Incidence Of Premature Cardiovascular Disease Research Articles

Temporal Trends in Incidence of Premature Cardiovascular Disease Over the Past 7 Decades: The Framingham Heart Study.

Background Premature onset of cardiovascular disease (CVD) imposes a significant societal burden and challenges prevention efforts. Methods and Results Trends in the incidence of premature CVD (before age 55, 60, or 65 years, separate analysis for each threshold) were evaluated in 14 464 Framingham Heart Study participants over 7 decades of observation (1950-2019). The change in the incidence of premature CVD (per decade) in men and women was assessed using overdispersed Poisson regression (accounting for cohort effects), adjusting for age at entry and age at onset of premature CVD within each decade. CVD was defined as a composite of fatal or nonfatal coronary heart disease, stroke or transient ischemic attack, peripheral vascular disease, and heart failure. There were 2223 first CVD events (832 in women) before age 65 years during 282 481 person-years of observations (154 587 in women) between 1950 and 2019. The age-adjusted CVD incidence before age 65 years decreased from 14.8 per 1000 person-years (1950-1959) to 4.69 per 1000 person-years (2010-2019) in men and from 7.23 per 1000 person-years (1950-1959) to 1.73 per 1000 person-years (2010-2019)in women. In adjusted analyses, the incidence of premature CVD decreased per decade in men (18.4% [95% CI, 12.0%-24.0%], for onset before age 55 years; 19.5% [95% CI, 12.0%-27.0%], for onset before age 60 years; 21.3% [95% CI, 16.0%-27.0%], for onset before age 65 years) and women (15.1% [95% CI, 7.0%-22.0%], for onset before age 55 years; 14.0% [95% CI, 6.0%-22.0%], for onset before age 60 years; 18.2% [95% CI, 12.0%-24.0%], for onset before age 65 years). The decline in premature CVD was accompanied by a reduction in smoking and increased use of lipid-lowering treatments across the decades. Incidence of premature coronary heart disease decreased, whereas the contribution of stroke to premature CVD burden increased over time. Conclusions The incidence of premature CVD has decreased among White adults in the Framingham cohort over the past 70 years; the residual burden of premature stroke warrants further study. Additional studies of trends in premature CVD in more racially and geographically diverse populations are warranted to elucidate the generalizability of these findings.

Abstract 11518: Association of Individual- and Neighborhood-Level Determinants Across Young Adulthood with Racial Disparity in Premature Cardiovascular Disease: The Coronary Artery Risk Development in Young Adults Study

Introduction: Black adults experience higher rates of cardiovascular disease (CVD) compared with White adults, particularly across young adulthood. To identify intervention targets to reduce disparities, we quantified the contribution of individual- and neighborhood-level determinants across young adulthood to Black-White differences in incidence of premature CVD. Methods: In Black and White adults (baseline age 18-30 years) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the associations of clinical, lifestyle, psychosocial, socioeconomic, and neighborhood determinants with racial disparities in incident CVD were evaluated with sex-stratified Cox proportional hazards models adjusted for time-updated risk factors. Percent reduction in the ß estimate (log-hazard ratio [HR]) for race quantified the contribution of each risk factor group, individually and combined, to incident CVD racial disparities. Results: In 1707 Black and 2001 White young adults followed for median 33.9 (IQR 33.7-34.0) years, Black adults had higher risk of incident CVD than White adults (Figure). The fully adjusted model yielded significant attenuation of the disparity: HR 1.22 (0.68-2.21) for Black vs. White women, HR 1.42 (0.91-2.23) for Black vs. White men. In women, clinical risk factors were associated with the largest percent reduction in the ß estimate (83%) for race. In men, socioeconomic, lifestyle and clinical risk factors were each associated with significant percent reductions in ß estimates (45%, 37%, and 28%, respectively). Conclusions: In CARDIA, risk for premature CVD was no longer significantly higher in Black vs. White adults after adjustment for upstream determinants across multiple domains. The largest contribution to racial disparities was from clinical factors in women and socioeconomic factors in men. These findings may inform earlier-life interventions to reduce disparities in premature CVD.

Depression and Progression of Subclinical Cardiovascular Disease in Systemic Lupus Erythematosus.

Women with systemic lupus erythematosus (SLE) have an increased incidence of premature cardiovascular disease (CVD). A relationship between depression and increased inflammation leading to CVD has been proposed. The aim of this study was to evaluate the relationship between depression and the progression of subclinical atherosclerosis in women with SLE. In this prospective case-control study, 149 participants with SLE and 126 controls were followed over 5 years. Evaluation included laboratory studies, assessment of CVD risk factors, depression screening, ultrasound evaluations of carotid intima-media thickness (CIMT) and carotid plaque, and assessment of SLE disease activity for the SLE cases. The SLE group had a higher rate of depression: 29% compared with 11% in the control group (P = 0.003). When controlling for traditional CVD risk factors, the presence of baseline depression correlated with increased progression of CIMT in the SLE group, but not in the control group. The mean increase in CIMT was 0.026 mm in the SLE group without depression versus 0.064 mm in the depressed SLE group (P = 0.0096). There was no association between depression and carotid plaque in either group, with a calculated odds ratio for plaque progression in the depressed SLE group of 1.118 (95% confidence interval 0.476, 2.623) in the adjusted model. Women with SLE and concomitant depression have an increased risk of developing subclinical atherosclerosis, as measured by CIMT, but not by carotid plaque. The data suggest that depression, a potentially modifiable risk factor, may contribute to the increased risk of subclinical atherosclerosis in women with SLE.

The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common monogenic disorders, and the high concentrations of low-density lipoprotein (LDL) cholesterol presented since birth confers on these patients an increased cardiovascular risk. More than 1,600 alterations have been described in the LDL receptor gene (LDLR), but a large number need to be validated as mutations causing disease to establish a diagnosis of FH. This study aims to characterize, both at the phenotypic and genotypic levels, families with a clinical diagnosis of FH and present evidence for the importance of the integration of clinical, molecular, and functional data for the correct diagnosis of patients with FH. A detailed analysis of the phenotype and genotype presented by 55 families with 13 different alterations in the LDLR was conducted. For eight of these, an extensive functional characterization was performed by flow cytometry, confocal microscopy, and reverse transcriptase polymerase chain reaction. Carriers of neutral alterations presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75(th) percentile. presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75th percentile However, the functional study was essential to determine the pathogenicity of variants. The data collected illustrate the importance of this integrated analysis for the correct assessment of patients with FH who can otherwise be misdiagnosed.

Pioglitazone protects HDL2&3 against oxidation in overweight and obese men

The worldwide epidemic of obesity is a major public health concern and is persuasively linked to the rising prevalence of diabetes and cardiovascular disease. Obesity is often associated with an abnormal lipoprotein profile, which may be partly negated by pioglitazone intervention, as this can influence the composition and oxidation characteristics of low-density lipoprotein (LDL). However, as pioglitazone's impact on these parameters within high-density lipoprotein (HDL), specifically HDL(2&3), is absent from the literature, this study was performed to address this shortcoming. Twenty men were randomized to placebo or pioglitazone (30 mg/day) for 12 weeks. HDL(2&3) were isolated by rapid-ultracentrifugation. HDL(2&3)-cholesterol and phospholipid content were assessed by enzymatic assays and apolipoprotein AI (apoAI) content by single-radial immunodiffusion. HDL(2&3) oxidation characteristics were assessed by monitoring conjugated diene production and paraoxonase-1 activity by spectrophotometric assays. Compared with the placebo group, pioglitazone influenced the composition and oxidation potential of HDL(2&3). Specifically, total cholesterol (P < 0.05), phospholipid (P < 0.001) and apoAI (P < 0.001) were enriched within HDL(2). Furthermore, the resistance of HDL(2&3) to oxidation (P < 0.05) and the activity of paroxonase-1 were also increased (P < 0.001). Overall, these findings indicate that pioglitazone treatment induced antiatherogenic changes within HDL(2&3), which may help reduce the incidence of premature cardiovascular disease linked with obesity.

Effect of reuse of polysulfone membrane on oxidative stress during hemodialysis

Patients with chronic renal failure, especially those on long-term hemodialysis (HD), have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is an excessive free radical production or low antioxidant level, has recently been implicated as a causative factor in atherogenesis. Hourly changes in malondialdehyde (MDA) and antioxidant enzymes, vitamins, lipid profile and ferric reducing ability of plasma (FRAP) were studied with the first use and immediate subsequent reuse of polysulfone dialysis membrane in 27 patients on regular HD treatment. Data were corrected for hemoconcentration and standardized to measure the rate of change. Increase in MDA and erythrocyte catalase along with decrease in plasma vitamin E and FRAP levels and no change in glutathione peroxidase levels were observed as a result of both fresh and reuse dialysis. These findings indicate a net oxidative stress in both fresh as well as dialyzer reuse sessions. There was no significant change in oxidative stress in both fresh and reuse sessions. The oxidative stress with reuse dialysis was less when compared to first use dialysis, but the difference was not statistically significant.

Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPARα agonist (fenofibrate) and a PPARγ agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment ( p = 0.001) and, in keeping with this, adiponectin increased by 85.2% ( p < 0.001). Pro-inflammatory cytokine levels (TNFα, IL-6 and IL-1β) fell with both treatments ( p < 0.01 for TNFα and IL-1β, p < 0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments ( p < 0.001 for VCAM-1, p < 0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment ( p = 0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment ( p < 0.001) and 16.3% with pioglitazone treatment ( p < 0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.

Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy

There is a high incidence of premature cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Free radical-induced tissue damage is thought to play a major role in the pathogenesis of atherosclerosis, and there are several reports indicating an increased oxidative stress in ESRD. However, it is not well established that increased oxidative stress predicts cardiovascular mortality in ESRD. Plasmalogens, a group of phospholipids with a vinyl ether bond in the sn-1 position, are considered to be sensitive markers of oxidative stress. Cardiovascular and non-cardiovascular mortality was recorded (follow-up time 1860+/-94 days) in 105 ESRD patients (mean age 51+/-2 years) in whom the fasting ratio of the erythrocyte levels of plasmalogens (DMA 16/C16:0 and DMA 18/C18:0) had been determined at the start of renal replacement therapy (RRT). The prevalence of malnutrition (subjective global assessment), diabetes mellitus (DM), smoking habits and CVD was also determined. Thirty-eight patients who died of CVD (0.066+/-0.003) had a significantly lower DMA 16/C16:0 ratio than 15 patients who died of non-cardiovascular causes (0.078+/-0.005; P<0.05) and 52 patients alive at follow-up (0.075+/-0.003; P<0.05). A Cox proportional hazard model analysis showed that a low (<median) DMA 16/C16:0 ratio at the start of RRT was associated (relative risk 1.50; confidence interval 1.07-2.16; P<0.05) with CVD mortality independently of age, gender, DM and CVD. These results suggest that increased oxidative stress may be a risk factor for cardiovascular mortality in ESRD.

Circulating heavy chain IgG, a pathological mediator for coronary artery disease, recognizes platelet surface receptors of both prostacyclin and insulin

Although an increased incidence of premature cardiovascular disease has been determined to be the major cause of mortality in subjects with chronic spinal cord injury the identity of the pathophysiological mediators of cardiovascular disease in spinal cord injury remains obscure. Because both insulin and prostacyclin could be important in the prevention of thrombosis, the status of insulin-induced nitric oxide production and the prostacyclin high-affinity receptor interaction in platelets in subjects with spinal cord injury was studied. It was established that the insulin-induced nitric oxide synthesis in platelets from spinal cord-injured subjects was markedly impaired (0.053-0.058, P=0.37-0.44) compared to (0.062-0.53 μM/108 platelets, P<0.001) due to the presence of a free heavy chain IgG (Mr 47 kDa) in the circulation of subjects with spinal cord injury. This IgG not only blocked insulin receptor binding sites (without affecting dissociation constant of the hormone binding, Kd1= 2 × 10−9 M) for the synthesis of nitric oxide but also blocked the prostacyclin receptor interaction in normal platelets. Since the presence of circulating heavy chain of IgG could block the antithrombotic effect of both insulin and prostacyclin, the free heavy chain of the IgG molecule was thought to be one of the pathological mediators for the increased incidence of cardiovascular disease in individuals with spinal cord injury. The cross-reactivity of the free heavy chain with two different receptors antigens was thought to be related to the presence of several regions of homology in the amino acid sequence in the insulin and prostacyclin receptor molecules.

Oxidative stress in haemodialysis

Patients with chronic renal failure, including those receiving regular long-term haemodialysis, have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, has recently been implicated as a causative factor in atherogenesis. The aim of this study was to determine if chronic renal failure and haemodialysis were associated with increased oxidative stress. Serum malondialdehyde was measured as a marker of lipid peroxidation in 15 patients with conservatively managed chronic renal failure (CRF), 15 patients with CRF undergoing regular haemodialysis and 15 healthy controls. Selenium, glutathione peroxidase and antioxidant vitamins were also measured. Malondialdehyde was elevated in dialysis patients in comparison to CRF and control groups (dialysis 1.16 +/- 0.08 mumol/l, CRF 0.94 +/- 0.07, controls 0.66 +/- 0.10). Antioxidants, including vitamin C, selenium and glutathione peroxidase, were decreased in dialysis patients and to a lesser extent in the CRF group (vitamin C-dialysis 16.43 +/- 3.76 mumol/l, CRF 34.5 +/- 8.6, controls 56.11 +/- 7.41; selenium-dialysis 0.77 +/- 0.07 mumol/l, CRF 0.69 +/- 0.06, controls 1.09 +/- 0.06: glutathione peroxidase-dialysis 101 +/- 5 U/l, CRF 160 +/- 11, controls 290 +/- 10). These findings indicate oxidative stress in patients with CRF which is further exacerbated by haemodialysis, as evidenced by increased lipid peroxidation and low antioxidant levels. This stress may play a role in the development of atherosclerosis in these groups.

Atenolol therapy for exercise-induced hypertension after aortic coarctation repair

After successful repair of coarctation of the aorta in childhood, exercise-induced upper body systolic hypertension is well documented. Beta blockade has been shown to reduce the arm/leg gradient in untreated coarctation of the aorta; treatment before coarctation repair has decreased paradoxical hypertension after repair. Ten patients with successful surgical repair of coarctation, defined as a resting arm/leg gradient of ≤18 mm Hg, were evaluated by treadmill exercise before and after β blockade with atenolol. Mean age was 5.5 years at repair and 18 at study. At baseline evaluation, systolic blood pressures at termination of exercise ranged from 201 to 270 mm Hg (mean 229 mm Hg). Arm/leg gradients at exercise termination ranged from 30 to 143 mm Hg (mean 84). Followup treadmill exercise studies were performed after β blockade. Upper extremity systolic pressures at exercise termination were normalized in 9 of 10 patients. Maximal systolic blood pressure recorded at exercise termination ranged from 163 to 223 mm Hg (mean 196 mm Hg, p < 0.005). Arm/leg gradient at termination of exercise also decreased significantly to a mean of 51 mm Hg (p < 0.05). No patient had symptoms on atenolol and exercise endurance times were unchanged. The study results in this small series suggest that cardioselective β blockade can be used to treat exercise-induced upper body hypertension effectively after surgical repair of coarctation. Because a high incidence of premature cardiovascular disease has been well documented after satisfactory surgical repair, the findings are of importance for this group of postoperative patients.

Apolipoprotein A-I metabolism in subjects with a PstI restriction fragment length polymorphism of the apoA-I gene and familial hypoalphalipoproteinemia

Familial hypoalphalipoproteinemia (hypoalpha), characterized by a decreased high density lipoprotein level, is associated with an increased incidence of premature cardiovascular disease. Restriction fragment length polymorphism analysis of genomic DNA has detected a polymorphism for the PstI restriction endonuclease near the apoA-I gene, with either a 2.2 or a 3.3 kb fragment. The latter has been previously found to occur with significantly higher frequency in probands of families with familial hypoalpha. ApoA-I was isolated from three unrelated subjects with familial hypoalpha and the 3.3 kb PstI polymorphism of the apoA-I gene, and from normal control subjects. The apoA-I from the hypoalpha subjects was structurally normal as determined by amino acid analysis and by two-dimensional gel electrophoresis. When normal apoA-I and hypoalpha apoA-I were simultaneously injected into either normal controls or hypoalpha subjects, both forms of apoA-I were catabolized at the same rate in the same subject, indicating that the hypoalpha apoA-I is also metabolically normal. Analysis of the kinetics of metabolism of apoA-I in the hypoalpha subjects, compared to the normal controls, revealed that the reduced plasma levels of apoA-I were due to an increased apoA-I fractional catabolic rate, and that the synthetic rate was normal. Based on these results, we conclude that the apoA-I gene in these hypoalpha subjects is normal, and the PstI polymorphism near the apoA-I gene, which is associated with familial hypoalpha, is likely to be a marker for a mutant gene closely linked to, but not in, the apoA-I gene.

Prognosis of surgically corrected coarctation of the aorta. A 20-year postoperative appraisal.

A long-term retrospective analysis of 248 patients, 11-25 years after surgical correction of coarctation of the aorta, revealed a high incidence of premature cardiovascular disease. Twelve percent of patients with follow-up have died. It is suggested that premature death in patients with adequate surgical repair may be related to the duration of preoperative hypertension. Fifty-nine patients were evaluated on a standard hospital protocol. Seventy-eight percent had evidence of cardiovascular disease and over 40% had no change or had increased blood pressure over the preoperative value. These data emphasize the importance of early diagnosis and treatment for patients with coarctation of the aorta as well as the need for close postoperative follow-up.