Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFß3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.

Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise training improves peak oxygen uptake (V.O2peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined. OBJECTIVES: The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF. METHODS: This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values. RESULTS: At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training. CONCLUSIONS: In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V.O2peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947).

Circulating Reactive Oxygen Species in Adults with Congenital Heart Disease.

Oxidative stress is an important pathophysiological mechanism in the development of numerous cardiovascular disorders, but few studies have examined the levels of oxidative stress in adults with congenital heart disease (CHD). The objective of this study was to investigate oxidative stress levels in adults with CHD and the association with inflammation, exercise capacity and endothelial function. To this end, 36 adults with different types of CHD and 36 age- and gender-matched healthy controls were enrolled. Blood cell counts, hs-CRP, NT-proBNP, fasting glucose, cholesterol levels, iron saturation and folic acid concentrations were determined in venous blood samples. Levels of superoxide anion radical in whole blood were determined using electron paramagnetic resonance spectroscopy in combination with the spin probe CMH. Physical activity was assessed with the IPAQ-SF questionnaire. Vascular function assessment (EndoPAT) and cardiopulmonary exercise testing were performed in the patient group. Superoxide anion radical levels were not statistically significantly different between adults with CHD and the matched controls. Moreover, oxidative stress did not correlate with inflammation, or with endothelial function or cardiorespiratory fitness in CHD; however, a significant negative correlation with iron saturation was observed. Overall, whole blood superoxide anion radical levels in adults with CHD were not elevated, but iron levels seem to play a more important role in oxidative stress mechanisms in CHD than in healthy controls. More research will be needed to improve our understanding of the underlying pathophysiology of CHD.

Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy.

BACKGROUND: The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives. METHODS: Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant. RESULTS: Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered. CONCLUSIONS: Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk.

Plasma-Derived microRNAs Are Influenced by Acute and Chronic Exercise in Patients With Heart Failure With Reduced Ejection Fraction.

Background: Exercise training improves VO2peak in heart failure with reduced ejection fraction (HFrEF), but the effect is highly variable as it is dependent on peripheral adaptations. We evaluated changes in plasma-derived miRNAs by acute and chronic exercise to investigate whether these can mechanistically be involved in the variability of exercise-induced adaptations. Methods: Twenty-five male HFrEF patients (left ventricular ejection fraction < 40%, New York Heart Association class ≥ II) participated in a 15-week combined strength and aerobic training program. The effect of training on plasma miRNA levels was compared to 21 male age-matched sedentary HFrEF controls. Additionally, the effect of a single acute exercise bout on plasma miRNA levels was assessed. Levels of 5 miRNAs involved in pathways relevant for exercise adaptation (miR-23a, miR-140, miR-146a, miR-191, and miR-210) were quantified using RT-qPCR and correlated with cardiopulmonary exercise test (CPET), echocardiographic, vascular function, and muscle strength variables. Results: Expression levels of miR-146a decreased with training compared to controls. Acute exercise resulted in a decrease in miR-191 before, but not after training. Baseline miR-23a predicted change in VO2peak independent of age and left ventricular ejection fraction (LVEF). Baseline miR-140 was independently correlated with change in load at the respiratory compensation point and change in body mass index, and baseline miR-146a with change in left ventricular mass index. Conclusion: Plasma-derived miRNAs may reflect the underlying mechanisms of exercise-induced adaptation. In HFrEF patients, baseline miR-23a predicted VO2peak response to training. Several miRNAs were influenced by acute or repeated exercise. These findings warrant exploration in larger patient populations and further mechanistic in vitro studies on their molecular involvement.

Cardiogeneticsbank@UZA: A Collection of DNA, Tissues, and Cell Lines as a Translational Tool.

Cardiogeneticsbank@UZA is an academic hospital integrated biobank that collects aortic tissue, blood, cell lines (fibroblasts, vascular smooth muscle cells, peripheral blood mononuclear cells, and induced pluripotent stem cells), and DNA from patients with cardiogenetic disorders, for both diagnostic and research purposes. We adhere to a quality management system and have established standard protocols for the sampling and processing of all cardiogenetic patient related materials. Cardiogeneticsbank@UZA is embedded in the Biobanking and Biomolecular Resources Research Infrastructure Belgium (BBMRI.be) and samples from this biobank are available for commercial and academic researchers, through an established access procedure. Currently, the extremely valuable cardiogenetics collection consists of more than 8,700 DNA samples, 380 tissue samples, and 500 cell lines of 7,578 patients, and is linked with extensive clinical data. Some interesting potential research applications are discussed.

Low-flow mediated constriction as a marker of endothelial function in healthy pregnancy and preeclampsia: A pilot study.

OBJECTIVES: Overwhelming clinical evidence exists on disturbed vascular and endothelial function in the pathophysiology of preeclampsia (PE). In a non-pregnant (NP) population, L-FMC (low-flow mediated constriction) provides insight in the 'resting' endothelial capacity in contrast to the gold standard of flow mediated dilatation (FMD), reflecting endothelial nitric oxide bioavailability. STUDY DESIGN: Longitudinal follow-up of 100 healthy pregnant (HP) women, 33 PE women and 16 NP controls with non-invasive vascular assessments. HP women were evaluated at 12 and 35 weeks of gestation and at 6 months postpartum. PE patients were assessed at diagnosis (mean 30 weeks) and 6 months postpartum. MAIN OUTCOME MEASURES: Endothelial function (L-FMC, FMD, peripheral arterial tonometry (PAT)) and arterial stiffness (pulse wave velocity (PWV) and analysis (PWA)) were measured at the different visits and compared between groups. RESULTS: Overall endothelial dysfunction is present in PE (FMD HP 9.09 ±â€¯4.20 vs PE 5.21 ±â€¯4.47, p = 0.0004; L-FMC HP -1.90 ±â€¯2.66 vs PE -0.40 ±â€¯2.09, p = 0.03). L-FMC gradually elevates during the course of a HP (1st trim -0.31 ±â€¯1.75 vs 3rd trim -1.97 ±â€¯3.02, p < 0.0001) and is present in 85% of women in the third trimester. In NP, only 27% of women has L-FMC. In PE, L-FMC is present in 50% of cases. Arterial stiffness is increased in PE (all p < 0.0001). There is no correlation between L-FMC and other markers of vascular function (p > 0.05). CONCLUSION: PE is characterized by dysfunction of both resting and recruitable endothelial capacity. This study offers new insights in different aspects of endothelial function in pregnancy, since L-FMC reflects an adaptation in HP that is absent in PE.

Predictive value of Type D personality for impaired endothelial function in patients with coronary artery disease.

BACKGROUND: Type D personality (high negative affectivity and social inhibition) is associated with cardiovascular events and coronary plaque severity. Whether Type D is also related to functional vasomotion abnormalities is unknown. We examined concurrent and predictive associations of Type D with endothelial dysfunction in patients with coronary artery disease (CAD). METHODS: At baseline, 180 CAD patients (90% men; M = 58.0 years) completed Type D (DS14) and depression scales, and entered a 12-week exercise program. Flow-mediated dilation (FMD) of the brachial artery and circulating CD34+/KDR+/CD45+dim endothelial progenitor cells (EPCs) were assessed at baseline, 3 months, and 12 months. Logistic regression and linear mixed models were used to analyze endothelial function. RESULTS: Type D personality was associated with decreased FMD across baseline, 3 months, and 12 months (mixed model analysis, p = 0.04), after adjustment for clinical characteristics, exercise training and depression. There was no significant association between Type D and decreased EPCs (p = 0.07). Age and smoking were other significant correlates of FMD and EPCs. Using a FMD <5.5% cut-off, Type D patients more often had endothelial dysfunction at baseline (24/37 = 65%) than non-Type Ds (63/143 = 44%); OR = 3.03, 95% CI 1.04-8.80. This significant Type D effect was confirmed in prospective analyses of endothelial dysfunction at 12 months (OR = 3.43, 95% CI 1.01-11.64), and in subgroup analyses of male patients. CONCLUSIONS: Type D personality was associated with impaired endothelial function in men with CAD. This association was robust across time, independent from depressive symptoms, and supports the notion that Type D has an adverse effect on cardiovascular health in patients with CAD.

Flow-mediated dilation and peripheral arterial tonometry are disturbed in preeclampsia and reflect different aspects of endothelial function.

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy (P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy (P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy (P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy (P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy.

A non-contact approach for PWV detection: application in a clinical setting.

A need for screening methods for arteriosclerosis led to the development of several approaches to measure pulse wave velocity (PWV) being indicative of arterial stiffness. Carotid-femoral PWV (cfPWV) can be measured between common carotid artery (CCA) and femoral artery (FA) displaying the physiologically important stiffness of the conduit arteries. However, this measurement approach has several disadvantages, and a local PWV-measurement of CCA-stiffness has been proposed as an alternative in the past. In the presented pilot study, laser Doppler vibrometry (LDV) is used to measure PWV locally in the CCA (PWVLDV) in 48 patients aged between 48 and 70, with known atherosclerotic arterial disease: stabilized coronary artery disease (CAD), cerebro-vascular disease (CVD) or peripheral artery disease (PAD). Additionally, cfPWV, CCA distensibility coefficient (DC), CCA intima-media thickness (IMT), blood pressure (BP) and age were evaluated. LDV is a valid method for local PWV-measurement. The method is potentially easy to use, and causes no discomfort to the patient. PWVLDV correlates with age (R = 0.432; p = 0.002) as reported in related studies using other techniques, and measured values lay between 2.5 and 5.8 m s(-1), which is well in line with literature measures of local PWV in the CCA. In conclusion, PWVLDV potentially is a marker for arterial health, but more research in a larger and more homogeneous patient population is mandatory. In future studies, blood velocity measurements should be incorporated, as well as a reference method such as pulse wave imaging (PWI) or magnetic resonance imaging (MRI).

Digital image correlation for full-field time-resolved assessment of arterial stiffness.

Pulse wave velocity (PWV) of the arterial system is a very important parameter to evaluate cardiovascular health. Currently, however, there is no golden standard for PWV measurement. Digital image correlation (DIC) was used for full-field time-resolved assessment of displacement, velocity, acceleration, and strains of the skin in the neck directly above the common carotid artery. By assessing these parameters, propagation of the pulse wave could be tracked, leading to a new method for PWV detection based on DIC. The method was tested on five healthy subjects. As a means of validation, PWV was measured with ultrasound (US) as well. Measured PWV values were between 3.68 and 5.19 m/s as measured with DIC and between 5.14 and 6.58 m/s as measured with US, with a maximum absolute difference of 2.78 m/s between the two methods. DIC measurements of the neck region can serve as a test base for determining a robust strategy for PWV detection, they can serve as reference for three-dimensional fluid-structure interaction models, or they may even evolve into a screening method of their own. Moreover, full-field, time-resolved DIC can be adapted for other applications in biomechanics.

Carotid artery intima-media thickness is associated with coronary artery disease.

OBJECTIVE: The intima-media thickness (IMT) of the carotid artery is dependent on the risk factor load during life and correlates well with the degree of atherosclerosis, also in other vascular beds. METHODS: We reviewed our database of IMT measurements, from January 2002 to February 2007. We compared the mean IMT values of patients without a history of coronary artery disease (group 1) with those with a history of coronary artery disease (group 2). For both groups we divided the results of measurements according to age. We compared the IMT between both groups and looked for a correlation with increasing age. The IMT was measured with high-resolution echography at the posterior wall of the common carotid artery, using an automated edge-tracking method. RESULTS: The database contained 598 IMT measurements in group 1 and 672 in group 2. In both groups we observed a significant increase in IMT with increasing age. Within a certain age group, a significant difference in IMT between group 1 and 2 occurred at an age of 40 years or above (age 40-65: IMT 645.54 versus 671.71 microm, respectively, P = 0.04, and age > 65 years: IMT 715.2 versus 772.91 microm, respectively, P = 0.01). CONCLUSIONS: IMT increases with age and is higher in patients with a history of vascular disease. This difference is significant in patients of 40 years or older. This finding supports the recommendations of the prevention conference of the American Heart Association, that carefully performed IMT measurement can add incremental information to traditional risk factor assessment in asymptomatic individuals above the age of 45 years.

A maximal exercise bout increases the number of circulating CD34+/KDR+ endothelial progenitor cells in healthy subjects. Relation with lipid profile.

Mobilization of bone marrow-derived endothelial progenitor cells (EPC) might explain exercise-induced improvement of endothelial function. We assessed whether a maximal exercise bout could alter the number of circulating EPC in healthy subjects and whether this effect is related to their cardiovascular risk profile. Additionally, we investigated possible mediators of this effect, namely nitric oxide (NO) bioavailability and vascular endothelial growth factor (VEGF) release. Healthy subjects (group 1, n = 11; group 2, n = 14) performed a symptom-limited cardiopulmonary exercise test on a bicycle ergometer. Numbers of CD34+/kinase insert domain receptor (KDR)+ cells were determined by flow-cytometric analysis, either after magnetic separation of CD34+ cells (group 1) or starting from whole blood (group 2). Serum concentrations of VEGF and NO metabolites were measured by using ELISA. Following exercise, EPC increased by 76% (15.4 +/- 10.7 cells/ml vs. 27.2 +/- 13.7 cells/ml; P = 0.01) in group 1 and by 69% in group 2 (30.9 +/- 14.6 cells/ml vs. 52.5 +/- 42.6 cells/ml; P = 0.03). The increase in EPC correlated positively with LDL and total cholesterol/HDL ratio and negatively with peak oxygen consumption and oxygen consumption at anaerobic threshold. VEGF levels increased with exercise, with a strong trend toward significance (P = 0.055). NO levels remained unchanged. The present study demonstrates that a maximal bout of exercise induces a significant shift in CD34+ cells toward CD34+/KDR+ cells. This response was larger in subjects with a less favorable lipid profile.

Impact of oxidative stress on the endothelial dysfunction of children and adolescents with type 1 diabetes mellitus: protection by superoxide dismutase?

Diabetes mellitus is associated with endothelial dysfunction and oxidative stress (OS). We investigated whether these abnormalities are interrelated in children and adolescents with type 1 diabetes mellitus (T1DM) and if early OS markers predictive of vascular dysfunction can be identified. Thirty-five T1DM patients were matched for sex, age, height, and weight with nondiabetic subjects as healthy controls (CO). Flow-mediated dilatation (FMD), carotid intima media thickness (IMT), and OS status in fasting blood were measured. Diabetic children had impaired FMD (6.68+/-1.98 versus 7.92+/-1.60% in CO, p=0.004), which was more pronounced in boys. The degree of FMD impairment was not related to the lower plasma levels of antioxidants or to the higher glucose, glycation, lipids, and peroxidation products. Erythrocyte superoxide dismutase activity, copper/zinc superoxide dismutase (Cu/Zn SOD), was higher in diabetic subjects (1008+/-224 versus 845+/-195 U/g Hb in CO, p=0.003) and was positively associated with FMD. After correcting for diabetes and gender, the subgroup of children with high Cu/Zn SOD (>955 U/g Hb) had a significantly better FMD (p=0.035). These results suggest that higher circulating Cu/Zn SOD could protect T1DM children and adolescents against endothelial dysfunction. Low Cu/Zn SOD is a potential early marker of susceptibility to diabetic vascular disease.

Multislice cardiac computed tomography in symptomatic middle-aged women.

OBJECTIVE: To assess the accuracy of multislice cardiac computed tomography (MSCT) for detection of significant coronary artery disease (CAD) in middle-aged symptomatic women. METHODS: We included 70 women (51+/-8 years) with complaints of chest pain or dyspnea, and an abnormal maximum exercise electrocardiogram (ECG) (8.6+/-1.4 metabolic equivalents). All had a MSCT using a 16 detector rows scanner, and coronary arteriography (CA). Blinded results of the two modalities were compared using a segment, vessel, and patient-based analysis. RESULTS: On MSCT 36% had normal coronaries, 24% had significant CAD requiring revascularization, and the remainder had mild CAD. MSCT had reasonably high diagnostic accuracy at segment level (negative predictive value of 95%, positive predictive value 81%, specificity 99%, and sensitivity 50%), regarding single or multivessel CAD when both nonassessable and assessable segments were included in the analysis. The agreement between the segments comparing MSCT and CA for significant CAD was excellent at 98% (kappa value 0.89). CONCLUSIONS: In this cohort of middle-aged symptomatic women with an abnormal stress test, 24% had significant CAD requiring intervention. MSCT was highly accurate in diagnosing significant CAD with an excellent negative predictive value.

Effect of folic acid on endothelial function following acute myocardial infarction.

The aim of this study was to test the influence of high-dose folic acid (10 mg/d) on endothelial function in patients referred for coronary intervention after an acute myocardial infarction (AMI) and determine its relation to homocysteine levels. Flow-mediated dilation (FMD) of the brachial artery was performed in 40 patients after AMI (16 with normal homocysteine levels and 24 patients with elevated levels [>11 micromol/L]). Subjects were randomized to receive first folic acid (10 mg/day; group A) or placebo (group B) for 6 weeks in a double-blind crossover trial with a 2-week washout. Plasma folate, total homocysteine and its subtypes (oxidized, reduced, and protein-bound), FMD, and nitroglycerin-mediated dilation were assessed at baseline and at 6 and 14 weeks. In group A, folic acid improved FMD from 3.98 +/- 0.35% to 6.44 +/- 0.56% (p <0.001). This effect persisted after the crossover with placebo (5.42 +/- 0.59, p = 0.13). In group B, placebo did not increase FMD (4.01 +/- 0.34% vs 4.46 +/- 0.38, p = 0.38); however, a significant increase was observed in the second active treatment period (6.49 +/- 0.56%, p = 0.005). In both groups, improved FMD neither correlated with basal levels of homocysteine and its subtypes nor with changes induced during the folate treatment. Nitroglycerin-mediated dilation did not change significantly in either group. Folic acid increased FMD in both normo- and hyperhomocysteinanemic groups (p = 0.006 and p <0.001). In conclusion, 6-week treatment with high-dose folic acid improves endothelial function in post-AMI patients, independent from homocysteine status. Folic acid can be recommended to improve postinfarction endothelial dysfunction in patients with normo- and hyperhomocysteinemia.

Can measurement of the intima-media thickness of the carotid artery improve the diagnostic value of exercise stress tests?

OBJECTIVE: The diagnostic value of the exercise electrocardiogram (ECG) for the detection of coronary artery disease is hampered by a high proportion of equivocal results, especially in asymptomatic patients. The intima-media thickness of the carotid artery correlates well with the degree of atherosclerosis, also in other vascular beds, such as the coronary arteries. The aim of this study is to evaluate whether measurements of intima-media thickness can improve the diagnostic value of stress ECG in the detection of coronary artery disease. METHODS: Patients without a history of vascular disease and with equivocal exercise stress ECG results were included. The intima-media thickness was measured with high resolution echography at the posterior wall of the common carotid artery, using an automated edge-tracking method. The diagnosis of coronary artery disease was based on the presence of reversible perfusion defects on exercise MIBI-scintigrams. RESULTS: A total of 90 patients (46 men, 44 women) with a mean age of 53.7 years were included. The MIBI-scintigraphy was positive in 17. There was no difference in mean intima-media thickness between MIBI positive and MIBI negative patients (635.76 +/- 84.56 microm and 643.89 +/- 107.06 microm, respectively, p = 0.8). Using multiple regression analysis, neither intima-media thickness measurements, nor classic risk factors could predict the result of MIBI-scintigraphy. Intima-media thickness was mainly influenced by age and hypertension. CONCLUSIONS: In this study, neither intima-media thickness measurements, nor classic risk factors could improve the diagnostic value of stress ECG in the detection of coronary artery disease. In case of equivocal stress results, additional cardiovascular imaging techniques remain recommended.

Flow mediated dilatation and cardiac function in type 1 diabetes mellitus.

The present study sought to examine the occurrence of subclinical markers of cardiovascular risk and cardiac dysfunction with increasing disease duration in type 1 diabetes mellitus (DM). There are few data on subclinical cardiovascular abnormalities in type 1 DM. The study included 100 patients without any cardiovascular complaints (mean age 46.6 years, range 22 to 63), with a history of type 1 DM ranging from 2 to 36 years, and 75 age-matched controls. Standard 2-dimensional and Doppler echocardiography and pulse-wave tissue Doppler (tD) mapping of systolic (Sm) and diastolic (Em, Am) velocities (12 left ventricular [LV] segments and right-sided cardiac) were performed. An Em/Am ratio of <1 was considered to represent abnormal segmental diastolic function. Flow-mediated dilation (FMD) of the brachial artery, carotid intima media thickness (IMT) measurement, and extensive laboratory analysis were performed. The FMD was reduced, and IMT increased in patients (p < 0.01). Regional tD-derived diastolic and systolic functional abnormalities were observed within the first decade of the disease. Significant correlations were found between FMD and LV segments with tD-derived dysfunction, the duration of DM, and fibrinogen (p < 0.0001 for all). Stepwise regression analysis showed that FMD was the strongest predictor of abnormal segmental function (p < 0.0001). Data further presented as an analysis of tertiles by DM duration show an increasing occurrence of subclinical cardiac dysfunction and cardiovascular risk markers compared with age-matched controls. In conclusion, FMD is associated with abnormal segmental cardiac function in type 1 DM.

Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool?

Brachial arterial flow-mediated dilation (FMD), assessed by high-resolution ultrasonography, reflects endothelium-dependent vasodilator function. FMD is diminished in patients with atherosclerosis and with coronary risk factors, and improves with risk-reduction therapy. Therefore, the measurement of FMD can be a good prognostic instrument in preventive cardiology, is useful to predict short-term postoperative cardiovascular events in a high-risk population and to assess long-term cardiovascular risk in a lower risk population, and is an excellent experimental tool to detect changes in endothelial function after new therapeutic interventions. In this review article, the pathophysiology of FMD, based on reactive hyperemia, is extensively discussed. Furthermore, an overview is given of the actual clinical indications of FMD measurement.