Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants

Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 – 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes—glycoprotein IIIa, PAI-1 and angiotensinogen—show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.     

Effects of statins on carotid disease and stroke

The results of recent trials indicate that statin treatment reduces not only the risk of coronary heart disease, but also the risk of stroke, in patients with existing heart disease. The need for the treatment of such patients is now generally recognized. Mechanisms for risk reduction include the retardation of plaque progression, plaque stabilization, and reducing the risk of coronary events. Questions remain regarding the discrepancy between epidemiological data and statin trials data, the precise mechanism of action of statins, and their role in the prevention of recurrent stroke in individuals who have experienced a previous stroke or transient ischemic attack but are free of coronary disease.     

Prenatal Diagnosis and Genetic Counseling

Since the early 1960''s knowledge regarding human genetics has increased at an exponential rate. Because genetics was not commonly taught in medical schools before the late 1960''s, this review article is intended to acquaint physicians or refresh their knowledge regarding chromosomal, mendelian and multifactorial inheritance and the indications for prenatal diagnosis. Establishing an accurate diagnosis and mode of inheritance is essential in identifying and selecting those families at risk for genetic disease in their offspring. Medical genetics is evolving as a specialty in order to provide consultation and, if needed, management of those families who would benefit by genetic services. Families who would benefit from genetic counseling include, for example, those in whom any of the following conditions is present: known chromosomal disorders, known disorders due to mendelian inheritance, mental retardation of unknown origin, failure of sexual maturation or failure of sexual development, congenital malformations, floppy infant syndrome or leukemia.A list of more than 70 disorders now detectable in a fetus by means of amniocentesis provides a beginning in the prevention of genetic disease. Knowledge regarding these diseases allows a physician to provide families with accurate risk figures so that they may make informed decisions about having children. Also, a compassionate and nonjudgmental approach to counseling is essential. Decisions, in the final analysis, must be made by the family but aided and supported by the physician.     

Cryptic causation of human disease: reading between the (germ) lines

Most cases of complex human diseases arise sporadically. However, usually there is a significant level of familial aggregation of risk and genetic mapping has identified the responsible gene in a few mendelian cases. Although a disease can be causally genetic, intensified mapping efforts have so far been unable to identify genes that account for more than a small fraction of the familial risk, perhaps because the responsible variation arises by somatic mutation (SM). SM explains the kind of epidemiological pattern seen in cancer, and might have a comparable role in many other diseases. For example, in epilepsy, which has largely defied mapping analysis, the underlying disease pathology, undamped neuronal signaling, is closely connected to gene function. Better technologies to detect and characterize SM are becoming available. However, until it is studied directly, SM will remain a cryptic etiological force, even for diseases that are essentially "genetic".     

Physical activity and stroke in British middle aged men.

OBJECTIVES--To assess the relation between physical activity and stroke and to determine the overall benefit of physical activity for all major cardiovascular events. DESIGN--Prospective study of a cohort of men followed up for 9.5 years. SETTING--General practices in 24 towns in England, Wales, and Scotland (British regional heart study). SUBJECTS--7735 men aged 40-59 at screening, selected at random from one general practice in each of 24 towns. MAIN OUTCOME MEASURES--Fatal and non-fatal strokes and heart attacks. RESULTS--128 major strokes (fatal and non-fatal) occurred. Physical activity was inversely associated with risk of stroke independent of coronary risk factors, heavy drinking, and pre-existing ischaemic heart disease or stroke (relative risk 1.0 for inactivity, 0.6 moderate activity, and 0.3 vigorous activity; test for trend p = 0.008). The association remained after excluding men reporting regular sporting (vigorous) activity. However, vigorous physical activity was associated with a marginally significant increased risk of heart attack compared with moderate or moderately vigorous activity in men with no pre-existing ischaemic heart disease or stroke (relative risk 1.6%; 95% confidence interval 0.96 to 2.8). In men with symptomatic ischaemic heart disease or stroke those doing moderately vigorous or vigorous activity had a risk of heart attack slightly higher than that in inactive men (relative risk = 1.6; 0.8 to 3.3). CONCLUSIONS--Moderate physical activity significantly reduces the risk of stroke and heart attacks in men both with and without pre-existing ischaemic heart disease. More vigorous activity did not confer any further protection. Moderate activity, such as frequent walking and recreational activity or weekly sporting activity, should be encouraged without restriction.     

Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries

BackgroundTaller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke.Methods and findingsHeight-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations.ConclusionsThe findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

In a Mendelian randomization study, Andrew B. Linden and colleagues study the relationship between height and risk of stroke subtypes among individuals from the MEGASTROKE consortium, China Kadoorie Biobank, and UK Biobank.     

Snoring as a risk factor for ischaemic heart disease and stroke in men.

The association of snoring with ischaemic heart disease and stroke was studied prospectively in 4388 men aged 40-69. The men were asked, in a questionnaire sent to them, whether they snored habitually, frequently, occasionally, or never. Hospital records and death certificates were checked for the next three years to establish how many of the men developed ischaemic heart disease or stroke: the numbers were 149 and 42, respectively. Three categories of snoring were used for analysis: habitual and frequent snorers (n = 1294), occasional snorers (n = 2614), and non-snorers (n = 480). The age adjusted relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.91 (p less than 0.01) and for ischaemic heart disease or stroke, or both, 2.38 (p less than 0.001). There were no cases of stroke among the non-snorers. Adjustment for age, body mass index, history of hypertension, smoking, and alcohol use did not significantly decrease the relative risks, which were 1.71 (p greater than 0.05) for ischaemic heart disease and 2.08 (p less than 0.01) for ischaemic heart disease and stroke combined. At the beginning of follow up in 1981, 462 men reported a history of angina pectoris or myocardial infarction. For them the relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.30 (NS); for men without previous ischaemic heart disease 2.72 (p less than 0.05). Snoring seems to be a potential determinant of risk of ischaemic heart disease and stroke.     

Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology

Background

In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors, and reverse causation whereby disease status influences exposure rather than vice versa, may invalidate causal interpretations of observed associations. Conversely, genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies. Furthermore, disease onset will not influence genotype. Therefore, it has been suggested that genetic variants that are known to be associated with a modifiable (nongenetic) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes. This approach, mendelian randomization, is increasingly being applied within epidemiological studies. However, there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors. We examined the extent to which genetic variants, on the one hand, and nongenetic environmental exposures or phenotypic characteristics on the other, tend to be associated with each other, to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian randomization studies.

Methods and Findings

We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5%, 1%, and 0.01% level (α = 0.05, 0.01, and 0.0001, respectively) with the number expected by chance if all variables were in fact uncorrelated, using a two-sided binomial exact test. We demonstrate that behavioural, socioeconomic, and physiological factors are strongly interrelated, with 45% of all possible pairwise associations between 96 nongenetic characteristics (n = 4,560 correlations) being significant at the p < 0.01 level (the ratio of observed to expected significant associations was 45; p-value for difference between observed and expected < 0.000001). Similar findings were observed for other levels of significance. In contrast, genetic variants showed no greater association with each other, or with the 96 behavioural, socioeconomic, and physiological factors, than would be expected by chance.

Conclusions

These data illustrate why observational studies have produced misleading claims regarding potentially causal factors for disease. The findings demonstrate the potential power of a methodology that utilizes genetic variants as indicators of exposure level when studying environmentally modifiable risk factors.     

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial

Patients with type 2 diabetes are at increased risk of both macrovascular disease, including coronary heart disease and stroke, and microvascular disease, which includes retinopathy and nephropathy. Blood pressure and glucose levels are important determinants of the risk of developing vascular disease in patients with diabetes. For both these risk factors, the associations with macrovascular and microvascular disease appear continuous, with no evidence of a lower level of blood pressure or haemoglobin A1c below which the risks do not continue to decline.     

Mortality from cardiovascular disease among interregional migrants in England and Wales.

OBJECTIVE--To investigate the extent to which geographical variations in mortality from ischaemic heart disease and stroke in Britain are influenced by factors in early life or in adulthood. DESIGN--Longitudinal study of migrants. SUBJECTS--1% sample of residents in England and Wales born before October 1939 and enumerated at the 1971 census (the Office of Population Censuses and Surveys'' longitudinal study). MAIN OUTCOME MEASURE--18,221 deaths from ischaemic heart disease and 9899 deaths from stroke during 1971-88 were analysed by areas of residence in 1939 and 1971. These included 2928 deaths from ischaemic heart disease and 1608 deaths from stroke among individuals moving between 14 areas defined by the major conurbations and nine standard administrative regions of England and Wales. RESULTS--The southeast to northwest gradient in mortality from ischaemic heart disease was related significantly to both the 1939 area (chi 2 = 6.09, df = 1) and area in 1971 (chi 2 = 5.05, df = 1). Geographical variations in mortality from stroke were related significantly to the 1939 area (chi 2 = 4.09, df = 1) but the effect of area in 1971 was greater (chi 2 = 8.07, df = 1). The effect of 1971 area on mortality from stroke was largely due to a lower risk of death from stroke among individuals moving into Greater London compared with migrants to the rest of the South East region (chi 2 = 4.54, df = 1). CONCLUSIONS--Geographical variations in mortality from cardiovascular disease in Britain may be partly determined by genetic factors, environmental exposures, or lifestyle acquired early in life, but the risk of fatal ischaemic heart disease and stroke changes on migration between areas with differing mortality. The low risk of death from stroke associated with residence in Greater London is acquired by individuals who move there.     

Risk factors for stroke in middle aged British men.

OBJECTIVE--To determine the risk factors for stroke in a cohort representative of middle aged British men. DESIGN--Prospective study of a cohort of men followed up for eight years. SETTING--General practices in 24 towns in England, Wales, and Scotland (the British regional heart study). SUBJECTS--7735 men aged 40-59 at screening, selected at random from one general practice in each town. MAIN OUTCOME MEASURE--Fatal and non-fatal strokes. RESULTS--110 of the men had at least one stroke; there were four times as many non-fatal as fatal strokes. The relative risk of stroke was 12.1 in men who had high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg) and were current smokers compared with normotensive, non-smoking men. Diastolic blood pressure yielded no additional information, and former cigarette smokers had the same risk as men who had never smoked. Heavy alcohol intake was associated with a relative risk of stroke of 3.8 in men without previously diagnosed cardiovascular disease. Men with pre-existing ischaemic heart disease had an increased risk of stroke, but only when left ventricular hypertrophy on electrocardiography was also present. CONCLUSIONS--Systolic blood pressure, cigarette smoking, and left ventricular hypertrophy on electrocardiography in men with pre-existing ischaemic heart disease were found to be the major risk factors for stroke in middle aged British men. Heavy alcohol intake seemed to increase the risk of stroke in men without previously diagnosed cardiovascular disease. A large proportion of strokes should be preventable by controlling blood pressure and stopping smoking.     

Role of lipid-modifying therapy in the prevention of initial and recurrent stroke

PURPOSE OF REVIEW: To establish the role of cholesterol-modifying therapy in stroke prevention. RECENT FINDINGS: Population-based observational cohort studies show a variable weak positive relationship between increasing plasma total cholesterol concentrations and an increasing risk of ischaemic stroke, which is partly offset by a weaker negative association between decreasing total cholesterol concentrations and an increasing risk of with haemorrhagic stroke. However, randomized controlled trials show unequivocally that lowering plasma total cholesterol by approximately 1.2 mmol/l (and LDL-cholesterol by 1.0 mmol/l) is associated with a reduced relative risk of stroke and other serious vascular events by at least a quarter, and probably a third, without any increase in haemorrhagic stroke, in a wide range of men and women (including individuals with previous stroke). The proportional reduction in stroke risk is consistent, irrespective of the patient's age, baseline plasma cholesterol concentration, and absolute risk of stroke (although perhaps less in very low-risk individuals), but is increased with greater degrees of cholesterol lowering (15% or more), and thus with statin medications, which are more potent than non-statin interventions in lowering cholesterol levels. The absolute reduction in stroke risk achieved by statins is greatest among individuals at highest risk of stroke. Preliminary evidence suggests that lowering total cholesterol levels by diet may be an effective adjunctive therapy to statins, and raising plasma HDL-cholesterol concentrations among patients with coronary heart disease and low HDL-cholesterol levels ( 1 mmol/l) by means of gemfibrozil may also effectively prevent stroke. SUMMARY: Statin drugs are effective and safe in preventing initial and recurrent stroke. However, because they are costly, they should probably be restricted to individuals with an annual risk of stroke and other serious vascular events of 3% or greater, and possibly as low as 1.5%, because routine monitoring of plasma cholesterol, and liver and muscle enzyme concentrations is probably no longer necessary.     

Prediction Factors of Recurrent Ischemic Events in One Year after Minor Stroke

Background

The risk of a subsequent stroke following a minor stroke is high. However, there are no effective rating scales to predict recurrent stroke following a minor one. Therefore, we assessed the risk factors associated with recurrent ischemic stroke or transient ischemic attack (TIA) within one year of minor stroke onset in order to identify possible risk factors.

Methods

Eight hundred and sixty-three non-cardioembolic ischemic stroke patients in the Chinese IntraCranial AtheroSclerosis Study that presented with minor stroke, defined as an admission National Institutes of Health stroke scale (NIHSS) score of ≤3, were consecutively enrolled in our study. Clinical information and imaging features upon admission, and any recurrent ischemic stroke or TIA within one year was recorded. Cox regression was used to identify risk factors associated with recurrent ischemic stroke or TIA within the year following stroke onset.

Results

A total of 50 patients (6.1%) experienced recurrent ischemic stroke or TIA within one year of minor stroke onset. Multivariate Cox regression model identified lower admission NIHSS score (HR, 1.75; 95% CI, 1.32 to 2.33; P<0.0001), history of coronary heart disease (HR, 2.62; 95% CI, 1.17 to 5.86; P = 0.02), severe stenosis or occlusion of large cerebral artery (HR, 4.68; 95% CI, 1.87 to 11.7; P = 0.001), and multiple acute cerebral infarcts (HR, 2.61; 95% CI, 1.01 to 6.80; P = 0.05) as independent risk factors for recurrent ischemic stroke or TIA within one year.

Conclusions

Some minor stroke patients are at higher risk for recurrent ischemic stroke or TIA. Urgent and intensified therapy may be reasonable in these patients.     

Preventive health care, 1999 update: 2. Echocardiography for the detection of a cardiac source of embolus in patients with stroke

OBJECTIVE: To develop guidelines for the use of echocardiography in the investigation of patients with stroke. OPTIONS: (1) Routine transthoracic echocardiography (TTE); (2) routine transesophageal echocardiography (TEE); (3) routine TTE followed by TEE if the TTE findings are noncontributory; (4) selective TTE or TEE in patients with cardiac disease who would not otherwise receive anticoagulant therapy. OUTCOMES: This article reviews the available evidence on the yield of TTE and TEE in detecting cardiac sources of cerebral emboli in patients with stroke, the effectiveness of treatment for cardiac sources of emboli and the effectiveness of screening echocardiography for secondary stroke prevention. EVIDENCE: MEDLINE was searched for relevant articles published from January 1966 to April 1998; also reviewed were additional articles identified from the bibliographies and citations obtained from experts. BENEFITS, HARMS AND COSTS: Echocardiography can detect intracardiac masses (thrombus, vegetation or tumour) in about 4% (with TTE) to 11% (with TEE) of stroke patients. The yield is lower among patients without clinical evidence of cardiac disease by history, physical examination, electrocardiography or chest radiography (less than 2%) than among patients with clinical evidence of cardiac disease (less than 19%). The risks of echocardiography to patients are small. TTE has virtually no risks, and TEE is associated with cardiac, pulmonary and bleeding complications in 0.18%. Patients with an identified intracardiac thrombus are at increased risk for embolic events (absolute risk uncertain, range 0%-38%), and this appears to be reduced with anticoagulant therapy (absolute risk reduction uncertain). Anticoagulant therapy carries a risk of major hemorrhage of 1% to 3% per year. The overall effectiveness of echocardiography in the prevention of recurrent stroke is unknown. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: There is fair evidence to recommend echocardiography in patients with stroke and clinical evidence of cardiac disease by history, physical examination, electrocardiography or chest radiography (grade B recommendation). There is insufficient evidence to recommend for or against TEE in patients with normal results of TTE (grade C recommendation). There is insufficient evidence to recommend for or against routine echocardiography in patients (including young patients) without clinical cardiac disease (grade C recommendation). Routine echocardiography is not recommended for patients with clinical cardiac disease who have independent indications for or contraindications to anticoagulant therapy (grade D recommendation). There is fair evidence to recommend anticoagulant therapy in patients with stroke and intracardiac thrombus (grade B recommendation). There is insufficient (no) evidence to recommend for or against any specific therapy for patent foramen ovale (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.     

Role of missense mutation (M235T) in the angiotensinogen gene in development of cerebral ischemia

Possible correlation of M/T polymorphism of angiotensinogen gene with risk of ischemic stroke and basic risk factors of cerebral pathology (levels of arterial pressure and blood cholesterol; presence of diabetes mellitus, coronary heart disease, or myocardial infarction in anamnesis; and stenosis of major cerebral arteries) was studied. It was shown that M/T polymorphic variants of angiotensinogen gene were factors determining neither clinical variant of cerebral ischemia development (acute ischemic stroke or chronic brain ischemia) nor formation of main risk factors of stroke.     

Alternative hormone replacement regimens: is there a need for further clinical trials?

PURPOSE OF REVIEW: To review the randomized trials of hormone replacement therapy. RECENT FINDINGS: Studies have shown that conjugated equine estrogen 0.625 mg a day plus medroxyprogesterone acetate 2.5 mg a day increased the risk of cardiovascular events during the first year of treatment in women both with and without coronary heart disease. Conjugated equine estrogen plus medroxyprogesterone acetate also increased the overall risk of myocardial infarction and stroke in women without coronary heart disease, and myocardial infarction or death in women with coronary heart disease, and also increased the risk of breast cancer, cognitive decline and dementia. Unopposed, oral 17B-estradiol increased the risk of stroke during the first 6 months of treatment in women with a previous stroke. Oral 17B-estradiol with or without cyclic progestin had no effect on the progression of atherosclerosis or reinfarction. Transdermal 17B-estradiol plus cyclic progestin was associated with a non-significant increase in coronary heart disease events in women with coronary heart disease. Compared with placebo, cardiovascular events increased in the ongoing estrogen-only arm of the Women's Health Initiative, indicating that unopposed conjugated equine estrogen is unlikely to be cardioprotective. However, oral 17B-estradiol retarded the progression of subclinical atherosclerosis in younger women without coronary heart disease. SUMMARY: Hormone replacement therapy should not be initiated for the primary or secondary prevention of coronary heart disease in women. A trial of 17B-estradiol started at menopause in women without coronary heart disease should be considered.     

Association of Cytomegalovirus End-Organ Disease with Stroke in People Living with HIV/AIDS: A Nationwide Population-Based Cohort Study

Objectives

Cytomegalovirus (CMV) infection might increase the risk of cardiovascular event. However, data on the link between incident stroke and co-infections of CMV and human immunodeficiency virus (HIV) are limited and inconsistent. This nationwide population-based cohort study analyzed the association of CMV end-organ disease and stroke among people living with HIV/AIDS (PLWHA).

Methods

From January 1, 1998, this study identified adult HIV individuals with and without CMV end-organ disease in the Taiwan National Health Insurance Research Database. All patients were observed for incident stroke and were followed until December 31, 2012. Time-dependent analysis was used to evaluate associations of CMV end-organ disease with stroke.

Results

Of the 22,581 PLWHA identified (439 with CMV end-organ disease and 22,142 without CMV end-organ disease), 228 (1.01%) had all-cause stroke during a mean follow-up period of 4.85 years, including 169 (0.75%) with ischemic stroke and 59 (0.26%) with hemorrhagic stroke. After adjusting for age, sex, comorbidities, opportunistic infections after HIV diagnosis, and antiretroviral treatment, CMV end-organ disease was found to be an independent risk factor for incident all-cause stroke (adjusted hazard ratio [AHR], 3.07; 95% confidence interval [CI], 1.70 to 5.55). When stroke type was considered, CMV end-organ disease was significantly positively associated with the risk of ischemic stroke (AHR, 3.14; 95% CI, 1.49 to 6.62) but not hemorrhagic stroke (AHR, 2.52; 95% CI, 0.64 to 9.91).

Conclusions

This study suggested that CMV end-organ disease was an independent predictor of ischemic stroke among PLWHA.     

Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

Prevalence and Impact on Stroke in Patients Receiving Maintenance Hemodialysis versus Peritoneal Dialysis: A Prospective Observational Study

Background

Patients undergoing maintenance dialysis are at increased risk of stroke, however, less is known about the prevalence and impact on stroke in the patients.

Methods

In this prospective cohort study, 590 patients undergoing hemodialysis (HD; n = 285) or peritoneal dialysis (PD; n = 305) from January 1, 2008 to December 31, 2012 were recruited. Baseline demographic, clinical, and laboratory data were collected. Timeline incidence data were analyzed using a Poisson model. The Cox proportional hazards regression assessed adjusted differences in stroke risk, a multivariate analysis was also performed.

Results

62 strokes occurred during 1258 total patient-years of follow-up. Stroke occurred at a rate of 49.2/1,000 patient-years with a predominance in HD patients compared with PD patients (74.0 vs. 31.8/1,000 patient-years). The cumulative hazard of developing stroke was significantly higher in HD patients (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.15–3.62; p = 0.046) after adjusting for potential confounders. HD patients had an increased risk of ischemic stroke (HR, 2.62; 95% CI, 1.56–4.58; p = 0.002). The risk of hemorrhagic stroke was not significantly different between PD and HD patients. On multivariate Cox analysis, risk factors of stroke in both HD and PD patients were older age, diabetes, and cardiovascular disease. Other independent risk factors of stroke were lower albumin-corrected calcium in HD patients and higher triglycerides in PD patients.

Conclusions

Patients undergoing PD were less likely to develop ischemic stroke than those undergoing HD. Comprehensive control of diabetes, cardiovascular disease, calcium-phosphorus metabolism, and triglyceride levels may be useful preventive strategies for stroke in dialysis patients.     

Association between Voluntary/Involuntary Job Loss and the Development of Stroke or Cardiovascular Disease: A Prospective Study of Middle-Aged to Older Workers in a Rapidly Developing Asian Country

Background

The aim of this research was to investigate the association between job loss and the development of stroke or cardiovascular disease among middle-aged to older individuals in Korea. We also examined how this relationship was modified by gender and the nature of the job loss.

Methods

This study used samples from the first- to fourth-wave datasets from the Korean Longitudinal Study of Aging (KLoSA), which were collected in 2006, 2008, 2010, and 2012. The study collected data from a total of 10,254 subjects aged ≥45 years at baseline. After applying exclusion criteria, the final sample size for analysis consisted of 4,000 individuals. Information about employment status, development of stroke or cardiovascular disease, and covariates (age, income level, and behavioral factors) was obtained. Cox proportional hazards models were used to evaluate the association between voluntary/involuntary job loss and the development of stroke or cardiovascular disease. We performed these analyses separately according to disease, gender, and the nature of the job loss.

Results

Involuntary job loss significantly increased the risk of stroke or cardiovascular disease among males (adjusted hazard ratio [HR] = 3.560, 95% confidence interval [CI] = 2.055–6.168). Voluntary retirement also increased the risk of cardiovascular disease or stroke among males (adjusted HR = 2.879, 95% CI = 1.533–5.409). Job loss was more closely associated with stroke than with cardiovascular disease (stroke, adjusted HR = 6.208, 95% CI = 2.417–15.943; cardiovascular disease, adjusted HR = 2.768, 95% CI = 1.402–5.465).

Conclusion

Our findings suggest that both voluntary retirement and involuntary job loss increase the risk for stroke or cardiovascular disease in middle-aged to older individuals, especially males.