promptly and optimally are critical to ensure that this potentially challenging healthcare burden is minimized. Here, we review the prevalence of the metabolic syndrome, dyslipidemias, and CHD risk. Although changes in lifestyle are fundamental to reducing many of the CHD risk factors associated with the metabolic syndrome, pharmacologic interventions also play an important role. Retrospective subanalyses of the effects of statins on coronary event rates and lipid levels in patients with the metabolic syndrome included in clinical trials indicate that these agents are beneficial in correcting the extensive lipid abnormalities that are frequently present in these individuals. However, the optimal management of metabolic syndrome dyslipidemia will depend on the outcomes of future prospective clinical trials. This review examines the underlying causes and prevalence of the metabolic syndrome and its impact on CHD morbidity and mortality and discusses the role of statins in optimizing its management.

The impact of history of hypertension and type 2 diabetes at baseline on the incidence of stroke and stroke mortality.

BACKGROUND AND PURPOSE: Both hypertension and diabetes are strong predictors of stroke, but very few studies have assessed their joint effect on stroke risk. We evaluated prospectively the joint association of history of hypertension and type 2 diabetes on the incidence of stroke and stroke mortality. METHODS: We prospectively followed 49,582 Finnish subjects aged 25 to 74 years without a history of stroke and coronary heart disease at baseline. Hazards ratios (HRs) for stroke risk were estimated by the hypertension and diabetes status. RESULTS: During a mean follow-up of 19.1 years, 2978 incident stroke events were recorded, of which 924 were fatal. Age-, sex-, and study year-adjusted HRs of stroke incidence were 1.35 (95% CI, 1.21 to 1.51), 1.98 (95% CI, 1.79 to 2.19), 2.54 (95% CI, 1.61 to 4.01), 3.51 (95% CI, 2.40 to 5.14), and 4.50 (95% CI, 3.60 to 5.61), respectively, among subjects with hypertension I (blood pressure 140 to 159/90 to 94 mm Hg) only, with hypertension II (blood pressure > or =160/95 mm Hg, or using antihypertensive drugs) only, with diabetes only, with both hypertension I and diabetes, and with both hypertension II and diabetes compared with the subjects without either of the diseases. The corresponding HRs of stroke mortality were 1.47, 2.62, 3.06, 5.59, and 9.27, respectively. Additional adjustments for body mass index, cholesterol, education, smoking, alcohol consumption, and physical activity did not appreciably change these risk estimates. Blood pressure affected the risk of stroke similarly in diabetic and nondiabetic subjects. CONCLUSIONS: Hypertension and type 2 diabetes increase stroke risk independently, and their combination increases the risk drastically. A significant proportion of the risk of stroke assumed to be related to hypertension may be attributable to concomitant diabetes.

Leisure time, occupational, and commuting physical activity and the risk of stroke.

BACKGROUND AND PURPOSE: The role of physical activity, especially that of occupational and commuting physical activity, in the prediction of stroke risk is not properly established. We assessed the relationship of different types of physical activity with total and type-specific stroke risk. METHODS: We prospectively followed 47 721 Finnish subjects 25 to 64 years of age without a history of coronary heart disease, stroke, or cancer at baseline. Hazard ratios (HRs) for incident stroke were estimated for different levels of leisure time, occupational, and commuting physical activity. RESULTS: During a mean follow-up of 19.0 years, 2863 incident stroke events were ascertained. The multivariate-adjusted (age, sex, area, study year, body mass index, systolic blood pressure, cholesterol, education, smoking, alcohol consumption, diabetes, and other 2 types of physical activity) HRs associated with low, moderate, and high leisure time physical activity were 1.00, 0.86, and 0.74 (Ptrend<0.001) for total stroke, 1.00, 0.87, and 0.46 (Ptrend=0.011) for subarachnoid hemorrhage, 1.00, 0.77, and 0.63 (Ptrend=0.024) for intracerebral hemorrhage, and 1.00, 0.87, and 0.80 (Ptrend=0.001) for ischemic stroke, respectively. The multivariate-adjusted HRs associated with none, 1 to 29, and > or =30 minutes of active commuting were 1.00, 0.92, and 0.89 (Ptrend=0.043) for total stroke, and 1.00, 0.93, and 0.86 (Ptrend=0.028) for ischemic stroke, respectively. Occupational activity had a modest association with ischemic stroke in the multivariate analysis (Ptrend=0.046). CONCLUSIONS: A high level of leisure time physical activity reduces the risk of all subtypes of stroke. Daily active commuting also reduces the risk of ischemic stroke.

Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes.

We determined the magnitude of familial aggregation in the development of diabetic nephropathy (DN) among a population-based cohort of Finnish type 1 diabetic patients. Probands with type 1 diabetes were identified from the nationwide register of all Finnish cases diagnosed during 1965-1979. By 1998, there were 537 families with at least two siblings with type 1 diabetes. These 537 probands and their 616 diabetic siblings were followed for a diagnosis of DN until the end of 2001. We identified 323 cases of DN in these families. If the proband had DN, 38% of the siblings also had DN, whereas out of the diabetic siblings of the probands without DN, only 17% had DN (P = 0.001). Diabetic siblings of the nephropathic probands had a 2.3 times (95% CI 1.4-2.7) higher risk of DN compared with siblings of probands free of DN. The presence of a severe form of DN in the proband increases the risk threefold for diabetic siblings. Sex, the DN of the proband, the age at the onset of diabetes, and parental type 2 diabetes were significant predictors of DN among diabetic siblings. Although the majority of sibpairs with type 1 diabetes are discordant for DN, its presence in one sibling doubles the risk for the other diabetic siblings.

Diabetes worsens the outcome of acute ischemic stroke.

OBJECTIVE: To characterize acute stroke events in diabetic patients in a population-based stroke register and to determine the influence of diabetes on the outcome of acute stroke. METHODS: Four thousand three hundred and ninety patients were recorded in the FINMONICA and FINSTROKE registers after their first ischemic stroke from 1990 to 1998. We followed mortality and stroke outcome for up to 4 weeks after the onset of acute stroke. RESULTS: Of the 4390 patients who had had an ischemic stroke, 43.6% were male and 25.1% (1103) had diabetes. Their mean age was 72.4 (S.D. 12.0) years and this was similar in patients with and without diabetes (72.9 years versus 72.3 years, p=0.18). Subjects with diabetes were more likely to be hypertensive (55% versus 38%, p<0.001) and have a history of myocardial infarction (20% versus 16%, p<0.001) than the non-diabetic stroke patients. Mortality at 4 weeks from the onset was higher in diabetic than in non-diabetic patients (20.0% versus 16.9% p=0.020). At day 28 after the stroke attack, diabetic patients were more likely to be disabled when compared with non-diabetic subjects (43.3% versus 33.5%, p<0.001). Using logistic regression analysis, adjusted for age-group, sex, previous medical history (MI, AF or TIA), diabetes was found to be a significant predictor of disability after stroke (OR=1.51, 95% CI 1.27-1.81). CONCLUSIONS: Diabetes, which affected one-fourth of the ischemic stroke patients on our register, was associated with a higher risk of death and disability after the onset of stroke. Preventing diabetes in the elderly population improves the short-term prognosis of acute ischemic stroke.

The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.

BACKGROUND: After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. OBJECTIVE: To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. METHODS: Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. RESULTS: Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33). CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension.

OBJECTIVE: To examine the association of clinic and ambulatory heart rate with total, cardiovascular, and noncardiovascular death in a cohort of elderly subjects with isolated systolic hypertension from the Systolic Hypertension in Europe Trial. METHODS: A total of 4682 patients participated, whose untreated blood pressure on conventional measurement at baseline was 160 to 219 mm Hg systolic and lower than 95 mm Hg diastolic. Clinic heart rate was the mean of 6 readings during 3 visits. Ambulatory heart rate was recorded with a portable intermittent technique in 807 subjects. RESULTS: Raised baseline clinic heart rate was positively associated with a worse prognosis for total, cardiovascular, and noncardiovascular mortality among the 2293 men and women taking placebo. Subjects with heart rates higher than 79 beats/min (bpm) (top quintile) had a 1.89 times greater risk of mortality than subjects with heart rate lower than or equal to 79 bpm (95% confidence interval, 1.33-2.68 bpm). In a Cox regression analysis, predictors of time to death were heart rate (P<.001), age (P<.001), serum creatinine level (P =.001), presence of diabetes (P =.002), previous cardiovascular disease (P =.01), triglyceride readings (P =.02), smoking (P =.04), and elevated systolic blood pressure (P =.05), while total cholesterol level was found to be nonsignificant in the model. In the ambulatory monitoring subgroup, clinic and ambulatory heart rates predicted noncardiovascular but not cardiovascular mortality. However, in a Cox regression analysis in which clinic and ambulatory heart rates were included, a significant association with noncardiovascular mortality was found only for clinic heart rate (P =.004). In the active treatment group, the weak predictive power of clinic heart rate for mortality disappeared after adjustment for confounders. CONCLUSIONS: In untreated older patients with isolated systolic hypertension, a clinic heart rate greater than 79 bpm was a significant predictor of all-cause, cardiovascular, and noncardiovascular mortality. Ambulatory heart rate did not add prognostic information to that provided by clinic heart rate.

Long-term mortality in nationwide cohorts of childhood-onset type 1 diabetes in Japan and Finland.

OBJECTIVE: This study compares mortality from type 1 diabetes in Japan and Finland and examines the effects of sex, age at diagnosis, and calendar time period of diagnosis on mortality. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes from Japan (n = 1,408) and Finland (n = 5,126), diagnosed from 1965 through 1979, at age <18 years, were followed until 1994. Mortality was estimated with and without adjustment for that of the general population to assess absolute and relative mortality using Cox proportional hazard models. RESULTS: Overall mortality rates in Japan and Finland were 607 (95% CI 510-718) and 352 (315-393), respectively, per 100,000 person-years; standardized mortality ratios were 12.9 (10.8-15.3) and 3.7 (3.3-4.1), respectively. Absolute mortality was higher for men than for women in Finland, but relative mortality was higher for women than for men in both cohorts. Absolute mortality was higher in both cohorts among those whose diabetes was diagnosed during puberty, but relative mortality did not show any significant difference by age at diagnosis in either cohort. In Japan, both absolute and relative mortality were higher among those whose diagnosis was in the 1960s rather than the 1970s. CONCLUSIONS: Mortality from type 1 diabetes was higher in Japan compared with Finland. The increased risk of death from type 1 diabetes seems to vary by sex, age at diagnosis, and calendar time period of diagnosis. Further investigation, especially on cause-specific mortality, is warranted in the two countries.

Are changes in mortality from stroke caused by changes in stroke event rates or case fatality? Results from the WHO MONICA Project.

BACKGROUND AND PURPOSE: Mortality from stroke has been declining over recent decades in most countries, except in Eastern Europe. In this analysis, based on the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) Project, we explored to what extent these trends are due to changes in stroke event rate and to changes in case fatality. METHODS: The WHO MONICA Project collected standardized data from 14 populations in 9 countries. All acute strokes occurring in men and women 35 to 64 years of age were included. Registration was carried out between 1982 and 1995, resulting in time spans from 7 to 13 years. Trends in event rates and case fatality were calculated as average annual percentage change. RESULTS: Up to 6-fold differences were observed in stroke mortality. Mortality declined in 8 of 14 populations in men and in 10 of 14 populations in women. An increase in mortality was observed in Eastern Europe. In the populations with a declining trend, about two thirds of the change could be attributed to a decline in case fatality. In populations with increasing mortality, the rise was explained by an increase in case fatality. CONCLUSIONS: In most populations, changes in stroke mortality, whether declining or increasing, were principally attributable to changes in case fatality rather than changes in event rates. Whether this was due to changes in the management of stroke or changes in disease severity cannot be established on the basis of these results.

Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study.

BACKGROUND AND PURPOSE: The purpose of this study was to analyze the incidence and mortality trends in stroke events among persons 25 to 74 years of age in Finland during 1983 to 1997. METHODS: The population-based FINSTROKE register recorded 5650 new strokes among persons 25 to 74 years of age in 2 geographical areas of Finland: 2770 in the Kuopio area (east central Finland) and 2880 in Turku (southwestern Finland). Of these, 3065 were men and 2585 were women. RESULTS: The rates of acute stroke events fell during the whole study period in both men and women. In both FINSTROKE areas combined, the average annual decline in the age-standardized incidence of first stroke events was 2.0% (95% confidence interval [CI], -2.8 to -1.2; P<0.001) among men and 1.7% (95% CI, -2.6 to -0.8; P<0.001) among women. The decline in the incidence of ischemic stroke was even steeper, 2.9%/y (95% CI, -4.9 to -1.1; P<0.001) among men and 3.1%/y (95% CI, -5.0 to -1.1; P<0.001) among women, whereas the incidence of intracerebral hemorrhage and subarachnoid hemorrhage did not change. Mortality from all stroke events declined in the FINSTROKE areas by 3.7%/y (95% CI, -5.3 to -2.0; P<0.001) among men and by 4.1%/y (95% CI, -5.9 to -2.4; P<0.001) among women. The 28-day case fatality of all stroke events also tended to decline, but the decline was of borderline statistical significance only (P=0.07 among men, P=0.05 among women). CONCLUSIONS: Incidence and mortality of stroke events declined significantly in these 2 register areas in Finland during the 15-year period of 1983 to 1997.

Quality of life on randomized treatment for isolated systolic hypertension: results from the Syst-Eur Trial.

OBJECTIVE: To compare quality of life in elderly patients with isolated systolic hypertension allocated randomly to groups to receive placebo or active treatment in the Systolic Hypertension in the Elderly Trial. DESIGN: Double-blind randomized controlled trial. METHODS: Patients aged 60 years were allocated randomly to groups to receive first-line treatment with nitrendipine (with second- and third-line enalapril and hydrochlorothiazide) or placebo. Trained interviewers administered trail-making tests (Trail A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest, and Home work). RESULTS: Six hundred and ten patients completed a baseline and at least one follow-up questionnaire. Trail-making scores were slower in actively treated patients, especially in the first 6 months of follow-up when the between-group effect sizes were 0.25 [95% confidence interval (CI) 0.07 to 0.43] for Trail-making A and 0.13 (95% CI -0.05 to 0.31) for Trail-making B. Across the 4 years of follow-up, patients receiving active treatment were more likely to report problems on the Social Interaction scale than were placebo-treated patients (odds ratio 1.32, 95% CI 1.02 to 1.69), equivalent to a 7% difference. There were no significant differences between active and placebo treatment in the other Sickness Impact Profile dimensions or in the measure of depression. CONCLUSIONS: Active treatment in the Systolic Hypertension in Europe trial was associated with some small adverse impacts on quality of life.

Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.

BACKGROUND: To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. METHODS: The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. RESULTS: Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. CONCLUSIONS: Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

How well can blood pressure be controlled? Progress report on the Systolic Hypertension in Europe Follow-Up Study (Syst-Eur 2).

BACKGROUND: The randomised, double-blind, placebo-controlled Systolic Hypertension in Europe trial (Syst-Eur 1) proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in elderly patients with isolated systolic hypertension. In an attempt to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine, the Syst-Eur patients remained in open follow-up after the end of Syst-Eur 1. This paper presents the second progress report of this follow-up study (Syst-Eur 2). It describes BP control and adherence to study medications. METHODS: After the end of Syst-Eur 1 all patients, treated either actively or with placebo, were invited either to continue or to start antihypertensive treatment with the same drugs as previously used in the active treatment arm. In order to reach the target BP (sitting SBP <150 mmHg), the first line agent, nitrendipine, could be associated with enalapril and/or hydrochlorothiazide. RESULTS: Of the 3787 eligible patients, 3516 (93%) entered Syst-Eur 2. At the last available visit, 72% of the patients were taking nitrendipine. SBP/DBP at entry in Syst-Eur 2 averaged 160/83 mmHg in the former placebo group and 151/80 mmHg in the former active-treatment group. At the last follow-up visit SBP/DBP in the patients previously randomised to placebo or active treatment had decreased by 16/5 mmHg and 7/5 mmHg, respectively. The target BP was reached by 74% of the patients. CONCLUSION: Substantial reductions in systolic BP may be achieved in older patients with isolated systolic hypertension with a treatment strategy starting with the dihydropyridine calcium-channel blocker, nitrendipine, with the possible addition of enalapril and/or hydrochlorothiazide.