Nisha I. Parikh

Long-Term Trends in the Incidence of Heart Failure After Myocardial Infarction

Background— Although mortality after myocardial infarction (MI) has declined in the United States in recent decades, there have been few community-based investigations of the long-term trends in the incidence of heart failure after MI, and their results appear to be conflicting. Methods and Results— We evaluated 676 Framingham Heart Study participants between 45 and 85 years of age (mean age 67 years, 34% women) who developed a first MI between 1970 and 1999. We assessed the incidence rates of heart failure and of death without heart failure in each of 3 decades (1970 to 1979, 1980 to 1989, and 1990 to 1999). We estimated the multivariable-adjusted risk of events in the latter 2 decades, with the period 1970 to 1979 serving as the referent. The 30-day incidence of heart failure after MI rose from 10% in 1970 to 1979 to 23.1% in 1990 to 1999 (P for trend 0.003), whereas 30-day mortality after MI declined from 12.2% (1970 to 1979) to 4.1% (1990 to 1999). The 5-year incidence of heart failure after MI rose from 27.6% in 1970 to 1979 to 31.9% in 1990 to 1999 (P for trend 0.02), whereas 5-year mortality after MI declined from 41.1% (1970 to 1979) to 17.3% (1990 to 1999). In multivariable analyses, compared with the period 1970 to 1979, we observed higher 30-day (risk ratio 2.05, 95% confidence interval 1.25 to 3.36) and 5-year (risk ratio 1.74, 95% confidence interval 1.07 to 2.84) risks of heart failure in the decade 1990 to 1999. These trends were accompanied by lower 30-day (risk ratio 0.21, 95% confidence interval 0.09 to 0.47) and 5-year (risk ratio 0.31, 95% confidence interval 0.18 to 0.54) mortality rates in 1990 to 1999. Conclusions— In the present community-based sample, we observed an increase in the incidence of heart failure in recent decades that paralleled the decrease in mortality after MI.

Overweight, Obesity, and the Development of Stage 3 CKD: The Framingham Heart Study

BACKGROUND Prior research yielded conflicting results about the magnitude of the association between body mass index (BMI) and chronic kidney disease (CKD). STUDY DESIGN Prospective cohort study. SETTINGS & PARTICIPANTS Framingham Offspring participants (n = 2,676; 52% women; mean age, 43 years) free of stage 3 CKD at baseline who participated in examination cycles 2 (1978-1981) and 7 (1998-2001). PREDICTOR BMI. OUTCOME Stage 3 CKD (estimated glomerular filtration rate < 59 mL/min/1.73 m(2) for women and < 64 mL/min/1.73 m(2) for men). MEASUREMENTS Age-, sex-, and multivariable-adjusted (diabetes, systolic blood pressure, hypertension treatment, current smoking status, and high-density lipoprotein cholesterol level) logistic regression models were used to examine the relationship between BMI at baseline and incident stage 3 CKD and incident dipstick proteinuria (trace or greater). RESULTS At baseline, 36% of the sample was overweight and 12% was obese; 7.9% (n = 212) developed stage 3 CKD during 18.5 years of follow-up. Relative to participants with normal BMI, there was no association between overweight individuals and stage 3 CKD incidence in age- and sex-adjusted models (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.93 to 1.81; P = 0.1) or multivariable models (OR, 1.06; 95% CI, 0.75 to 1.50; P = 0.8). Obese individuals had a 68% increased odds of developing stage 3 CKD (OR, 1.68; 95% CI, 1.10 to 2.57; P = 0.02), which became nonsignificant in multivariable models (OR, 1.09; 95% CI, 0.69 to 1.73; P = 0.7). Similar findings were observed when BMI was modeled as a continuous variable or quartiles. Incident proteinuria occurred in 14.4%; overweight and obese individuals were at increased odds of proteinuria in multivariable models (OR, 1.43; 95% CI, 1.09 to 1.88; OR, 1.56; 95% CI, 1.08 to 2.26, respectively). LIMITATIONS BMI is measure of generalized obesity and not abdominal obesity. Participants are predominantly white, and these findings may not apply to different ethnic groups. CONCLUSIONS Obesity is associated with increased risk of developing stage 3 CKD, which was no longer significant after adjustment for known cardiovascular disease risk factors. The relationship between obesity and stage 3 CKD may be mediated through cardiovascular disease risk factors.

A Risk Score for Predicting Near-Term Incidence of Hypertension: The Framingham Heart Study

Context Identifying adults with a high probability of developing high blood pressure could help target nonpharmacologic measures to prevent hypertension. Contribution Using data from the Framingham cohort study, the investigators devised a simple risk score with good performance characteristics that identified adults without diabetes who had low (<5%), medium (5% to 10%), or high (>10%) probability of developing hypertension within 4 years. The risk score included points for age, sex, systolic and diastolic blood pressure, body mass index, parental hypertension, and cigarette smoking. Implication If this risk score is validated in additional patient populations, it could help clinicians identify high-risk patients with prehypertension. The Editors In 2003, the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure created a prehypertension category for persons with blood pressures ranging from 120 to 139 mm Hg (systolic) or from 80 to 89 mm Hg (diastolic). The committee strongly advocated lifestyle and behavioral modification for individuals with prehypertension (1). This new recommendation was based largely on epidemiologic evidence that individuals with nonoptimal blood pressure (>120/80 mm Hg) are at increased risk for progression to overt hypertension (1, 2) and that cardiovascular disease risk increases in a graded fashion beginning at a blood pressure of 115/75 mm Hg, well within the normal range (1, 3). However, this new categorization scheme resulted in 70 million people being considered prehypertensive, a situation that poses a challenge for both physicians and patients. Recent clinical trials have focused on the treatment of persons with prehypertension to determine whether hypertension onset can be delayed. A recent clinical trial demonstrated that individuals with blood pressures of 130 to 139 mm Hg (systolic) and 80 to 85 mm Hg (diastolic) who were treated for 2 years with candesartan, an angiotensin II receptor blocker, had a 15% reduction in the incidence of hypertension over 4 years compared with patients randomly assigned to placebo (4). A clinical trial of lifestyle modification among overweight individuals without hypertension demonstrated that a low-salt diet and regular physical exercise reduced hypertension incidence in the short term and several years after the clinical trial (5, 6). Although these investigations have demonstrated the feasibility and efficacy of preventing hypertension, a strategy that targets all individuals with prehypertension is likely to be associated with substantial medical and economic resources. Evidence suggests that the risk for progression to hypertension depends on clinical factors, such as baseline blood pressure, age, and body mass index (2). An individualized approach of risk stratification and targeted treatment of the nonhypertensive persons who are at greatest risk for progression may be more desirable. We developed a simple risk score that can be used in a physicians office to estimate the probability that an individual will develop hypertension over 1 to 4 years and to identify the persons who are at the highest risk for hypertension. Such high-risk individuals will probably derive the maximal benefit from nonpharmacologic (lifestyle-related) and pharmacologic interventions aimed at preventing hypertension. Thus, we believe that knowledge of the risk for hypertension will aid patient education and counseling, and it will assist clinical decision making and design of future interventional studies. Supplement. Risk Calculator Methods Sample The Framingham Heart Study is a community-based, prospective cohort study that began in 1948 with the enrollment of 5209 men and women (whom we refer to as the original cohort) (7). In 1971, 5124 men and women were enrolled into the Framingham Offspring Study cohort, which included the children of the original cohort and the spouses of the children. Participant examinations for the offspring cohort occurred approximately every 4 years. The design and methods of the Framingham Offspring Study are described elsewhere (8). For our investigation, offspring cohort participants were eligible if they attended 2 consecutive examinations between the second (1979 to 1983) and seventh examinations (1998 to 2001) and if both of their parents were in the original cohort (8813 person-examinations) (Figure 1). Participants were eligible for inclusion at more than 1 heart study examination cycle if they reached the next examination without meeting any exclusion criteria. We excluded participants who had prevalent hypertension (n= 2542), prevalent cardiovascular disease (n= 233), or serum creatinine values greater than 177 mol/L (2 mg/dL) (n= 4); were younger than age 20 years or older than age 69 years (n= 77); had missing covariates (n= 46); or had prevalent diabetes mellitus (n= 97). We excluded persons with diabetes from our analysis because lower cut-points of systolic and diastolic pressure define the target blood pressure goal in these individuals (1). After we applied the exclusion criteria, 5814 person-examinations from 1717 unique individuals (54% women) remained eligible for analysis. All participants provided written informed consent, and the study protocol was approved by the Boston University Medical Center Institutional Review Board. Figure 1. Number of participants available for evaluation of hypertension incidence at baseline examination and number of participants with incident hypertension at follow-up examination. Assessment of Risk Factors At each Framingham Heart Study examination, participants underwent a medical history and physical examination, anthropometric measurements, and laboratory assessment of vascular risk factors. Blood pressure was measured on the left arm of seated participants by a physician using a mercury-column sphygmomanometer, a cuff of the appropriate size, and a standardized protocol. Participants had rested in a chair for 5 minutes before blood pressure was measured, and the average of 2 readings obtained by a physician was considered the examination blood pressure. Systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or use of blood pressurelowering medications defined hypertension. Current smoking was defined as regular cigarette smoking in the year before the examination. Body mass index was calculated as body weight (in kilograms) divided by the square of height (in meters). Consumption of more than 7 drinks per week in women and more than 14 drinks per week in men defined moderate alcohol intake (1). A fasting blood glucose level of 7.0 mmol/L (126 mg/dL) or more, use of hypoglycemic medications, or both defined diabetes mellitus. Parental hypertension was defined as documented maternal and paternal hypertension at or before the baseline examination at which offspring were eligible for our investigation. Parental hypertension status was ascertained on the basis of blood pressure readings of the original cohort participants by using serial data from examination cycle 3 (1952 to 1956) through examination 27 (2002 to 2004). Prevalent cardiovascular disease was defined as presence of coronary heart disease, stroke, transient ischemic attack, intermittent claudication, or heart failure at any examination. The criteria for diagnosis of these cardiovascular events are described elsewhere (9). Statistical Analysis We measured hypertension incidence during the interval between offspring cohort examinations (median, 3.8 years). If a person remained without hypertension at the follow-up examination, he or she remained eligible to contribute to the next 4-year period. A Weibull regression model for interval-censored data (10) was used because only the interval during which new hypertension developed was available; the exact date of onset of hypertension between 2 Framingham Heart Study examinations could not be determined. Significant predictors of hypertension incidence were identified by entering candidate risk factors (age, sex, body weight, body mass index, physical activity index, diabetes, systolic blood pressure, diastolic blood pressure, moderate alcohol intake, current smoking, and parental occurrence of hypertension [modeled as 0, 1, or 2 parents with hypertension]) into a stepwise model. These risk factors have been associated with hypertension in other studies (1). Because diastolic blood pressure decreases with age (11), we evaluated an interaction term for diastolic blood pressure by age, along with the other candidate risk factors. We also tested the following additional interaction terms in multivariable models: diastolic blood pressure by sex, systolic blood pressure by sex, body mass index by smoking, parental hypertension by age, parental hypertension by sex, and parental hypertension by body mass index. We developed a risk prediction score from -coefficients for variables associated with hypertension incidence in multivariable Weibull regression models by using methods described elsewhere (12). Continuous variables were divided into categories to facilitate risk estimation: Age was divided into 10-year groups; systolic blood pressure was divided into 5mm Hg categories beginning with 110 mm Hg and ending with 139 mm Hg; and diastolic blood pressure was divided into 5mm Hg categories beginning with 70 mm Hg and ending with 89 mm Hg. Body mass index was classified into 3 levels: less than 25 kg/m2 (normal), 25 to less than 30 kg/m2 (overweight), and 30 kg/m2 or more (obesity). We derived 1-, 2- and 4-year rates of hypertension incidence directly from the Weibull model (Appendix). We chose to assess 4-year risk because examination cycles in the Framingham Offspring Study occurred approximately every 4 years, and we were interested in assessing a short-term risk score for hypertension. We present 1- and 2-year risks for hypertension because we believe that these short-term risk estima

Long-Term Trends in Myocardial Infarction Incidence and Case Fatality in the National Heart, Lung, and Blood Institute’s Framingham Heart Study

Background— Whereas the prevalence of coronary heart disease risk factors has declined over the past decades in the United States, acute myocardial infarction (AMI) rates have been steady. We hypothesized that this paradox is due partly to the advent of increasingly sensitive biomarkers for AMI diagnosis. Methods and Results— In Framingham Heart Study participants over 4 decades, we compared the incidence and survival rates of initial AMI diagnosis by ECG (AMI-ECG) regardless of biomarkers with those based exclusively on infarction biomarkers (AMI-marker). We used Poisson regression to calculate annual incidence rates of first AMI over 4 decades (1960 to 1969, 1970 to 1979, 1980 to 1989, and 1990 to 1999) and compared rates of AMI-ECG with rates of AMI-marker. Cox proportional-hazards analysis was used to compare AMI case fatality over 4 decades. In 9824 persons (54% women; follow-up, 212 539 person-years; age, 40 to 89 years), 941 AMIs occurred, including 639 AMI-ECG and 302 AMI-marker events. From 1960 to 1999, rates of AMI-ECG declined by ≈50% and rates of AMI-marker increased ≈2-fold. Crude 30-day, 1-year, and 5-year case fatality rates in 1960 to 1969 and 1990 to 1999 were 0.20 and 0.14, 0.24 and 0.21, and 0.45 and 0.41, respectively. Age- and sex-adjusted 30-day, 1-year, and 5-year AMI case fatality declined by 60% in 1960 to 1999 (P for trend <0.001), with parallel declines noted after AMI-ECG and AMI-marker. Conclusions— Over the past 40 years, rates of AMI-ECG have declined by 50%, whereas rates of AMI-marker have doubled. Our findings offer an explanation for the apparently steady national AMI rates in the face of improvements in primary prevention.

Parental Occurrence of Premature Cardiovascular Disease Predicts Increased Coronary Artery and Abdominal Aortic Calcification in the Framingham Offspring and Third Generation Cohorts

Background— Parental premature cardiovascular disease (CVD) is a risk factor for coronary heart disease (CHD). We related validated parental premature CVD with the subclinical measures of coronary artery (CAC) and abdominal aortic (AAC) calcification in the community. Methods and Results— We studied 2 generations of Framingham Heart Study subjects who underwent multidetector computed tomography measurements of CAC and AAC and who had 2 parents in the study. Subjects included 797 Framingham Offspring (mean age, 63 years; 56% women) and 1238 Third Generation (Gen3) (mean age, 46 years; 47% women) participants free of CVD. Generalized estimating equations adjusted for major CVD risk factors were used to relate validated parental premature CVD and CHD to CAC and AAC, defined by >90th percentile age- and sex-specific cut points from a healthy subsample. Parental premature CVD was associated with CAC among Gen3 (odds ratio=2.17 [1.41 to 3.33]; P<0.001) and nonsignificantly among Offspring (odds ratio=1.42 [0.91 to 2.22]; P=0.12). Parental premature CHD was associated with CAC among Gen3 (odds ratio=2.22 [1.22 to 4.01]) but not Offspring. Parental premature CVD was not associated with AAC in either cohort. Parental premature CHD was associated with AAC among Gen3 (odds ratio=1.65 [0.99 to 2.75]; P=0.05) but not among Offspring. The magnitude of risk conferred was greater for paternal than maternal premature CVD. Conclusions— Parental premature CVD is associated with CAC, and premature CHD is associated with AAC, after adjustment for risk factors, particularly in younger middle-aged adults. Risk conferred by parental premature CVD on vascular calcification may be mediated through novel mechanisms not accounted for by classic CVD risk factors known to cause atherosclerosis.

Parity and risk of later-life maternal cardiovascular disease

BACKGROUND Prior studies relating parity with maternal cardiovascular disease (CVD) have been performed in relatively small study samples without accounting for pregnancy-related complications associated with CVD. METHODS We examined the associations between parity and maternal risk of later-life CVD in a population-based cohort study using data from the Swedish population registers. Women born from 1932 to 1955 were followed until the occurrence of CVD, death, emigration, or end of follow-up (December 31, 2005). Cox proportional hazards models were used to estimate associations between parity and risk of CVD accounting for birth year, yearly income, education level, country of birth, hypertension (pregestational hypertension or gestational hypertension, with or without proteinuria), diabetes (type 1, type 2, or gestational diabetes), preterm birth, small for gestational age, and stillbirth. RESULTS During a median follow-up time of 9.5 years (range 0-23.5), there were 65,204 CVD events in the full sample of women. Among 1,332,062 women, parity was associated with CVD in a J-shaped fashion, with 2 births representing the nadir of risk (global P value < .0001). Upon accounting for pregnancy-related complications in a subset of women with at least 1 childbirth after 1973 (n = 590,725), the association of parity with CVD was similar. Compared with women with 2 childbirths, the multivariable-adjusted hazard ratios (95% CIs) for women with 1 and >/=5 births were 1.09 (1.03-1.15) and 1.47 (1.37-1.57), respectively. CONCLUSIONS In conclusion, parity was associated with incident maternal CVD in a J-shaped fashion, even after accounting for socioeconomic factors and pregnancy-related complications.

Chronic Kidney Disease as a Predictor of Cardiovascular Disease (from the Framingham Heart Study)

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), although shared risk factors may mediate much of the association. CKD and CVD were related in the setting of specific CVD risk factors, and whether more advanced CKD was a CVD risk equivalent was determined. The Framingham Heart Study original cohort (n = 2,471, mean age 68 years, 58.9% women) was studied. Glomerular filtration rate was estimated (eGFR) using the simplified Modification of Diet in Renal Disease Study equation. CKD was defined as eGFR <59 (women) and <64 ml/min/1.73 m(2) (men), and stage 3b CKD was defined as eGFR of 30 to 44 (women) and 30 to 50 ml/min/1.73 m(2) (men). Cox proportional hazard models adjusting for CVD risk factors were used to relate CKD to CVD. Effect modification by CVD risk factors was tested for. Overall, 23.2% of the study sample had CKD (n = 574, mean eGFR 50 ml/min/1.73 m(2)) and 5.3% had stage 3b CKD (n = 131, mean eGFR 42 ml/min/1.73 m(2)). In multivariable models (mean follow-up 16 years), stage 3 CKD was marginally associated with CVD (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.99 to 1.38, p = 0.06), whereas stage 3b CKD was associated with CVD (HR 1.41, 95% CI 1.05 to 1.91, p = 0.02). Testing CVD risk equivalency, the risk of CVD for stage 3b CKD in subjects with previous CVD was significantly lower compared with subjects with previous CVD and no stage 3b CKD (age- and sex-adjusted HR for CVD 0.66, 95% CI 0.47 to 0.91, p = 0.01). Low high-density lipoprotein cholesterol modified the association between CKD and CVD (p = 0.004 for interaction). Stage 3b CKD was associated with CVD, but was not a CVD risk equivalent. In conclusion, CVD risk in the setting of CKD is higher in the setting of low high-density lipoprotein cholesterol.

Visceral and subcutaneous adiposity and brachial artery vasodilator function.

Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous adipose tissue (SAT) is more related to endothelium‐dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n = 3,020, mean age 50 years, 47% women), we used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography (CT)‐assessed VAT and SAT, BMI, and waist circumference (WC), with brachial artery measures. In multivariable‐adjusted models, BMI, WC, VAT, and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all P < 0.001), but not hyperemic mean flow velocity. In multivariable‐adjusted models, BMI (P = 0.002), WC (P = 0.001), and VAT (P = 0.01), but not SAT (P = 0.24) were inversely associated with percentage of flow‐mediated dilation (FMD%). However, there was little incremental increase in the proportion of variability explained by VAT (R2 = 0.266) as compared to SAT (R2 = 0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal.

Breastfeeding in Infancy and Adult Cardiovascular Disease Risk Factors

BACKGROUND Public health recommendations advocate breastfeeding in infancy as a means to reduce obesity in later life. Several prior studies relating breastfeeding to cardiovascular risk factors have been limited by lack of adjustment for maternal and participant confounding factors. METHODS We ascertained breastfeeding history via questionnaire from mothers enrolled in the Framingham Offspring Study. In their young to middle-aged adult children enrolled in the Framingham Third Generation, we examined the relations between maternal breastfeeding history (yes, no) and cardiovascular risk factors, including body mass index (BMI), high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, fasting blood glucose, and systolic and diastolic blood pressure levels. We applied generalized estimating equations to account for sibling correlations and adjusted for maternal and participant lifestyle, education, and cardiovascular risk factors. RESULTS In Third Generation participants (n = 962, mean age = 41 years, 54% were women), 26% of their mothers reported breastfeeding. Compared with non-breastfed individuals, breastfed adult participants had lower multivariable-adjusted BMI (26.1 kg/m2 vs 26.9 kg/m2, P = .04) and higher HDL cholesterol levels (HDL 56.6 mg/dL vs 53.7 mg/dL, P = .01). On additional adjustment for BMI, the association between breastfeeding and HDL cholesterol was attenuated (P = .09). Breastfeeding was not associated with total cholesterol, triglycerides, fasting blood glucose, systolic blood pressure, or diastolic blood pressure. CONCLUSION Breastfeeding in infancy is inversely associated with adult BMI and positively associated with HDL cholesterol. Associations between breastfeeding and BMI may mediate the association between breastfeeding and HDL cholesterol.

Clinical Correlates and Heritability of Cystatin C (from the Framingham Offspring Study)

Cystatin C (CysC) is associated with cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined the clinical correlates and heritability of CysC and determined if associations between CVD risk factors and CysC differed by CKD status. Among Framingham Heart Study offspring (examined from 1998-2001, n = 3,241, mean age 61 years, 54% women), the 95(th) percentile cut-point was developed for CysC in a healthy subset (n = 779) after excluding participants with diabetes, hypertension, low high-density lipoproteins, obesity, smoking, high triglycerides, prevalent CVD, and CKD (as defined by glomerular filtration rate <60 mL/min per 1.73 m(2)). Multivariable logistic regression was used to evaluate the association between CVD risk factors and high CysC (CysC > or =95(th) percentile cut-point). In a family-based subset (n = 1,188), we estimated CysC heritability using the variance-components method. The cut-point for high CysC was 1.07 mg/L. Age, hypertension treatment, low diastolic blood pressure, body mass index, low high-density lipoprotein cholesterol, and smoking were associated with high CysC in multivariable models. These factors and estimated glomerular filtration rate (egFR) explained 39.2% of CysC variability (R(2)). Excluding CKD did not materially change associations. Multivariable-adjusted heritability for CysC was 0.35 (p <0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD.