Acute vitamin C improves cardiac function, not exercise capacity, in adults with type 2 diabetes.

BACKGROUND: People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. METHODS: Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m2) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m2) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. RESULTS: Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E' (P < 0.01), but did not change RH (P = 0.92), or VO2peak (P = 0.33) in any participants. CONCLUSION: Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets.Trial registration NCT00786019. Prospectively registered May 2008.

Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers.

Women with polycystic ovarian syndrome (PCOS) have evidence of subclinical cardiovascular disease (CVD). However, insulin resistance, an important factor in the development of CVD in adults, is common in adolescents with PCOS, yet data in adolescents are limited. Therefore, we sought to measure insulin resistance and CVD markers in obese youth with and without PCOS. Thirty-six PCOS and 17 non-PCOS adolescent girls who were obese, sedentary, and non-hypertensive were recruited from clinics located within the Children's Hospital Colorado. Following 3 days of controlled diet and restricted exercise, fasting plasma samples were obtained prior to a hyperinsulinemic euglycemic clamp. PCOS girls were more insulin resistant than controls (glucose infusion rate 5.24±1.86 mg/kg/min vs 9.10±2.69; p<0.001). Girls with PCOS had blood pressure in the normal range, but had greater carotid intima-media thickness (cIMT) (0.49±0.07 mm vs 0.44±0.06; p=0.038), beta stiffness index (5.1±1.3 U vs 4.4±0.9; p=0.037), and reduced arterial compliance (1.95±0.47 mm2/mmHg × 10-1 vs 2.13±0.43; p=0.047). PCOS girls had a normal mean lipid profile, yet had a more atherogenic lipoprotein cholesterol distribution and had persistent elevations of free fatty acids despite hyperinsulinemia (68±28 µmol/mL vs 41±10; p=0.001), both potential contributors to CVD. Free fatty acid concentrations correlated best with all CVD markers. In summary, adolescent girls with PCOS have greater cIMT and stiffer arteries than girls without PCOS, perhaps related to altered lipid metabolism, even when clinical measures of blood pressure and cholesterol profiles are 'normal'. Therefore, management of adolescent PCOS should include assessment of CVD risk factor development.

Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes.

BACKGROUND: Exercise is recommended as a cornerstone of treatment for type 2 diabetes mellitus (T2DM), however, it is often poorly adopted by patients. Even in the absence of apparent cardiovascular disease, persons with T2DM have an impaired ability to carry out maximal and submaximal exercise and these impairments are correlated with cardiac and endothelial dysfunction. Glucagon-like pepetide-1 (GLP-1) augments endothelial and cardiac function in T2DM. We hypothesized that administration of a GLP-1 agonist (exenatide) would improve exercise capacity in T2DM. METHODS AND RESULTS: Twenty-three participants (64±4years; mean±SE) with uncomplicated T2DM were randomized in a double-blinded manner to receive either 10µg BID of exenatide or matching placebo after baseline measurements. Treatment with exenatide did not improve VO2peak (P=0.1464) or VO2 kinetics (P=0.2775). Diastolic function, assessed via resting lateral E:E', was improved with administration of exenatide compared with placebo (Placebo Pre: 7.6±1.0 vs. Post: 8.4±1.2 vs. Exenatide Pre: 8.1±0.7 vs. Post: 6.7±0.6; P=0.0127). Additionally, arterial stiffness measured by pulse wave velocity, was reduced with exenatide treatment compared with placebo (Placebo Pre: 10.5±0.8 vs. Post: 11.5±1.1s vs. Exenatide Pre: 11.4±1.8 vs. Post: 10.2±1.4s; P=0.0373). Exenatide treatment did not improve endothelial function (P=0.1793). CONCLUSIONS: Administration of exenatide improved cardiac function and reduced arterial stiffness, however, these changes were not accompanied by improved functional exercise capacity. In order to realize the benefits of this drug on exercise capacity, combining exenatide with aerobic exercise training in participants with T2DM may be warranted.

Youth with type 1 diabetes have worse strain and less pronounced sex differences in early echocardiographic markers of diabetic cardiomyopathy compared to their normoglycemic peers: A RESistance to InSulin in Type 1 ANd Type 2 diabetes (RESISTANT) Study.

OBJECTIVE: Diabetic cardiomyopathy is a major cause of morbidity, but limited data are available on early cardiac abnormalities in type 1 diabetes (T1D). We investigated differences in myocardial strain in adolescents with and without T1D. We hypothesized that adolescents with T1D would have worse strain than their normoglycemic peers, which boys would have worse strain than girls, and that strain would correlate with glycemic control and adipokines. METHODS: We performed fasting laboratory measures and echocardiograms with speckle tracking to evaluate traditional echocardiographic measures in addition to longitudinal (LS) and circumferential (CS) strain, and in adolescents (15±2years) with (19 boys; 22 girls) and without (16 boys; 32 girls) type 1 diabetes. RESULTS: Compared to controls, adolescents with type 1 diabetes had significantly lower CS (-20.9 vs. -22.7%, p=0.02), but not LS (p=0.83). Boys with T1D had significantly lower LS than girls with T1D (-17.5 vs. -19.7%, p=0.047), adjusted for Tanner stage. The significant sex differences observed in indexed left ventricular mass, left end-diastolic volume, diastolic septal and posterior wall thickness in our controls were lacking in adolescents with T1D. CONCLUSIONS: Our observations suggest that youth with T1D have worse myocardial strain than normoglycemic peers. In addition, the relatively favorable cardiac profile observed in girls vs. boys in the control group, was attenuated in T1D. These early cardiovascular changes in youth with T1D are concerning and warrant longitudinal and mechanistic studies.

Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension and resulting right ventricular (RV) dysfunction are associated with significant perioperative morbidity and mortality. Although echocardiography permits real-time, noninvasive assessment of RV function, objective and comparative measures are underdeveloped, and appropriate animal models to study their utility are lacking. Longitudinal strain analysis is a novel echocardiographic method to quantify RV performance. Herein, we hypothesized that peak RV longitudinal strain would worsen in a bovine model of pulmonary hypertension compared with control animals. METHODS: Newborn Holstein calves were randomly chosen for induction of pulmonary hypertension versus control conditions. Pulmonary hypertension was induced by exposing animals to 14 days of hypoxia (equivalent to 4570 m above sea level or 430 mm Hg barometric pressure). Control animals were kept at ambient pressure/normoxia. At the end of the intervention, transthoracic echocardiography was performed in awake calves. Longitudinal wall strain was analyzed from modified apical 4-chamber views focused on the RV. Comparisons between measurements in hypoxic versus nonhypoxic conditions were performed using Student t test for independent samples and unequal variances. RESULTS: After 14 days at normoxic versus hypoxic conditions, 15 calves were examined with echocardiography. Pulmonary hypertension was confirmed by right heart catheterization and associated with reduced RV systolic function. Mean systolic strain measurements were compared in normoxia-exposed animals (n = 8) and hypoxia-exposed animals (n = 7). Peak global systolic longitudinal RV strain after hypoxia worsened compared to normoxia (-10.5% vs -16.1%, P = 0.0031). Peak RV free wall strain also worsened after hypoxia compared to normoxia (-9.6% vs -17.3%, P = 0.0031). Findings from strain analysis were confirmed by measurement of tricuspid annular peak systolic excursion. CONCLUSIONS: Peak longitudinal RV strain detected worsened RV function in animals with hypoxia-induced pulmonary hypertension compared with control animals. This relationship was demonstrated in the transthoracic echocardiographic 4-chamber view independently for the RV free wall and for the combination of the free and septal walls. This innovative model of bovine pulmonary hypertension may prove useful to compare different monitoring technologies for the assessment of early events of RV dysfunction. Further studies linking novel RV imaging applications with mechanistic and therapeutic approaches are needed.

Cardiopulmonary Dysfunction and Adiponectin in Adolescents With Type 2 Diabetes.

BACKGROUND: Myocardial mechanics are altered in adults with obesity and type 2 diabetes (T2D); insulin resistance and adipokines have been implicated as important risk factors for cardiovascular disease, but these relationships are poorly described in adolescents. We hypothesized that obese adolescents and adolescents with T2D would have abnormal cardiac function compared to lean adolescents. In addition, we hypothesized that insulin sensitivity (IS), adiposity, and adipokines would be associated with altered cardiac strain and cardiopulmonary fitness in adolescents with T2D. METHODS AND RESULTS: Adolescents (15±2 years) with T2D (n=37), obesity without diabetes (n=41), and lean controls (n=31) of similar age and pubertal stage underwent echocardiography with speckle tracking, assessment of IS by hyperinsulinemic-euglycemic clamp, body composition by dual-energy x-ray absorptiometry, peak oxygen consumption (VO2peak) by cycle ergometry, adiponectin, and leptin. Compared to lean and to obese controls, adolescents with T2D had significantly lower cardiac circumferential strain (CS) (-18.9±4.6 [T2D] versus -21.5±3.5 [obese] versus -22.0±4.2% [lean], P=0.04) and VO2peak (37.6±7.5 [T2D] versus 43.4±8.2 [obese] versus 47.6±8.6 mL/lean kg/min [lean], P<0.0001). In T2D youth, VO2peak was associated with CS, and the association remained significant after adjusting for age, sex, and IS (ß±SE: -0.73±0.26, P=0.02). Among adolescents with T2D, CS was also associated with adiponectin, longitudinal strain with leptin, and VO2peak with adiponectin and IS. CONCLUSIONS: Adolescents with T2D had abnormal CS and reduced VO2peak compared to obese and lean controls, which may represent the earliest evidence of cardiac functional impairment in T2D. Low adiponectin, rather than conventional risk factors and IS, correlated with CS, while both adiponectin and IS related to cardiopulmonary fitness.

Speckle Tracking Echocardiography to Evaluate for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), increasing morbidity and mortality. Current echocardiographic measures have poor predictive value for the diagnosis of PH in COPD. Right ventricular (RV) strain obtained by speckle tracking echocardiography (STE) is a measure of myocardial deformation which correlates with RV function and survival in subjects with pulmonary arterial hypertension. We hypothesized that RV strain measurements would be feasible and correlate with invasive hemodynamic measurements in patients with COPD. Retrospective analysis of RV strain values from subjects with severe COPD with echocardiogram within 48 hours of right heart catheterization was performed. First, 54 subjects were included in the analysis. Right ventricular systolic pressure (RVSP) and RV strain could be estimated in 31% and 57%, respectively. Then, 61% had RV-focused apical views, and of those, RV strain could be obtained for 94%. RV free wall strain correlated with PVR (r = 0.41, p = 0.02). Subjects with pulmonary vascular resistance (PVR) > 3 Wood units (WU) had less negative (worse) RV free wall strain values than those with PVR ≤ 3 WU, with a median strain of -20 (-23, -12) versus -23 (-29, -15), p < 0.05. A receiver operating characteristic curve demonstrated an RV free wall strain of > -23 to be 92% sensitive and 44% specific for identifying PVR > 3 WU (AUC 0.71). RV strain estimates are feasible in the majority of subjects with severe COPD. RV strain correlates with PVR and may improve screening for PH in subjects with COPD.

Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation.

BACKGROUND: Cellular rejection after cardiac transplantation is treatable with timely diagnosis. Because noninvasive methods for diagnosis are limited, surveillance endomyocardial biopsies are routinely performed in the first year after transplantation. The aim of this study was to test whether myocardial strain and strain rate as assessed by speckle-tracking echocardiography would be a sensitive noninvasive method for the detection of asymptomatic rejection. METHODS: Surveillance biopsies and echocardiograms obtained in the first year after transplantation were retrospectively reviewed, and patients with asymptomatic biopsy-proven cellular rejection were identified, as well as control transplantation patients without rejection or cardiac complications. Circumferential and longitudinal strain and strain rate were measured using Velocity Vector Imaging software from echocardiograms performed at three time points for patients with rejection-baseline (no rejection), rejection, and resolution (of rejection)-and three time points for control patients-baseline (within the first month after transplantation), 6 months, and 12 months after transplantation. RESULTS: Speckle-tracking strain and strain rate measurements were obtained from 30 patients with asymptomatic biopsy-proven rejection and 14 control transplantation patients. There were no significant differences in circumferential and longitudinal strain or strain rate between the baseline, rejection, and resolution studies. Furthermore, there were no significant differences in strain and strain rate in control transplantation patients during the first year after transplantation or compared with patients with rejection. CONCLUSIONS: Speckle-tracking analysis was unable to detect changes on serial studies from patients with asymptomatic rejection and thus cannot replace biopsy. Other noninvasive methods for the diagnosis of cellular-mediated rejection are needed.

A sinus venosus atrial septal defect is diagnosed by echocardiography with an unusual bubble study.

A 68-year-old man underwent echocardiogram with agitated saline for a presumed diagnosis of primary pulmonary hypertension. Surprisingly, the bubbles from the agitated saline enter the left heart before filling the right side, leading to a diagnosis of Eisenmeger's syndrome from a sinus venosus atrial septal defect. Because of high right-sided pressure, the bubbles preferentially travel from the superior vena cava through the defect to the right superior pulmonary vein and left atrium, rather than the right side. This diagnosis was later confirmed on cardiac MRI.

Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis.

OBJECTIVES: The primary aim of this systematic review is to objectively evaluate the test performance characteristics of three-dimensional echocardiography (3DE) in measuring left ventricular (LV) volumes and ejection fraction (EF). BACKGROUND: Despite its growing use in clinical laboratories, the accuracy of 3DE has not been studied on a large scale. It is unclear if this technology offers an advantage over traditional two-dimensional (2D) methods. METHODS: We searched for studies that compared LV volumes and EF measured by 3DE and cardiac magnetic resonance (CMR) imaging. A subset of those also compared standard 2D methods with CMR. We used meta-analyses to determine the overall bias and limits of agreement of LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF measured by 3DE and 2D echocardiography (2DE). RESULTS: Twenty-three studies (1,638 echocardiograms) were included. The pooled biases ± 2 SDs for 3DE were -19.1 ± 34.2 ml, -10.1 ± 29.7 ml, and - 0.6 ± 11.8% for EDV, ESV, and EF, respectively. Nine studies also included data from 2DE, where the pooled biases were -48.2 ± 55.9 ml, -27.7 ± 45.7 ml, and 0.1 ± 13.9% for EDV, ESV, and EF, respectively. In this subset, the difference in bias between 3DE and 2D volumes was statistically significant (p = 0.01 for both EDV and ESV). The difference in variance was statistically significant (p < 0.001) for all 3 measurements. CONCLUSIONS: Three-dimensional echocardiography underestimates volumes and has wide limits of agreement, but compared with traditional 2D methods in these carefully performed studies, 3DE is more accurate for volumes and more precise in all 3 measurements.

Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function.

CONTEXT: Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. OBJECTIVE: We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. DESIGN AND PARTICIPANTS: This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. OUTCOME MEASURES: Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. RESULTS: T1D adolescents had significantly decreased VO(2)peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO(2)peak. CONCLUSIONS: T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

A restrictive inflow pattern does not predict implantable cardioverter-defibrillator therapy in primary prevention.

BACKGROUND: Current guidelines for the use of implantable cardioverter-defibrillators (ICDs) are broad and significantly increase the cost of caring for patients with heart failure. In an effort to identify the specific subset of patients who benefit from this therapy, the predictive value of numerous echocardiographic parameters have been studied. Severe diastolic dysfunction has been shown to predict adverse events in a group of patients who received an ICD for secondary prevention, but has not been tested in those who receive ICDs for primary prevention. HYPOTHESIS: We tested the hypothesis that a restrictive mitral inflow pattern on echocardiography will predict the risk of appropriate therapy in this patient population. METHODS: This retrospective study identified 145 consecutive patients who met primary prevention criteria for ICD implantation and had an echo performed no more than 1 year prior to receiving the ICD. A restrictive pattern was defined as a mitral inflow E/A > 2 or a deceleration time < 150 ms. RESULTS: A restrictive pattern was present in 69 patients (40.7% of the group). Appropriate ICD therapy occurred in 8 (11.5%) subjects with a restrictive pattern and 14 (18.4%) with a nonrestrictive pattern over 680 days of average follow-up (P = not significant). Cox regression analysis showed the presence of a restrictive pattern was not helpful in predicting time to first ICD therapy. CONCLUSIONS: In a population of patients who received ICDs for primary prevention, echocardiographic findings of severe diastolic dysfunction were not helpful in targeting the use of ICDs to those at highest risk.

Updates in cardiac rehabilitation.

Cardiac rehabilitation is one of the most effective treatments for secondary prevention for patients with heart disease. In particular, exercise training confers a variety of clinical benefits that leads to an increase in functional ability and a decrease in mortality in patients with a variety of cardiac diagnoses. Although they require a long-term commitment, standard training programs are safe and cost-effective. Despite its proven benefit, however, cardiac rehabilitation is underused in the United States.

Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity.

CONTEXT: The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood. OBJECTIVE: We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level. MAIN OUTCOME MEASURES: Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers. RESULTS: Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak. CONCLUSIONS: Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

Comparison of tissue Doppler and propagation velocity to invasive measures for measuring left ventricular filling pressures.

The utility of tissue Doppler and propagation velocity in identifying patients with abnormal left ventricular filling pressures was assessed in 50 patients who underwent catheterization and echocardiography on the same day. The ratios of the peak velocity of early mitral inflow to early mitral annular velocity (E/Ea) and the velocity of propagation (E/Vp) were compared with invasive measurements of pre-A-wave left ventricular pressures. Echocardiography measures were 77% to 92% accurate in identifying patients with a pre-A-wave pressure >15 mm Hg. Tissue Doppler imaging is more accurate than propagation velocity.

Three-dimensional visual guidance improves the accuracy of calculating right ventricular volume with two-dimensional echocardiography.

Three-dimensional guidance programs have been shown to increase the reproducibility of 2-dimensional (2D) left ventricular volume calculations, but these systems have not been tested in 2D measurements of the right ventricle. Using magnetic fields to identify the probe location, we developed a new 3-dimensional guidance system that displays the line of intersection, the plane of intersection, and the numeric angle of intersection between the current image plane and previously saved scout views. When used by both an experienced and an inexperienced sonographer, this guidance system increases the accuracy of the 2D right ventricular volume measurements using a monoplane pyramidal model. Furthermore, a reconstruction of the right ventricle, with a computed volume similar to the calculated 2D volume, can be displayed quickly by tracing a few anatomic structures on 2D scans.