Noninvasive assessment of arterial stiffness and risk of atherosclerotic events

Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the development of readily available noninvasive assessment techniques. These include the measurement of pulse wave velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between arterial elasticity and endothelial function.     

Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk

OBJECTIVES: This prospective population study was conducted to assess the role of elevated lipoprotein(a) [Lp(a)] as a coronary risk factor. BACKGROUND: The role of elevated Lp(a) as a risk factor for coronary heart disease is controversial. In addition, little attention has been paid to the interaction of Lp(a) with other risk factors. METHODS: A total of 788 male participants of the Prospective Cardiovascular Münster (PROCAM) study aged 35 to 65 years were followed for 10 years. Both Lp(a) and traditional cardiovascular risk factors (e.g., age, low density lipoprotein [LDL] cholesterol, high density lipoprotein [HDL] cholesterol, triglycerides, systolic blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family history of myocardial infarction) were evaluated in 44 men who suffered from myocardial infarction, and in 744 men who survived without major coronary events or stroke. A multiple logistic function algorithm was used to estimate global cardiovascular risk by the combined effects of traditional risk factors. RESULTS: Overall, the risk of a coronary event in men with an Lp(a) > or =0.2 g/liter was 2.7 times that of men with lower levels (95% confidence interval [CI]: 1.4 to 5.2). This increase in risk was most prominent in men with LDL cholesterol level > or =4.1 mmol/liter (relative risk [RR]: 2.6; 95% CI: 1.2 to 5.7), with HDL cholesterol < or =0.9 mmol/liter (RR 8.3; 95% CI: 2.0 to 35.5), with hypertension (RR 3.2; 95% CI: 1.4 to 7.2), or within the two highest global risk quintiles (relative risk: 2.7; 95% CI: 1.3 to 5.7). CONCLUSIONS: Lp(a) increases the coronary risk, especially in men with high LDL cholesterol, low HDL cholesterol, hypertension and/or high global cardiovascular risk.     

A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis

OBJECTIVES: This study examined the effect of aspirin on the risk of embolic events in infective endocarditis (IE). BACKGROUND: Embolism is a major complication of IE, and studies in animal models have shown that platelet inhibition with aspirin can lead to more rapid vegetation resolution and a lower rate of embolic events. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial of aspirin treatment (325 mg/day) for four weeks in patients with IE to test the hypothesis that the addition of aspirin would reduce the incidence of clinical systemic embolic events. Patients with perivalvular abscess were excluded. Serial cerebral computed tomograms and transesophageal echocardiograms were obtained in a subset of patients. RESULTS: During the four-year study period, 115 patients were enrolled: 60 assigned to aspirin and 55 assigned to placebo. Embolic events occurred in 17 patients (28.3%) on aspirin and 11 patients (20.0%) on placebo, with an odds ratio (OR) of 1.62 (95% confidence interval [CI] 0.68 to 3.86, p = 0.29). There was a trend toward a higher incidence of bleeding in the patients taking aspirin versus placebo (OR 1.92, 95% CI 0.76 to 4.86, p = 0.075). Development of new intracranial lesions was similar in both groups. Aspirin had no effect on vegetation resolution and valvular dysfunction. CONCLUSIONS: In endocarditis patients already receiving antibiotic treatment, the addition of aspirin does not appear to reduce the risk of embolic events and is likely associated with an increased risk of bleeding. Aspirin is not indicated in the early management of patients with IE.     

Comparison of atherosclerotic calcification burden in persons with the cardiometabolic syndrome and diabetes

The cardiometabolic syndrome (CMS) and diabetes are associated with higher cardiovascular risk. The authors compared the association of CMS risk factors and diabetes with coronary and aortic calcium. A total of 4468 adults (42% female) underwent computed tomography for determination of coronary artery calcium (CAC) and thoracic aortic calcium (TAC) and were classified according to the presence of diabetes mellitus (DM) and number of CMS risk factors. The prevalence of CAC ranged from 51% in men and 35% in women with neither DM nor CMS to 75% in men and 58% in women with both DM and CMS, whereas TAC ranged from 29% to 44% in men and 36% to 55% in women. Women with four or five CMS risk factors more often had CAC (53%) and TAC (51%) than those with DM without CMS (40% and 35%, respectively) (p<0.001 across all disease groups). Adjusted odds (and 95% confidence intervals) of CAC for those with three CMS risk factors, four CMS risk factors, DM without CMS, and DM with CMS vs. those without CMS were 1.14 (0.93-1.39), 1.46 (1.12-1.90), 1.59 (1.06-2.38), and 2.10 (1.52-2.90) for CAC and 1.14 (0.91-1.42), 1.03 (0.77-1.37), 1.03 (0.68-1.54), and 1.41 (1.03-1.92) for TAC. Multiple CMS risk factors are associated with increased CAC, but not TAC; DM with CMS has the highest prevalence of CAC and TAC.     

Performance of the Pooled Cohort atherosclerotic cardiovascular disease risk score in hepatitis C virus‐infected persons

Chronic hepatitis C virus (HCV) infection has been associated with an increased risk for cardiovascular disease (CVD). The recommended Pooled Cohort atherosclerotic cardiovascular disease (ASCVD) risk equation for estimation of 10‐year CVD risk has not been validated in HCV‐infected populations. We examined the performance of the ASCVD risk score in HCV‐infected persons, using the national Electronically Retrieved Cohort of HCV Infected Veterans to derive a cohort of HCV‐infected and uninfected subjects without baseline ASCVD, hepatitis B, or HIV infection, and with low‐density lipoprotein cholesterol level<190 mg/dL. Performance of the ASCVD risk equation was assessed by Cox proportional hazard regression, C‐statistics and Hosmer‐Lemeshow statistic. The cohort included 70 490 HCV‐infected and 97 766 HCV‐uninfected men with mean age of 55 years, 56% White and 29% Black. Incident CVD event rates were similar between the two groups (13.2 and 13.4 events/1000 person‐years), with a higher incidence of coronary heart disease events in the HCV‐uninfected group and of stroke events in the HCV‐infected group. Adjusting for ASCVD risk score, HCV infection was associated with higher risk for an ASCVD event in the subgroup with baseline ASCVD risk ≥7.5% (HR: 1.19, P<.0001). C‐statistics were poor in both the HCV‐infected and uninfected groups (0.60 and 0.61, respectively). By Hosmer‐Lemeshow test, the ASCVD risk equation overestimated risk amongst lower risk patients and underestimated risk amongst higher risk patients in both the HCV‐infected and uninfected groups. Further investigation is needed to determine whether a modified equation to accurately predict ASCVD risk in HCV‐infected persons is warranted.     

Carotid intima-media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study.

AIMS: Carotid intima-media thickness (CIMT) is an independent predictor of vascular events in the general population. Currently, little is known about the relationship between CIMT and new vascular events in patients with manifest arterial disease. We aimed to assess the strength of this relationship. METHODS AND RESULTS: The study was performed in the first consecutive 2374 patients with manifest arterial disease enrolled in the cohort study SMART (Second Manifestations of ARTerial disease), a cohort study among patients with manifest arterial disease or cardiovascular risk factors. Common CIMT was measured at baseline in both carotid arteries. Vascular events were vascular death, non-fatal myocardial infarction, or stroke, whichever occurred first. Adjusted for age and sex, an increase in common CIMT of 1 SD ( approximately 0.32 mm) was associated with the occurrence of vascular events [hazard ratio (HR) 1.18; 95% confidence interval (95% CI) 1.04-1.32]. Increasing CIMT was most strongly related to ischaemic stroke incidence (HR 1.35; 95% CI 1.16-1.59). Results were similar in the 2177 patients without large common carotid plaques (CIMT <2 mm at all measurements sites). The findings were similar after additional adjustment for risk factors of CIMT and vascular risk. CONCLUSION: Common CIMT is associated with the occurrence of new vascular events, mostly for ischaemic stroke, in patients with manifest arterial disease. This relation does not appear to depend on the presence of plaques.     

Homocysteine. The association with atherosclerotic vascular disease in older persons

Plasma homocysteine is a risk factor for coronary artery disease, stroke, peripheral arterial disease, extracranial carotid arterial disease, aortic atherosclerosis, deep vein thrombosis, and possibly dementia and Alzheimer's disease in older persons. Randomized trials are in progress investigating whether multivitamin therapy with folic acid, vitamin B12, and vitamin B6 to reduce plasma homocysteine levels will reduce the risk for atherosclerotic vascular disease.     

Increased urinary albumin excretion aggregates with atherosclerotic risk factors in type 2 (non-insulin-dependent) diabetes mellitus

Supranormal urinary albumin excretion (microalbuminuria) is an early indicator of microangiopathy, i.e. diabetic nephropathy, and is associated with higher cardiovascular mortality in both type 1 and type 2 diabetes. The relationship between the presence of microalbuminuria and some atherosclerotic risk factors has been evaluated in 318 (170 male, 148 female) type 2 (non-insulin-dependent) diabetic subjects [age 63±10 years; known duration of diabetes 10.9±8.8 years; age at diabetes diagnosis 52±11 years; systolic blood pressure (BP) 150±23 mmHg; diastolic BP 86±11 mmHg (mean±SD)]. In early morning urine samples, albumin (immunonephelometry) and creatinine were assayed. On the basis of the albumin/creatinine ratio (A/C, mg/mmol), patients were categorized as normoalbuminuric (Na; A/C<2.0;n=159, 50%), microalbuminuric (ma; A/C 2–20;n=135, 42.5%) or macroalbuminuric (Ma; A/C >20;n=24, 7.5%). The three groups were closely matched for age, age at diagnosis, duration of diabetes, and fasting plasma and urinary glucose levels. Systolic and diastolic BP rose progressively with increasing urinary A/C ratio levels. While high-density lipoprotein (HDL) cholesterol was unaffected by albuminuria, total cholesterol (218±45 vs 198±43 mg/dl,P<0.001) and low-density lipoprotein (LDL) cholesterol (145±42 vs 131±38 mg/dl,P<0.05) levels were higher in microalbuminuric than in normoalbuminuric patients. Further, a significant correlation (r=0.16,P<0.01) existed between albuminuria and triglyceride concentrations. Prevalence of arterial hypertension, defined as BP160/95 mmHg and/or drug treatment (Na, 51%; ma, 65%; Ma, 78%;P<0.001) and obesity, defined as body mass index (BMI)>30 (Na, 15%; ma, 26%; Ma, 32%;P<0.05) rose with increasing A/C ratios. Both coronary heart disease (30% vs 15%) and intermittent claudication (18% vs 7%) were more frequent in microalbuminuric than in normoalbuminuric subjects. Finally, multiple stepwise regression analysis showed that urinary albumin excretion is significantly and independently associated with coronary heart disease and intermittent claudication, also taking into account hypertension and other established cardiovascular risk factors. In type 2 diabetes microalbuminuria tends to aggregate with risk factors for atherosclerotic vascular disease, e.g. increased prevalence of hypertension and obesity, elevated total and LDL cholesterol, and raised triglycerides levels. These abnormalities may only explain the excess of cardiovascular morbidity and mortality in part. Microalbuminuria per se may be an important and independent cardiovascular risk factor.     

Cardiorenal protective effects of vasopeptidase inhibition with omapatrilat in hypertensive transgenic (mREN-2)27 rats

Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.     

Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene

Development and progression of atherosclerotic lesions and aneurysm formation were investigated in mice with single or combined deficiency of apolipoprotein E (ApoE) and tissue inhibitor of metalloproteinase-1 (TIMP-1) kept on a cholesterol-rich diet for 30 weeks. Atherosclerotic lesions throughout the thoracic aorta were significantly (P<0.001) larger in mice wild-type for TIMP-1 (ApoE-/-:TIMP-1+/+) than in mice deficient in TIMP-1 (ApoE-/-:TIMP-1-/-). Aneurysms in the thoracic and abdominal aortas were less frequent in ApoE-/-:TIMP-1+/+ mice than in ApoE-/-:TIMP-1-/- mice (11+/-3.0 versus 23+/-5.1 aneurysms per 100 sections analyzed, mean+/-SD, P<0.001). Immunocytochemistry revealed enhanced accumulation of Oil red O-stained lipids, colocalizing with macrophages in atherosclerotic lesions of ApoE-/-:TIMP-1-/- mice (P<0.05). In situ zymography using a casein substrate showed enhanced lysis in plaques of ApoE-/-:TIMP-1-/- mice as compared with ApoE-/-:TIMP-1+/+ mice (P<0.01). MMP activity was most pronounced at sites where degradation of the elastic lamina occurred. These data suggest that enhanced MMP activity, as a result of TIMP-1 deficiency, contributes to a reduction of atherosclerotic plaque size but promotes aneurysm formation.     

Excess risk of diabetes in persons with hypertension

ProblemPersons with hypertension appear to be at increased risk of diabetes, an important predictor of cardiovascular disease. Whether, and to what extent, this risk may vary across subgroups defined on the basis of important clinical characteristics has not been well characterized.MethodsStudy population included members of Kaiser Permanente Northwest Region, a large health maintenance organization, aged ≥35 years and free of diabetes in 1998. Persons in the study population were stratified based on whether or not they had hypertension, and onset of diabetes was ascertained over a 6-year period beginning January 1999. Excess risk of diabetes was characterized in terms of risk differences between persons with and without hypertension, and was estimated on an overall basis and for subgroups defined on the basis of age, sex, and body mass index (BMI).ResultsStudy population totaled 104,368; 44% had hypertension. Relative risk (RR) of developing diabetes was 2.7 (95% CI: 2.6–2.8) for those with vs. without hypertension [21.0 (95% CI: 20.7–21.4) vs. 7.8 (95% CI: 7.6–8.0) per 1000 person-years, respectively]. Adjusted for age, sex, and BMI, RR of diabetes was 1.8 (95% CI: 1.7–1.9). With one exception (men, aged ≥75 years), risk of diabetes was higher across all age and BMI strata for both men and women with vs. without hypertension; differences in risk were greatest among those with high BMI (≥35 kg/m²). Across BMI strata, RR of developing diabetes was generally higher at younger ages.ConclusionAll persons with hypertension, irrespective of age, sex, and BMI, are at elevated risk of developing diabetes. Men and women with hypertension who are overweight or obese are at substantially elevated risk of diabetes, regardless of age, and should be monitored especially closely for the development of this disease.