Prevalence of coronary heart disease,left ventricular failure and hypertension in middle-aged,newly diagnosed Type 2 (non-insulin-dependent) diabetic subjects

Summary The prevalence of coronary heart disease, left ventricular failure and hypertension was examined in a representative group of 133 newly diagnosed Type 2 (non-insulin-dependent) diabetic subjects (70 men, 63 women), aged 45 to 64 years, and in a group of 144 randomly selected non-diabetic control subjects (62 men, 82 women) of the same age group. The prevalence of previous myocardial infarction (major Q-QS abnormalities in resting ECG and/or myocardial infarction verified at hospital) was increased 1.7-fold in male (NS) and 4.4-fold in female (p = 0.007) diabetic patients compared with that found in non-diabetic subjects. Chest pain symptoms and ischaemic ECG abnormalities were about twice as common among diabetic than among non-diabetic subjects. The frequency of coronary heart disease defined by chest pain symptoms and ECG abnormalities was 3.5 times higher in male (p = 0.001) and 3.1 times higher in female (p = 0.001) diabetic patients than in the respective non-diabetic subjects. The frequency of current digitalis therapy was increased 3.3-fold in male (p = 0.006) and 3.9-fold in female (p = 0.001) diabetic patients suggesting an increased frequency of left ventricular failure among diabetic subjects. The prevalence of hypertension, based on the elevated blood pressure levels and/or current use of antihypertensive drugs, was increased 1.6–1.7-fold among the diabetic patients.     

The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed Type 2 (non-insulin-dependent) diabetes

Summary The relationship of cardiovascular risk factors to the prevalence of coronary heart disease was examined in 133 newly diagnosed Type 2 (non-insulin-dependent) diabetic patients (70 men, 63 women) aged from 45 to 64 years and in 144 randomly selected non-diabetic control subjects (62 men, 82 women) of the same age. The prevalence of coronary heart disease in diabetic patients, defined by symptoms and ischaemic ECG abnormalities in resting or exercise ECG, was more than threefold that in non-diabetic subjects. In multiple logistic analyses (including age, history of smoking, hypertension (+/-), serum cholesterol, HDL-cholesterol, triglycerides, 2-h post-glucose serum insulin, body mass index and diabetes (+/-)) carried out separately for men and women, diabetes showed an independent, significant association to coronary heart disease in both sexes. In addition, age and hypertension had a borderline association to coronary heart disease in men, whereas smoking and high 2-h postglucose serum insulin level showed a significant association in women.     

Left Ventricular Function in Newly Diagnosed Non-insulin-dependent (Type 2) Diabetics Evaluated by Systolic Time Intervals and Echocardiography

ABSTRACT Systolic time intervals (STI) and echocardiography were recorded in 133 (70 men, 63 women) newly diagnosed non-insulin-dependent diabetics aged 45–64 years and in 144 (62 men, 82 women) non-diabetic control subjects of the same age. Both male and female diabetics had significantly increased pre-ejection period/left ventricular ejection time ratio (PEP/LVET) in STI as compared with the respective non-diabetic control subjects. Male diabetics showed a reduced ejection fraction (EF) in echocardiography, but no significant difference was found in this respect between female diabetics and controls. A significant negative correlation was found between 2-hour postglucose serum insulin level and EF in male and female diabetics. After adjusting for the effect of age, coronary heart disease, hypertension, obesity and haemoglobin concentration, male diabetics still had a higher PEP/LVET ratio and a lower EF than male controls. In women, no significant differences were found between diabetics and controls in the PEP/LVET ratio or EF adjusted for the above factors. The results of this study are compatible with the view that impaired left ventricular function may be an early phenomenon in the clinical course of non-insulin-dependent diabetes.     

Diabetic Cardiomyopathy in the Elderly

Diabetic cardiomyopathy is a microvascular disorder that occurs in diabetics that may lead to congestive heart failure (CHF) in the absence of hypertension, coronary artery disease, or valvular heart disease. In a large study of elderly subjects with 865 men and 1872 women, mean age 81?±?9 years, CHF developed in 272 of 690 diabetics (39 %) and in 467 of 2047 nondiabetics (23 %) (P?<?0.0001) at 43-month follow-up. Cox regression analysis showed that diabetes mellitus (risk ratio = 1.34, P?=?0.0003) was an independent significant predictor of time to development of CHF. For each 1 % increase in hemoglobin A1c, in 25,958 men and 22,900 women with diabetes, there was an 8 % increased risk of CHF (95 % CI, 5 %–12 %). The pathologic substrate of diabetic cardiomyopathy is characterized by myocardial damage, left ventricular hypertrophy, interstitial fibrosis, structural and functional changes of the coronary vessels, metabolic abnormalities, and autonomic cardiac neuropathy.     

Vectocardiographic "bites" as possible early findings of cardiac involvement in diabetic patients without clinical evidence of heart disease

We performed a standard vectorcardiogram (VCG) in 87 diabetics, aged 20-77 years, orally- or insulin-treated, and in 41 normal subjects. None had cardiac history or symptoms. Among diabetics, 31 had no vectocardiographic abnormalities, 23 had various VCG changes, 33 showed electrical "bites" of various length (6-22 msec) and voltage (0.05-0.3 mV). In 8 normal subjects (19.4%) we found "bites" of similar voltage and length as in diabetic patients. A significantly positive linear relation was found between "bites" length and diabetes duration, in insulin-dependent diabetics only. By step-wise regression analysis we detected, in all diabetic patients with "bites," at a fixed value of diabetes duration, a significantly negative relation between "bites" length and patients' age. Moreover, the insulin treated patients showed a metabolic regulation index significantly worse than orally-treated diabetics; also diabetes duration was significantly higher in insulin-treated subjects. If "bites" may reflect an early heart involvement in diabetes, insulin-dependent patients seem to have a more severe cardiac damage in dependence of the diabetes duration. Finally, in the younger diabetics the heart diseases seems to be earlier and more advanced.     

Diabetes mellitus and chronic heart failure

Diabetes mellitus is one of the significant risk factors for many cardiovascular diseases. Diabetes mellitus is 3-4 times more frequent in patients with heart failure compared to patients without heart failure. Prognosis of patients with heart failure and diabetes mellitus is worse than prognosis of non-diabetic patients with the same left ventricular dysfunction. The term diabetic cardiomyopathy refers to a relation between diabetes mellitus and heart disease, but it probably isn't a separate morphology unit. In treatment of patients with diabetes mellitus general rules apply to heart failure management. The effect of ACE inhibitors was in majority of studies stronger in diabetics than in non-diabetics, the effect of beta blockers was comparable or smaller. Treatment is based on good compensation of metabolic parameters, blood pressure, titration of ACE inhibitors into recommended doses, and an optimal dose of a beta blocker. Type II diabetics with heart failure will, due to decreased resorption and metabolism, need insulin more often than diabetics without heart failure.     

High density lipoprotein subfractions in insulin-dependent diabetic and normal subjects

Serum lipoproteins have been separated by preparative ultracentrifugation in randomly selected groups of insulin-dependent diabetics and in age- and sex-matched non-diabetic controls. The major high density lipoprotein (HDL) subclass; HDL2 (density (d) 1.063-1.125 kg X m-3) and HDL3 (d greater than 1.125) and the further fractions of HDL2:HDL2b (d 1.063-1.100) and HDL2a (d 1.100-1.125) were also separated and their cholesterol (C) concentrations determined. These diabetic men and women were relatively normolipaemic and the major difference from controls was a significantly raised total HDL-C in men which was confirmed by a separate chemical precipitation method. This increase was associated with a significant rise in HDL2a-C and in total HDL2-C concentration. The non-significant increase in diabetic women compared to men was associated with poorer metabolic control. Among factors influencing serum HDL2-C concentration, the most important was the negative association with the level of very low density lipoprotein-triglycerides. Although insulin-dependent diabetics have an increased risk of atherosclerotic coronary heart disease (CHD), this is not reflected in their HDL subfraction-C distribution which, if present in non-diabetics, would be expected to confer protection from CHD.     

Diabetic cardiomyopathy

Summary Diabetic cardiomyopathy as a distinct entity was first recognized by Rubler et al. in diabetics with congestive heart failure (CHF), who had no evidence of coronary atherosclerosis. The Framingham study showed a 2.4-fold increased incidence of CHF in diabetic men and a 5.1-fold increase in diabetic women over 18 years. Pathological studies show left ventricular hypertrophy and fibrosis with varying degrees of small vessel disease, the functional significance of which is uncertain. Hypertension was recognized as an important cofactor in the development of fatal congestive heart failure in diabetics. On cardiac catheterization, in patients symptomatic of heart failure, either congestive or restrictive patterns have been observed. In contrast, asymptomatic diabetics had decreased left ventricular compliance but normal systolic function on hemodynamic study. Noninvasive studies show alterations in systolic and especially diastolic function, particularly in diabetics with microvascular complications and/or coexistent hypertension. Using load-independent measures of contractility, however, systolic function was generally found to be normal in asymptomatic normotensive diabetics. Experimental studies have focused on the mildly diabetic dog and the severely diabetic rat. Decreased left ventricular compliance and increased interstitial connective tissue were observed in chronically diabetic dogs. In contrast, ventricular myocardium from diabetic rats exhibits a reversible decrease in the speed of contraction, prolongation of contraction, and a delay in relaxation. These mechanical changes are associated with a decreased myosin ATPase, a shift in myosin isoenzyme distribution, alterations in a variety of Ca²⁺ fluxes, and changes in responses to alpha- and beta-adrenergic and cholinergic stimulation. These biochemical changes may be secondary to alterations in carbohydrate, lipid, and adenine nucleotide metabolism in the diabetic heart. When drug induced diabetes was combined with hypertension, a lethal cardiomyopathy with increased left ventricular hypertrophy and fibrosis, increased microvascular pathology and pulmonary congestion were observed. Compared to animals with isolated diabetes or hypertension, greater changes in papillary muscle function, isolated perfused heart performance, cellular electrophysiology, and contractile protein biochemistry were observed. Several studies suggest a protective effect of calcium channel blockers (verapamil and diltiazem) in experimental diabetic cardiomyopathy. Currently the clinical approach to this disorder emphasizes control of hyperglycemia and coexistent hypertension.     

The Vectorcardiogram and the Main Dromotropic Disturbances

Until the mid-1980s, it was believed that the vectorcardiogram (VCG) presented a greater specificity, sensitivity and accuracy in comparison to the 12-lead electrocardiogram (ECG), in the cardiology diagnosis. Currently, the VCG still is superior to the ECG in specific situations, such as in the evaluation of myocardial infarctions when associated with intraventricular conduction disturbances, in the identification and location of accessory pathways in ventricular preexcitation, in the differential diagnosis of patterns varying from normal of electrical axis deviation, in the evaluation of particular aspects of Brugada syndrome, Brugada phenocopies, concealed form of arrhythmogenic right ventricular cardiomyopathy and zonal or fascicular blocks of the right bundle branch on right ventricular free wall.VCG allows us to analyze the presence of left septal fascicular block more accurately than ECG and in the diagnosis of the interatrial blocks and severity of some chambers enlargements. The three-dimensional spatial orientation of both the atrial and the ventricular activity provides a far more complete observation tool than the linear ECG. We believe that the ECG/VCG binomial simultaneously obtained by the technique called electro-vectorcardiography (ECG/VCG) brought a significant gain for the differential diagnosis of several pathologies. Finally, in the field of education and research, VCG provided a better and more rational tridimensional insight into the electrical phenomena that occurs spatially, and represented an important impact on the progress of electrocardiography.     

Does NIDDM increase the risk for coronary heart disease similarly in both low- and high-risk populations?

Summary Finland has marked regional differences in the occurrence of coronary heart disease (CHD). Although the causes for these differences in CHD mortality and morbidity in the Finnish population are unknown, it offers an excellent opportunity to investigate the effects of non-insulin-dependent diabetes mellitus (NIDDM) on CHD risk in two populations differing significantly with respect to the occurrence of CHD. Therefore, we carried out a 7-year prospective population-based study including a large number of patients with NIDDM (East Finland: 253 men and 257 women; West Finland: 328 men, 221 women) and corresponding non-diabetic subjects (East Finland: 313 men, 336 women; West Finland: 325 men, 399 women). In both study populations the presence of NIDDM increased significantly the risk for CHD events (CHD mortality or all CHD events including CHD mortality or non-fatal myocardial infarction). Diabetic men had 3–4 fold higher and diabetic women 8–11-fold higher risk for CHD than corresponding non-diabetic subjects. Both non-diabetic and diabetic subjects had odds ratios (East vs West) for CHD events of about 2 indicating a similar East-West difference in the CHD risk. Regional difference was quite similar in men and women. These results imply that factors related to NIDDM, independently of conventional risk factors and the occurrence of atherothrombosis in the background population, must play a major role in the pathogenesis of atherosclerotic vascular disease in NIDDM diabetes.Abbreviations CHD Coronary heart disease - NIDDM non-insulin dependent diabetes mellitus - MI myocardial infarction     

Aortic and lower limb artery calcification in type 2 (non-insulin-dependent) diabetic patients and non-diabetic control subjects. A five year follow-up study

The purpose of the present study was to assess among a representative group of middle-aged newly diagnosed type 2 diabetics and control subjects the baseline prevalence and 5-year incidence of arterial calcifications of aorta and lower limb and their relationship to cardiovascular morbidity. The relationship of baseline risk factors to the development of arterial calcifications was also studied. At the time of diagnosis the age-adjusted prevalence of aortic and lower limb intimal calcifications was higher in diabetics than in control subjects (aortic calcifications: 29 vs. 17% for men, P = 0.05; 26 vs. 19% for women, P = 0.06; lower limb intimal calcifications: 24 vs. 12% for men, P = 0.02; 10 vs. 7% for women; P = NS), whereas no significant difference in baseline prevalence of lower limb medial calcifications was observed (15 vs. 21% for men, 9 vs. 10% for women). The 5-yr incidence of aortic calcifications in both sexes and of lower limb calcifications in men was similar in diabetic and control subjects, but the incidence of lower limb calcifications was higher in diabetic women than in control women (intimal: 33 vs. 11%, P = 0.009: medial: 29 vs. 14%, P = 0.05). The baseline prevalence of abdominal aortic (37 vs. 22%, P = NS for diabetics; 42 vs. 16%, P = 0.02 for control subjects), lower limb intimal (24 vs. 16% for diabetics, P = NS; 15 vs. 7% for control subjects, P = NS) and medial calcifications (23 vs. 7% for diabetics, P = 0.03) were higher in subjects who developed intermittent claudication during the follow-up than in those free of it at the 5-yr examination. Abnormalities in VLDL-metabolism and high systolic blood pressure were associated with the development of aortic calcification in diabetic subjects. In conclusion, already at the time of diagnosis atherosclerotic calcifications are more prevalent in type 2 diabetics than in nondiabetic subjects. During the follow-up diabetic women, but not men, had higher incidence of lower limb intimal and medial calcifications than non-diabetic subjects. Arterial calcifications tended to be associated with the development of intermittent claudication during the follow-up in diabetic and control subjects.     

Lipid and lipoprotein abnormalities in diabetic patients with peripheral vascular disease

Coronary heart disease in insulin-dependent (IDDM) and in non-insulin-dependent diabetes (NIDDM) is associated with lipid and lipoprotein changes favouring atherosclerosis. Whether lipid and lipoprotein abnormalities are associated also with peripheral vascular disease in both types of diabetes is largely unknown. Therefore, we studied lipid and lipoprotein levels and their association with claudication in a representative sample of diabetic and non-diabetic subjects in East Finland. Altogether 87 subjects had IDDM (43 men, 44 women), 264 subjects NIDDM (126 men, 138 women) and 120 subjects were non-diabetic controls (63 men, 57 women). Patients with IDDM had an increased level of HDL and HDL2-cholesterol and patients with NIDDM a decreased level of HDL and HDL2-cholesterol and an increased level of total, LDL and VLDL triglycerides than did non-diabetic subjects. Analyses in both types of diabetes by claudication status revealed that total and LDL-cholesterol and total and VLDL triglycerides tended to be higher and HDL and HDL2-cholesterol lower in those having claudication as compared to those without a claudication symptom. Similarly, total cholesterol/HDL-cholesterol ratio and LDL-cholesterol/HDL-cholesterol ratio were also more atherogenic in patients with claudication than in those without claudication. In conclusion, our results indicate that in both types of diabetes peripheral vascular disease is associated with lipid and lipoprotein abnormalities favouring atherosclerosis.     

Role of diabetes in congestive heart failure: the Framingham study

The incidence of congestive heart failure was determined in relation to prior diabetic status in 5,209 men and women aged 30 to 62 years followed up for 18 years in the Framingham study. Men aged 45 to 74 years had more than twice the frequency of congestive failure as their nondiabetic cohorts, and diabetic women had a fivefold increased risk. This excessive risk appears to be caused by factors other than accelerated atherogenesis and coronary heart disease. Even when patients with prior coronary or rheumatic heart disease were excluded, the diabetic subjects had a four- to fivefold increased risk of congestive heart failure. In women (but not men) with prior coronary disease, diabetes also imposed a threefold increased risk of congestive failure. Furthermore, the increased risk of heart failure in the diabetic patients persisted after taking into account age, blood pressure, weight and cholesterol values as well as coronary heart disease. Women with diabetes appeared to be especially vulnerable and, irrespective of coronary disease status, had twice the frequency of congestive heart failure as men. The excessive risk of heart failure among diabetic subjects was confined to those treated with insulin. The data suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes, as a result of either small vessel disease or metabolic disorders.     

Electro-vectorcardiographic behavior of right bundle branch block in endocardial cushion defects. Its probable relation to the so-called left anterior fascicular hemiblock

We have investigated the possible ECG signs of incomplete Left Anterior Hemiblock (LAH). As an experimental model we chose the endocardial cushion defect, which is proved to have a ventricular activation correspondent to different degrees of LAH due to the particular disposition of the AV node and the His bundle. The VCG of 50 patients with endocardial cushion defect were divided into 5 groups according to the entity of the left and superior deviation of the maximum left vector. Comparison with the ECG signs shows that: a) minimal degrees of LAH occur with simple counterclockwise rotation of the frontal loop without a significant left axis deviation; b) there is no linear correlation between the importance of the left axis deviation and the signs of left ventricular activation asincronism. We conclude that, with the exception of this particular congenital heart disease, minimal LAH degrees can only be suspected on the basis of a counterclockwise VCG frontal loop, because the ECG diagnosis is possible only when the left axis deviation becomes important.     

Relation of serum total sialic acid concentrations with diabetic complications and cardiovascular risk factors in Kuwaiti Type 2 diabetic patients

Serum total sialic acid is a marker of the acute phase response. Elevated levels have also been associated with cardiovascular disease in the general Caucasian population and especially in Type 2 diabetic subjects. The purpose of this study was to estimate serum total sialic acid concentrations among Kuwaiti Type 2 diabetic subjects and to investigate its association with macro and microvascular diabetes-related complications in that population. Serum total sialic acid levels were estimated by an enzymatic spectro-photometric assay in two groups of subjects: (i) 358 Kuwaiti Type 2 diabetics (156 men and 202 women) referred for their annual evaluation to the specialised diabetic clinic at the main university teaching hospital in Kuwait, and (ii) 47 healthy age and sex matched non-diabetic Kuwaiti control population (13 men and 34 women). Serum sialic acid levels were significantly higher (P<0.001) among the diabetic patients (mean+/-S.D.) (81.2+/-13.2 mg/dl) compared to the non-diabetic controls (66.9+/-11.0 mg/dl). Kuwaiti diabetic women had significantly higher concentrations compared to diabetic men (85.2+/-12.1 vs. 75.9+/-13.0 mg/dl, P<0.001). Among the controls there was no significant gender difference in sialic acid levels of women, (68.3+/-11.6 mg/dl) versus men (63.2+/-8.2 mg/dl). The gender difference in the diabetic patients was unrelated to the degree of obesity. Significant correlations were found between serum total sialic acid concentrations and such cardiovascular risk factors as plasma levels of apolipoprotein B, low density lipoprotein cholesterol, triglycerides and uric acid in the diabetic subjects. Furthermore, there was a significant elevation in serum total sialic acid concentrations with increasing urinary albumin excretion, P<0.001, but not with retinopathy or neuropathy.     

Peripheral vascular disease in newly diagnosed non-insulin-dependent diabetic.

The aim of this study was to assess the prevalence of peripheral vascular disease (PVD) in newly diagnosed diabetic patients and the possible relationship to various risk factors. One hundred and twenty non-insulin-dependent diabetics (NIDDs) aged 50-70 years and 93 non-diabetic subjects, matched for age and sex, were studied using Doppler ultrasound. None had a history of alcoholic abuse, while 12 diabetic and 8 non-diabetic subjects were smokers. There were 6 male subjects with PVD (5 NIDDs, 1 control subject) and 2 female diabetic subjects with PVD (p: No SD). In group of male diabetics with PVD, HDL-C levels were found to be lower and triglyceride levels higher, than in those without diabetes, but the difference was not significant. Hypertension, body mass index and smoking were not associated with the presence of PVD in either female or male diabetic subjects. It is concluded that, although PVD tended to be more common in men with newly diagnosed diabetes, the overall findings support the view that macrovascular disease is related to duration of diabetes.     

Peripheral Arterial Disease and Its Relationship to Cardiovascular Risk Factors and Coronary Heart Disease in Newly Diagnosed Non-insulin-dependent Diabetics

ABSTRACT The prevalence of peripheral arterial disease and its relationship to cardiovascular risk factors was investigated in 133 patients aged 45–64 years with newly diagnosed non-insulin-dependent diabetes and in 144 randomly selected non-diabetic subjects of the same age. History of intermittent claudication, absent foot pulses, decreased ankle-arm blood pressure ratio (<0.9) and radiologically detectable arterial calcifications of the lower limbs were used as indicators of the presence of peripheral arterial disease. Peripheral arterial disease tended to be somewhat more common in men with newly diagnosed non-insulin-dependent diabetes than in non-diabetic men, whereas no difference was found in prevalence of peripheral arterial disease between diabetic and non-diabetic women. The association of various indicators of peripheral arterial disease with cardiovascular risk factors and coronary heart disease was low or absent.     

Cardiologic findings in newly manifested type II diabetics of the diabetes intervention study

In 1,126 newly manifested primarily purely dietetic manageable type II-diabetics (628 men, 498 women) of the diabetes intervention study (DIS) at the age from 30 to 55 years the prevalence of the ischaemic heart disease was established with the help of the ECG in rest (Minnesota code) and in 70% of the test persons by an additional electrocardiography after work. Including the two parameters in 9.2% of the diabetic men and 26.1% of the women electrocardiographic findings of an ischaemic heart disease could be proved. The proportion of pathological findings of the ECG increased with age. While the proportion of a probable ischaemic heart disease (code 1.1-1.2) in the ECG in rest and with 1.4% the same size in the two sexes, in women, the percentage of a possible ischaemic heart disease (code 1.3, 4.1-4.3/5-5.3/8.3) prevailed with statistical significance after the 45th year of age. The at present numerically largest study on newly detected diabetics of type II gives evidences to the previous cardial lesion when the diabetes is manifest at medium age on the basis of the homogeneity of the number of patients.     

Diabetes as a risk factor for stroke. A population perspective

Summary Stroke incidence, case fatality and mortality in diabetic patients were compared to non-diabetic subjects in a 35–74-year-old population in northern Sweden (target population 241,000). During an 8-year period, 1,544 stroke events in diabetic patients and 4,826 events in non-diabetic subjects were recorded. The crude incidence of stroke was 1,000 per 100,000 in the diabetic men vs 247 in the non-diabetic men (relative risk 4.1; 95% confidence interval 3.2–5.2). Among diabetic women, the crude incidence was 757 per 100,000 and 152 in non-diabetic women (relative risk 5.8; 95% confidence interval 3.7–6.9). The 28-day case fatality among men was similar in the diabetic and non-diabetic stroke patients (18.6 vs 17.1%; p=0.311), but significantly higher in diabetic women compared with non-diabetic women (22.2 vs 17.9%; p=0.02). When compared with the non-diabetic population, the overall mortality from stroke in the diabetic population (first and recurrent) was 4.4-times higher in male and 5.1-times higher in the female patients. Hypertension, atrial fibrillation, heart failure or myocardial infarction were all significantly more common in diabetic than in non-diabetic stroke patients. The population attributable risk, a crude estimate of all strokes ascribed to diabetes mellitus, was 18% in men and 22% in women. In Sweden, about 50 strokes are annually directly attributed to diabetes in a population of 100,000 in this age group.Abbreviations MONICA Multinational Monitoring of Trends and Determinants in Cardiovascular Disease - ICD International Classification of Diseases - CT computerised tomography - CI confidence interval - RR relative risk - CF case fatality