A genetic variant of the atrial natriuretic peptide gene is associated with left ventricular hypertrophy in a non-diabetic population - the Malmo preventive project study

Background: Epidemiological studies have shown considerable heritability of blood pressure, thus suggesting a role for genetic factors. Previous studies have shown an association of a single nucleotide polymorphism rs5068 in the NPPA locus gene with higher levels of circulating atrial natriuretic peptide as well as with lower intra individual blood pressure, but up to date, no association between rs5068 and cardiac organ damage, i.e. left ventricular hypertrophy, has been accounted for in humans. We sought to explore if rs5068 is associated with left ventricular hypertrophy as measured by echocardiographic examination in a non-diabetic population. Methods: 968 non-diabetic individuals from the Malmo Preventive Project (mean age 67 years; 31% women) were genotyped and examined with echocardiography. Logistic regression was used to adjust for covariates. Results: The minor allele of rs5068 was associated with decreased prevalence of left ventricular hypertrophy (p = 0.021) after adjustment for sex and age. In the multivariate logistic analysis including; age, sex, systolic blood pressure, antihypertensive and/or cardioprotective treatment, body mass index and fasting plasma glucose, the association of rs5068 with left ventricular hypertrophy was, as expected, attenuated (p = 0.061). Conclusion: In a non-diabetic population, the minor allele of rs5068 was associated with lower left ventricular mass. These findings suggest that rs5068, or genetic variants in linkage disequilibrium, might affect susceptibility to left ventricular hypertrophy and support the possible protective role of natriuretic peptides

A diabetes-predictive amino acid score and future cardiovascular disease.

AimsWe recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.Methods and resultsWe performed a matched case-control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD. During 12 years of follow-up, 253 individuals developed CVD and were matched for age, sex, and Framingham risk score with 253 controls. Amino acids were profiled in baseline plasma samples, using liquid chromatography-tandem mass spectrometry, and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether the amino acid score also correlated with anatomical [intima-media thickness (IMT) and plaque formation] and functional (exercise-induced myocardial ischaemia) abnormalities. Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for incident CVD in subjects belonging to quartiles 2, 3, and 4 was 1.27 (0.72-2.22), 1.96 (1.07-3.60), and 2.20 (1.12-4.31) (P(trend) = 0.010), respectively, after multivariate adjustment. Increasing quartile of the DM-AA score was cross-sectionally related to carotid IMT (P(trend) = 0.037) and with the presence of at least one plaque larger than 10 mm(2) (P(trend) = 0.001). Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for inducible ischaemia in subjects belonging to quartiles 2, 3, and 4 was 3.31 (1.05-10.4), 4.24 (1.36-13.3), and 4.86 (1.47-16.1) (P(trend) = 0.011), respectively.ConclusionThis study identifies branched-chain and aromatic amino acids as novel markers of CVD development and as an early link between diabetes and CVD susceptibility

Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals With Type 2 Diabetes

The parameters derived from reservoir-excess pressure analysis (RPA) have prognostic utility in several populations. However, evidence in type 2 diabetes (T2DM) remains scarce. We determined if these parameters were associated with T2DM, and whether they would predict cardiovascular events in individuals with T2DM.We studied 306people with T2DM and cardiovascular disease (CVD)(DMCVD:70.4±7.8yrs), 348people with T2DM but without CVD (DM:67.7±8.4yrs) and 178peoplewithout T2DM or CVD (CTRL:67.2±8.9yrs). RPA-derived parameters including reservoir pressure integral (INTPR), peak reservoir pressure (MAXPR), excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC) were obtained by radial artery tonometry. INTPR was lower in DMCVD and DM than CTRL. MAXPR was lower, and INTXSP was greater in DMCVD than DM and CTRL. SRC was lower in a stepwise manner among groups(DMCVD<DM<CTRL).DRC was greater in DMCVD than CTRL. In the sub group of individuals with T2DM (n=642), 14 deaths (6 cardiovascular and 9non-cardiovascular causes) and 108cardiovascular events occurred during a 3-yr follow-up period. Logistic regression analysis revealed that INTPR [odds ratio 0.59(95%CI:0.45-0.79)] and DRC [odds ratio 1.60(95%CI:1.25-2.06)] were independent predictors of cardiovascular events during follow-up after adjusting for conventional risk factors(both p<0.001). Further adjustments for potential confounders had no influence on associations. These findings demonstrate that altered RPA-derived parameters are associated with T2DM. Furthermore, baseline values of INTPR and DRC independently predict cardiovascular events in individuals with T2DM, indicating the potential clinical utility of these parameters for risk stratification in T2DM

Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes:The SUMMIT VIP Study

Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD

Ultrasound features of human carotid plaques

Atherosclerotic plaques in the carotid arteries are common in a middle-aged population. When a carotid plaque ruptures it may result in a cerebrovascular event. However, only a minor part of carotid plaques will eventually rupture. Finding those plaques is essential to decide the most appropriate treatment strategy. With non-invasive ultrasound the carotid plaques can be visualized for assessment of various features. Plaques that appear dark on the ultrasound image, i.e. echolucent plaques, are more prone to rupture. The aim of this thesis was to explore the relation between plaque features, mainly echogenicity measured as grey scale median (GSM), and some of the known risk factors for cardiovascular events, as well as treatment approaches. Measurement of GSM has in the last decades become common in research. It has not, however, been implemented in clinical practise yet. One reason could be the lack of consensus regarding measurement methods, resulting in a large variety of both range and mean values of GSM. We compared 2 softwares, using different standardization methods, for measurement of GSM in stored ultrasound images of the carotid plaques. Even though the agreement between methods was good, mean difference of GSM was large. This indicated that GSM measurements couldn’t be compared unless the same software and standardization method have been used. Subjects with diabetes have an increased risk of having a cardiovascular event. In a cohort of 100 healthy subjects, aged 70 years, we found that subjects with diabetes had increased echolucency as compared to non diabetics. This could indicate that subjects with diabetes have not only more pronounced atherosclerosis but also a different, more vulnerable, type. Treatment with metoprolol for 3 years decreased progression of intima-media thickness in the bulb. In a post hoc analysis, measuring echogenicity in ultrasound images of carotid plaques in subjects with and without metoprolol treatment, plaque in treated subjects had become more echogenic as compared to non treated. This finding suggested that treatment with beta-blockers could stabilize carotid plaques, previously attributed to statin treatment. However, the measurement of GSM is a rough method for assessing plaque features. We introduced a novel feature, namely plaque patchiness, describing the pattern of the plaque as being more or less spotty on the ultrasound image. Subjects with the combination of echolucent and spotty plaques had increased values of weight, body mass index, waist and hip. Since echolucency in plaques have been associated with increased cardiovascular risk, this finding may partly explain the increased risk of cardiovascular events among subjects with overweight and obesity. Whether the novel feature, plaque patchiness, is associated with increase in risk is still to be explored

Long-term treatment with low-dose metoprolol CR/XL is associated with increased plaque echogenicity: The Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS).

OBJECTIVES: To examine whether the decrease in IMT progression rate in the carotid bulb induced by metoprolol CR/XL treatment (25mg once daily) observed in the β-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS) was accompanied by an effect on carotid plaque echogenicity. METHODS: Gray scale median (GSM) in carotid plaques, used as a score of echogenicity, was measured at baseline and after 36 months in those 341 subjects (aged 49-69 years) with an asymptomatic moderate- to large-sized carotid plaque present at baseline and at follow-up. Participants were in a factorial design assigned to treatment with metoprolol CR/XL (25mg once daily), fluvastatin (40mg once daily) or corresponding placebo. RESULTS: After 36 months plaques were more echogenic in participants treated compared to those not treated with metoprolol CR/XL (57.3±16.8 versus 51.8±20.0, p=0.006). GSM had increased more from baseline in the metoprolol CR/XL treated subjects (25±15 versus 18±20, p<0.001), and plaques that had become more echolucent were less frequent in the metoprolol CR/XL treated subjects (3.6% versus 17.0%, p<0.001). CONCLUSIONS: Long-term treatment with low dose metoprolol CR/XL in clinically healthy subjects with moderate-sized carotid plaques was associated with increase in plaque echogenicity, suggesting a potential beneficial effect of the β-blocker treatment on plaque stability

Increased Echolucency of Carotid Plaques in Patients With Type 2 Diabetes.

Background and Purpose - Diabetes is associated with the presence of moderate to large atherosclerotic carotid plaques. Previous carotid ultrasound studies have associated plaques with low echogenicity with a higher risk of cerebrovascular events. The aim of this study was to evaluate whether patients with type 2 diabetes have different plaque echogenicity than do nondiabetic subjects. Methods - Forty-seven type 2 diabetic and 51 nondiabetic subjects with a carotid plaque in the right artery were included in this study. All patients were born in 1935 to 1936 and were participants in a population-based study. Carotid ultrasonography was performed and the risk factors for cardiovascular disease were determined. Plaque echogenicity was assessed quantitatively on B-mode ultrasound images by standardized gray-scale median values. Results - Gray-scale median values were significantly lower, indicating more echolucent plaques, in patients with type 2 diabetes compared with nondiabetics (37.0 +/- 14.8 vs 45.5 +/- 15.4, P=0.007). Of the other risk factors studied, only triglycerides were significantly associated with the echogenicity of the plaque. Conclusions - Patients with type 2 diabetes have more echolucent plaques compared with nondiabetic subjects. This might be associated with the higher risk of cardiovascular events among diabetics

Comparison of grey scale median (GSM) measurement in ultrasound images of human carotid plaques using two different softwares.

Grey scale median (GSM) measured on ultrasound images of carotid plaques has been used for several years now in research to find the vulnerable plaque. Centres have used different software and also different methods for GSM measurement. This has resulted in a wide range of GSM values and cut-off values for the detection of the vulnerable plaque. The aim of this study was to compare the values obtained with two different softwares, using different standardization methods, for the measurement of GSM on ultrasound images of carotid human plaques. GSM was measured with Adobe Photoshop(®) and with Artery Measurement System (AMS) on duplex ultrasound images of 100 consecutive medium- to large-sized carotid plaques of the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS). The mean values of GSM were 35·2 ± 19·3 and 55·8 ± 22·5 for Adobe Photoshop(®) and AMS, respectively. Mean difference was 20·45 (95% CI: 19·17-21·73). Although the absolute values of GSM differed, the agreement between the two measurements was good, correlation coefficient 0·95. A chi-square test revealed a kappa value of 0·68 when studying quartiles of GSM. The intra-observer variability was 1·9% for AMS and 2·5% for Adobe Photoshop. The difference between softwares and standardization methods must be taken into consideration when comparing studies. To avoid these problems, researcher should come to a consensus regarding software and standardization method for GSM measurement on ultrasound images of plaque in the arteries

Digital Photoplethysmography for Assessment of Arterial Stiffness: Repeatability and Comparison with Applanation Tonometry.

Arterial stiffness is an independent risk factor for cardiovascular morbidity and can be assessed by applanation tonometry by measuring pulse wave velocity (PWV) and augmentation index (AIX) by pressure pulse wave analysis (PWA). As an inexpensive and operator independent alternative, photoelectric plethysmography (PPG) has been introduced with analysis of the digital volume pulse wave (DPA) and its second derivatives of wave reflections