Pravastatin-induced improvement in coronary reactivity and circulating ATP and ADP levels in young adults with type 1 diabetes.

AIMS: Extracellular ATP and ADP regulate diverse inflammatory, prothrombotic and vasoactive responses in the vasculature. Statins have been shown to modulate their signaling pathways in vitro. We hypothesized that altered intravascular nucleotide turnover modulates vasodilation in patients with type 1 diabetes (T1DM), and this can be partly restored with pravastatin therapy. METHODS: In this randomized double blind study, plasma ATP and ADP levels and echocardiography-derived coronary flow velocity response to cold pressor test (CPT) were concurrently assessed in 42 normocholesterolemic patients with T1DM (age 30 ± 6 years, LDL cholesterol 2.5 ± 0.6 mmol/L) before and after four-month treatment with pravastatin 40 mg/day or placebo (n = 22 and n = 20, respectively), and in 41 healthy control subjects. RESULTS: Compared to controls, T1DM patients had significantly higher concentrations of ATP (p < 0.01) and ADP (p < 0.01) and these levels were partly restored after treatment with pravastatin (p = 0.002 and p = 0.007, respectively), but not after placebo (p = 0.06 and p = 0.14, respectively). Coronary flow velocity acceleration was significantly lower in T1DM patients compared to control subjects, and it increased from pre- to post-intervention in the pravastatin (p = 0.02), but not in placebo group (p = 0.15). CONCLUSIONS: Pravastatin treatment significantly reduces circulating ATP and ADP levels of T1DM patients, and concurrently improves coronary flow response to CPT. This study provides a novel insight in purinergic mechanisms involved in pleiotropic effects of pravastatin.

Cardiopulmonary involvement in Fabry's disease.

BACKGROUND: Fabry's disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipid in different tissues, including endothelial and smooth-muscle cells and cardiomyocytes. OBJECTIVES: There is controversial data on cardiopulmonary involvement in Fabry's disease, because many reports are based on small and selected populations with Fabry's disease. Furthermore, the aetiology of cardiopulmonary symptoms in Fabry's disease is poorly understood. METHODS: We studied cardiopulmonary involvement in seventeen patients with Fabry's disease (20-65 years, 6 men) using ECG, bicycle stress, cardiac magnetic resonance imaging, spirometry, diffusing capacity and pulmonary high-resolution computed tomography (HRCT) tests. Cardiopulmonary symptoms were compared to observed parameters in cardiopulmonary tests. RESULTS: Left ventricular hypertrophy (LVH) and reduced exercise capacity are the most apparent cardiac changes in both genders with Fabry's disease. ECG parameters were normal when excluding changes related to LVH. Spirometry showed mild reduction in vital capacity and forced expiratory volume in one second (FEV I), and mean values in diffusing capacity tests were within normal limits. Generally, only slight morphological pulmonary changes were detected using pulmonary HRCT, and they were not associated with changes in pulmonary function. The self-reported amount of pulmonary symptoms associated only with lower ejection fraction (P < 0.001) and longer QRS-duration (P = 0.04) of all measured cardiopulmonary parameters, whereas cardiac symptoms have no statistically significant association with any of these parameters. CONCLUSION: LVH and reduced exercise capacity are the most apparent cardiopulmonary changes in Fabry's disease but they have only a minor association to cardiopulmonary symptoms.Therefore, routine cardiopulmonary evaluation in Fabry's disease using echocardiography is maybe enough when integrated to counselling for aerobic exercise training.

Decreased endothelin-1 levels after acute consumption of red wine and de-alcoholized red wine.

BACKGROUND: Red wine consumption may influence on vasoconstrictive peptide endothelin-1 levels, and this may be one mechanism leading to improved vasodilation after red wine consumption. Endothelin-1 levels and their association with coronary epicardial diameter and flow rate, however, have not been studied in vivo after consumption of red wine and de-alcoholized red wine. The purpose of this randomized trial was to determine the acute effects of these beverages on endothelin-1 levels and compare them to coronary artery epicardial diameter and flow rate. METHODS: Twenty-two healthy men consumed a high dose (8.1+/-0.9 dL) of alcohol-containing red wine and de-alcoholized red wine in a cross-over design at one sitting with a two-week washout period. Endothelin-1 levels were determined and coronary artery diameter and flow rate assessed using transthoracic echocardiography before and acutely after intervention. RESULTS: Red wine and de-alcoholized red wine significantly decreased endothelin-1 levels (0.75+/-0.26 pg/mL to 0.61+/-0.20 pg/mL, p=0.002; 0.74+/-0.32 pg/mL to 0.63+/-0.24 pg/mL, p=0.04, respectively), but did not have a significant effect on epicardial diameter (1.1+/-0.3 mm vs. 1.1+/-0.3 mm, p=0.58; and 1.1+/-0.3 mm vs. 1.1+/-0.2 mm, p=0.10, respectively) or flow rate (7.8+/-4.0 mL/min to 6.4+/-3.6 mL/min, p=0.07; and 7.8+/-4.0 mL/min to 7.4+/-3.2 mL/min, p=0.53, respectively). CONCLUSIONS: Red wine and de-alcoholized red wine decreased plasma endothelin-1 levels after acute consumption, but this change was not reflected in coronary epicardial diameters or flow rate.

Cardiac magnetic resonance imaging in valvular heart disease.

Cardiac magnetic resonance imaging (CMR) has rapidly gained acceptance as an accurate, reproducible and non-invasive imaging method for assessment of a wide range of cardiovascular diseases. However, CMR has not been used widely for diagnostic purposes in valvular heart disease (VHD). Unlike echocardiography it has no body habitus-related limitations and can thus be used to complement echocardiography. It is an especially good alternative for clinical follow-up in patients with VHD, as it allows accurate measurement of valvular dysfunction and related ventricular burden. Additionally, CMR is an ideal method for evaluating complex congenital heart disease and determining the significance of its components. It can also be used to study the physiological course of valvular dysfunction and response to therapeutic interventions. In this review, we present a basic introduction to CMR methodology, including its advantages and potential problems, and the physiology and quantification in VHD. We also discuss clinical applications of CMR in VHD. Furthermore, we describe how a CMR study statement should be structured in order to increase clinical use of this valuable methodology in cardiology.

High dose of red wine elicits enhanced inhibition of fibrinolysis.

BACKGROUND AND DESIGN: The purpose of this randomized controlled cross-over study was to determine the acute effects of high doses of alcoholic beverages on circulating markers related to atherosclerosis and fibrinolysis. METHODS: Twenty-two healthy men consumed a high dose (8.1+/-0.9 dl) of alcohol-containing red wine and dealcoholized red wine, and an equal ethanol dose of cognac (2.4+/-0.3 dl). Blood samples were taken before and shortly after interventions. RESULTS: Red wine, unlike dealcoholized red wine and cognac, increased tissue plasminogen activator inhibitor-1 levels significantly, indicating an acute inhibition of fibrinolysis after a high dose. CONCLUSION: Findings may explain the increased risk of cardiovascular mortality among binge drinkers.

Echocardiography in Fabry disease: diagnostic value of endocardial border binary appearance.

BACKGROUND AND AIM: It has been reported that the endocardium in Fabry disease has a binary appearance on transthoracic echocardiography. It has been suggested that this sign could be used with good accuracy to differentiate Fabry disease from hypertrophic cardiomyopathy and even as a first filter to screen for suspected Fabry disease. METHODS: Therefore, we performed a blinded echocardiography in a non-selected population of patients with Fabry disease and matched controls. We included 23 echocardiographic studies of Fabry patients. RESULTS: Two of the Fabry patients had binary appearance of the endocardium. One of them had left ventricular hypertrophy (LVH) and the other had a normal left ventricular mass. Binary appearance of the endocardium was detected in four of the controls, and one of them had LVH. Subgroup analysis of patients who had LVH indicated a sensitivity of 12.5% and a specificity of 66.7% for binary appearance of the endocardium to detect Fabry disease as the underlying cause of LVH. Overall, binary appearance of the endocardium had a sensitivity and a specificity of 15.4 and 73.3%, respectively, to distinguish patients with Fabry disease from controls in our population. CONCLUSIONS: Binary appearance of the endocardium is not feasible for screening Fabry disease by echocardiography.

Effects of cognac on coronary flow reserve and plasma antioxidant status in healthy young men.

BACKGROUND: The cardioprotective effects of certain alcoholic beverages are partly related to their polyphenol content, which may improve the vasodilatory reactivity of arteries. Effect of cognac on coronary circulation, however, remains unknown. The purpose of this randomized controlled cross-over study was to determine whether moderate doses of cognac improve coronary reactivity as assessed with cold pressor testing (CPT) and coronary flow reserve (CFR) measurement. METHODS: Study group consisted of 23 subjects. Coronary flow velocity and epicardial diameter was assessed using transthoracic echocardiography at rest, during CPT and adenosine infusion-derived CFR measurements before drinking, after a moderate (1.2 +/- 0.1 dl) and an escalating high dose (total amount 2.4 +/- 0.3 dl) of cognac. To explore the bioavailability of antioxidants, the antioxidant contents of cognac was measured and the absorption from the digestive tract was verified by plasma antioxidant capacity determination. RESULTS: Serum alcohol levels increased to 1.2 +/- 0.2 per thousand and plasma antioxidant capacity from 301 +/- 43.9 micromol/l to 320 +/- 25.0 micromol/l by 7.6 +/- 11.8%, (p = 0.01) after high doses of cognac. There was no significant change in flow velocity during CPT after cognac ingestion compared to control day. CFR was 4.4 +/- 0.8, 4.1 +/- 0.9 (p = NS), and 4.5 +/- 1.2 (p = NS) before drinking and after moderate and high doses on cognac day, and 4.5 +/- 1.4, and 4.0 +/- 1.2 (p = NS) on control day. CONCLUSION: Cognac increased plasma antioxidant capacity, but it had no effect on coronary circulation in healthy young men. TRIAL REGISTRATION: NCT00330213.

Cardiac MRI: accuracy of simultaneous measurement of left and right ventricular parameters using three different sequences.

BACKGROUND AND AIM: We evaluated a value of Qp/Qs (left-to-right shunt measurement) using volumetric cardiac magnetic resonance (CMR) cardiac output (CO) measurements. We defined intraobserver, interobserver variability and reproducibility of left and right ventricular parameters by CMR. Furthermore, we studied whether shortened acquisition time has an effect on the accuracy of left and right ventricular parameters both in healthy volunteers and in patients with cardiovascular disease. METHODS: Sixteen subjects were enrolled in this study. Group A (n = 8, five males) consisted of healthy volunteers with a mean age of 25.9 years (range 24-30). Group B (n = 8, four males) was heterogenic consisting of patients with left ventricular (LV) hypertrophy, hypertension or coronary artery disease with their mean age of 56.3 years (range 38-70). RESULTS: The measured Qp/Qs as calculated from the right and LV CO was 0.87 +/- 0.13. Overall variability [as presented with the lowest coefficient of variation (CV)%- the highest CV % of intraobserver, interobserver variability or reproducibility] of LV parameters were for ejection fraction (EF) 1.5-2.8%, stroke volume (SV) 1.3-3.2%, CO 1.4-3.2%, end-diastolic volume 0.5-3.0%, end-systolic volume 1.8-6.2% and LV mass 1.1-2.6%. Corresponding values for right ventricular parameters were for EF 1.1-4.2%, SV 1.9-8.2%, CO 1.9-7.6%, end-diastolic volume 2.1-7.6%, end-systolic volume 2.8-10.2% and right ventricle mass 2.9-8.3%. There was no statistically significant difference between the results of different sequences. CONCLUSIONS: The CMR allows accurate Qp/Qs observation but the absolute value is at slightly different level compared with reference methods. Both left and right ventricular parameters are highly reproducible and even small clinically relevant changes can be measured with CMR. The shortened acquisition does not affect significantly to the accuracy of CMR-derived parameters.

A moderate dose of red wine, but not de-alcoholized red wine increases coronary flow reserve.

BACKGROUND: Red wine consumption is associated with reduced cardiovascular disease mortality. Its cardioprotective properties may be partly related to its ability to improve endothelial function. The purpose of this randomized controlled cross-over study was to determine whether moderate doses of red wine and de-alcoholized red wine improve coronary flow velocity reserve (CFR). METHODS: Using transthoracic Doppler echocardiography, 176 CFR measurements were made in 22 healthy men before and after ingestion of a moderate (4.0+/-0.4 dl) and an escalating high dose (total amount 8.1+/-0.9 dl) of alcohol-containing red wine and de-alcoholized red wine, which contained similar amounts of phenolic substances. The difference in plasma antioxidant capacity was determined by colorimetric assay kit. RESULTS: Red wine increased CFR from 3.8+/-1.4 to 4.5+/-1.4 (p<0.01) and 4.0+/-1.2 (p=NS) after moderate and high doses, respectively; whereas de-alcoholized red wine had no significant effects on CFR (4.0+/-0.7, 4.3+/-1.3 and 4.5+/-1.4, respectively). Plasma antioxidant capacity increased significantly after high dose of red wine (27.5+/-14.7%, p<0.001), but not after de-alcoholized red wine (0.5+/-10.5%, p=NS) despite similar amounts of phenolic substances. Differences between CFR and plasma antioxidant capacities before and after drinking had no significant association. CONCLUSIONS: A moderate dose of red wine, but not de-alcoholized red wine increases CFR. The increase of CFR is probably mediated by other than direct antioxidant properties of polyphenols, because the simultaneous increase of CFR and plasma antioxidant capacity were not associated.

Ingested acidic food and liquids may lead to misinterpretation of 24-hour ambulatory pH tests: focus on measurement of extra-esophageal reflux.

Normal values of extra-esophageal reflux are difficult to determine owing to variation in the location of the proximal electrode, limited information on the ingestion of acidic food, different exclusion periods for meals, and poor reproducibility of measurement of extra-esophageal reflux. We studied whether ambulatory esophageal pH testing is disturbed by acidic food ingestion. Eighteen healthy subjects were enrolled in standard dual-channel esophageal pH tests (recorder 1). Ten subjects were equipped with another pH device (recorder 2), positioned to measure extra-esophageal reflux. The subjects were exposed to controlled ingestion of different acidic food or liquid for five 1-min periods. The present study showed that acidic food ingestion for 5 min has a significant effect on the outcome of standard dual-channel ambulatory pH testing. Reflux occurs equally on proximal channels during ingestion of acidic food, whether the proximal channel position is normal or 2 cm above the upper esophageal sphincter. We recommend avoiding acidic food intake during esophageal pH testing.

Vasodilation of epicardial coronary artery can be measured with transthoracic echocardiography.

Transthoracic Doppler echocardiography (TTE) has been introduced as a noninvasive tool to measure coronary flow velocity reserve (CFVR). Velocity measurement, however, fails to take into account epicardial coronary artery vasodilation during hyperemia and this may cause underestimation of CFVR measurements. Therefore, we sought to determine whether the vasodilation of epicardial coronary artery can be measured during cold pressor test (CPT) and adenosine infusion simultaneously with the flow velocity measurement using TTE. We studied 41 healthy nonsmoking men with a linear high-frequency 8.0-MHz transducer. The CPT and adenosine infusion dilated the diameter of the distal left anterior descending coronary artery (LAD) from 1.4 +/- 0.4 mm to 1.5 +/- 0.4 mm (14 +/- 13%, p < 0.01) and from 1.4 +/- 0.4 mm to 1.8 +/- 0.5 mm (31 +/- 19%, p < 0.01), respectively. The CPT increased flow velocity and calculated coronary blood flow rate (velocity time integral x cross-sectional area) from 0.23 +/- 0.05 m/s to 0.36 +/- 0.13 m/s (31 +/- 34%, p < 0.01) and from 8.1 +/- 4.2 mL/min to 11.4 +/- 6.0 mL/min (47 +/- 51%, p < 0.01). CFVR and calculated coronary blood flow rate reserve were 3.9 +/- 1.0 and 6.0 +/- 1.9, respectively. In Bland-Altman analysis, velocity measurements underestimated the vasodilation response of the CPT and adenosine compared with the measurements where epicardial diameter dilation was taken into account. Intra- and interobserver variability of diameter measurements was low (coefficient of variation [CV] 2.6 to 6.5%). Day-to-day, within-day and intersonographer variabilities were of similar magnitude (CV 4.6 to 8.2%), suggesting good reproducibility. This study demonstrates that TTE can be used to assess changes in both epicardial coronary artery diameter and flow velocity simultaneously in the distal LAD artery.

Comparison of MRI and positron emission tomography for measuring myocardial perfusion reserve in healthy humans.

Myocardial perfusion reserve (MPR, defined as the ratio of the maximum myocardial blood flow (MBF) to the baseline) is an indicator of coronary artery disease and myocardial microvascular abnormalities. First-pass contrast-enhanced magnetic resonance imaging (CE-MRI) using gadolinium (Gd)-DTPA as a contrast agent (CA) has been used to assess MPR. Tracer kinetic models based on compartmental analysis of the CA uptake have been developed to provide quantitative measures of MBF by MRI. To study the accuracy of Gd-DTPA first-pass MRI and kinetic modeling for quantitative analysis of myocardial perfusion and MPR during dipyridamole infusion, we conducted a comparison with positron emission tomography (PET) in 18 healthy males (age = 40 +/- 14 years). Five planes were acquired at every second heartbeat with a 1.5T scanner using a saturation recovery turboFLASH sequence. A perfusion-related parameter, the unidirectional influx constant (Ki), was computed in three coronary artery territories. There was a significant correlation for both dipyridamole-induced flow (0.70, P = 0.001) and MPR (0.48, P = 0.04) between MRI and PET. However, we noticed that MRI provided lower MPR values compared to PET (2.5 +/- 1.0 vs. 4.3 +/- 1.8). We conclude that MRI supplemented with tracer kinetic modeling can be used to quantify myocardial perfusion.

Determinants of coronary flow velocity reserve in healthy young men.

The objective of this study was to identify risk markers for attenuated coronary flow velocity reserve (CFVR) that exist in healthy young men without evident atherosclerotic risk factors. Coronary blood flow velocity was measured with transthoracic Doppler echocardiography at baseline and during adenosine infusion in 37 healthy nonsmoking men [mean age, 27 yr (SD 4.0)]. Body composition and distribution of fat tissue were assessed with anthropometric measures and regulation of fat metabolism by determination of adiponectin and leptin levels. Physical performance capacity was tested with ergospirometry. The mean body mass index was 23 kg/m2 (SD 1.9), waist-to-hip ratio was 0.84 (SD 0.04), and CFVR was 3.5 (SD 0.61). Obesity indexes at study outset, leptin, adiponectin, maximal load (Max load in W/kg) and maximal oxygen consumption (Vo2 peak in ml x kg(-1) x min(-1)) in ergospirometry, rate-pressure product, and heart rate at rest were significantly associated with CFVR. In multivariate analysis, Max load (in W/kg) and waist-to-hip ratio were the only independent predictors of CFVR. We found no relationship between CFVR and serum lipids or body mass index. We conclude that abdominal fat accumulation and low aerobic fitness are independently associated with CFVR in men.

Transthoracic Doppler echocardiography as a noninvasive tool to assess coronary artery stenoses--a comparison with quantitative coronary angiography.

We prospectively tested the diagnostic accuracy of Doppler transthoracic echocardiography in detection of coronary artery stenoses throughout the main coronary arterial tree. In all, 84 patients referred for diagnostic quantitative coronary angiography were studied. Coronary artery stenosis was identified with color Doppler as local spot of turbulence, and local flow velocity was measured using pulsed wave Doppler. Angiography showed significant stenoses (diameter reduction > 50%) in 33 patients. An abnormal maximal-to-prestenotic blood flow velocity ratio greater than 2.0 in subtotal stenoses, or the detection of collateral blood flow in the absence of normal antegrade flow in the case of total occlusion (N = 6), resulted in overall sensitivity of 82% and specificity of 92%. The sensitivity and specificity were, respectively, 73% and 92% for left anterior descending coronary artery, 63% and 96% for right coronary artery, and 38% and 99% for left circumflex coronary artery stenoses. Transthoracic echocardiography is a promising noninvasive technique to diagnose significant coronary artery stenoses.

Coronary artery diameter can be assessed reliably with transthoracic echocardiography.

We studied whether diameters of coronary arteries can be measured accurately with the use of transthoracic echocardiography (TTE). By knowing the anatomic diameter of the coronary artery together with coronary flow velocity it is possible to measure coronary flow volume more precisely by TTE. However, the suitability of TTE for measurement of diameters of all main epicardial coronary arteries has not been systematically validated. We measured the diameters of the left main (LM), left anterior descending (LAD), left circumflex (LCX), and right coronary arteries (RCA) with the use of TTE [manual two-dimensional (2D), color-Doppler, and automated 2D analysis] in 30 patients who had normal coronary anatomy. We compared these diameters to those measured with quantitative coronary angiography (QCA). We could measure diameters of LM, LAD, LCX, and RCA by TTE in up to 37%, 63%, 7%, and 60% of patients, respectively. The overall correlation coefficients between TTE and QCA measurements were 0.83 (P < 0.01) with manual 2D analysis, 0.82 (P < 0.01) with automated 2D analysis, and 0.94 (P < 0.01) with a color-Doppler-based analysis. Interobserver variability of TTE measurements was low (coefficient of variation 5.4 +/- 4.6-7.5 +/- 8.8%). TTE is an accurate method to evaluate coronary artery diameter in patients with healthy coronary arteries.

Brachial artery dilatation responses in healthy children and adolescents.

To characterize brachial artery flow-mediated dilatation (FMD) in children, we monitored arterial diameter changes with ultrasound between 40 and 180 s after a 4.5-min forearm cuff occlusion-induced hyperemia in 105 healthy children (mean age, 11 yr; range, 9-16 yr). The peak FMD was 7.7 +/- 4.0% and occurred 79 +/- 33 s after cuff release. FMD at 60 s (5.3 +/- 4.0%) was significantly lower than the peak FMD (P < 0.0001). Twenty-three percent of the children (n = 24) reached peak FMD first after 110 s of postocclusion. Compared with others, these late responders weighed less, had smaller vessel size, and were more often girls, but had similar peak FMD. In multivariate analysis, FMD responses were inversely associated with brachial artery baseline diameter and serum cholesterol concentration. We conclude that the time to reach the peak FMD response in children varies considerably. When studying endothelial function in children with the use of the noninvasive ultrasound method, several brachial artery diameter measurements up to 120 s after cuff release are needed to determine the true FMD peak response.