Reduction In Left Ventricular Mass Research Articles

Safety and Feasibility of Achieving Lower Systolic Blood Pressure Goals in Persons With Type 2 Diabetes: The SANDS Trial

The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open-label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (< or =115/75 mm Hg vs < or =130/80 mm Hg), and low-density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal-medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/dL, aggressive systolic blood pressure-lowering resulted in a reduction in carotid intimal-medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin-angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus.

Magnetic Resonance Imaging Left Ventricular Mass Reduction With Fixed-Dose Angiotensin-Converting Enzyme Inhibitor–Based Regimens in Patients With High-Risk Hypertension

Left ventricular hypertrophy, a major cardiovascular risk factor for morbidity and mortality, is commonly caused by arterial hypertension. The renin-angiotensin-aldosterone system may contribute to the pathogenesis of left ventricular hypertrophy. The Assessment of Lotrel in Left Ventricular Hypertrophy and Hypertension Study compared a single-pill combination of amlodipine/benazepril at doses 5.0/20.0 mg, 5.0/40.0 mg, and 10.0/40.0 mg with hydrochlorothiazide/benazepril at doses 12.5/20.0 mg, 12.5/40.0 mg, and 25.0/40.0 mg on the reduction of left ventricular mass index measured by cardiac MRI in stage 2 hypertensive patients over 52 weeks of treatment in a randomized clinical trial. A total of 125 male and female patients, > or =55 years of age, with echocardiographic left ventricular hypertrophy and high-risk hypertension defined as blood pressure > or =160/100 mm Hg or current antihypertensive treatment were enrolled. After 52 weeks of treatment, left ventricular mass index was significantly reduced from baseline with amlodipine/benazepril (mean: 10.16 g/m(2)) or hydrochlorothiazide/benazepril (mean: 6.74 g/m(2); both P<0.0001), with a mean difference between treatment groups of 3.36 g/m(2) (P=0.16). No significant treatment differences were observed in subgroups defined by age, male gender, race, diabetes status, or dose level. However, in female patients, left ventricular mass index reduction was greater with amlodipine/benazepril (P=0.02). Both treatments were well tolerated.

Is Left Ventricular Hypertrophy Regression Important? Does the Tool Used to Detect It Matter?

Left ventricular hypertrophy (LVH) has been demonstrated to define an adverse cardiovascular prognosis. However, due to poor noninvasive tools in which to accurately define LVH, the clinical manifestations dictate an inexact manner in which to either initiate therapy or to gauge the success of LVH regression. Herein, the authors define the current state of imaging modalities available to interrogate LVH and its regression, but concentrating chiefly on the "gold standard" of cardiovascular magnetic resonance imaging (CMR). The authors review the data demonstrating the importance of LVH regression. Additionally, they highlight the strengths and weaknesses of CMR via several pinnacle studies that demonstrate the ease, efficiency, and accuracy of this new noninvasive reproducible and available tool to relatively inexpensively delineate LVH. Finally, upon pharmacologic administration of an antihypertensive regimen, the authors, for the first time, define a goal of left ventricular mass reduction (in grams) for echocardiography and CMR based in part on Framingham data aiming at improving cardiovascular risk.

Utilization of an abbreviated diabetes impact management scale to assess change in subjective disability during a trial of pulsatile insulin delivery demonstrates benefit

A prospective interventional study of pulsatile intravenous insulin infusion therapy has demonstrated reduction of left ventricular mass and blunting of progression of diabetic nephropathy. We anticipated that improvements in objective parameters would be associated with similar improvement measurable by the self-administered Diabetes Impact Management Scale (DIMS). The DIMS was administered at baseline and 12 months for 19 participants randomized to receive either standard insulin treatment of 3 to 4 injections of insulin daily or insulin treatment plus an additional day per week of 3 intravenous pulses over an 8-hour period. For standard vs pulsed intravenous insulin therapy, mean baseline scores were similar for the 12 total questions as well as the groups of 7 questions with emotional content and 5 with physical (neurologic) content. Mean study group scores at 1 year and changes over 1 year were not significantly different for the 7 questions with emotional content ( P = .3143, .7574). Score results for the 5 questions related to neurologic status at 1 year and changes over 1 year were significantly different between patients with standard and with pulsed insulin therapy ( P = .0144, 0.0004). Pulsatile intravenous insulin, when added to standard multiple-dose insulin therapy, was demonstrated to improve subjective perception of neurologic disability on repeated use of an abbreviated form of the DIMS.

Impact of diabetes on treatment-induced changes in left ventricular structure and function in hypertensive patients with left ventricular hypertrophy. The LIFE study

Background and aim Diabetes is associated with left ventricular hypertrophy (LVH) and impaired systolic function in hypertensive patients, but less is known about its impact on LVH regression and functional improvement during antihypertensive treatment. Methods and results We performed annual echocardiography in 730 non-diabetic and 93 diabetic patients (aged 55–80 years) with hypertension and electrocardiographic LVH during 4.8-year losartan- or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Baseline mean blood pressure (BP) and LV mass did not differ between groups. Diabetic patients had higher body mass index and pulse pressure, and lower LV ejection fraction, midwall shortening, stress-corrected midwall shortening, and estimated glomerular filtration rate (all p < 0.05), and were more likely to have albuminuria. Despite comparable BP reduction in diabetic and non-diabetic groups during treatment (33/18 vs. 28/16 mm Hg (ns)), diabetes was associated with higher prevalence of persistent LVH (47 vs. 39%, p < 0.05). In multivariate analyses, diabetes independently predicted less LV mass reduction and less improvement in stress-corrected LV midwall shortening (both p < 0.01). Conclusion Among hypertensive patients with LVH, diabetes is associated with more residual LVH and less improvement in systolic LV function by echocardiography over 4.8 years of antihypertensive treatment.

Exercise Training Alters Left Ventricular Geometry and Attenuates Heart Failure in Dahl Salt-Sensitive Hypertensive Rats

The clinical efficacy of exercise training in individuals with heart failure is well established, but the mechanism underlying such efficacy has remained unclear. An imbalance between cardiac hypertrophy and angiogenesis is implicated in the transition to heart failure. We investigated the effects of exercise training on cardiac pathophysiology in hypertensive rats. Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were assigned to sedentary or exercise (swimming)-trained groups at 9 weeks. Exercise training attenuated the development of heart failure and increased survival, without affecting blood pressure, at 18 weeks. It also attenuated left ventricular concentricity without a reduction in left ventricular mass or impairment of cardiac function. Interstitial fibrosis was increased and myocardial capillary density was decreased in the heart of sedentary rats, and these effects were attenuated by exercise. Exercise potentiated increases in the phosphorylation of Akt and mammalian target of rapamycin observed in the heart of sedentary rats, whereas it inhibited the downregulation of proangiogenic gene expression apparent in these animals. The abundance of the p110alpha isoform of phosphatidylinositol 3-kinase was decreased, whereas those of the p110gamma isoform of phosphatidylinositol 3-kinase and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were increased, in the heart of sedentary rats, and all of these effects were prevented by exercise. Thus, exercise training had a beneficial effect on cardiac remodeling and attenuated heart failure in hypertensive rats, with these effects likely being attributable to the attenuation of left ventricular concentricity and restoration of coronary angiogenesis through activation of phosphatidylinositol 3-kinase(p110alpha)-Akt-mammalian target of rapamycin signaling.

Cardiac remodeling after substantial weight loss: a prospective cardiac magnetic resonance study after bariatric surgery

Background Obesity is a risk factor for left ventricular (LV) hypertrophy and excess cardiovascular disease and mortality. Substantial weight loss is associated with a decrease in cardiovascular mortality. Using volumetric cardiovascular magnetic resonance (CMR) imaging, we studied changes in cardiac anatomy and systolic function in women undergoing substantial weight loss in a university hospital. Methods A total of 17 women (body mass index [BMI] 44.1 ± 4.2 kg/m 2; age 44 ± 11 yr) scheduled for bariatric surgery underwent volumetric CMR imaging before and 3 and 17 months after surgery. Results The body weight declined by 37.2 ± 10.5 kg (32%) with a decrease in BMI to 29.9 ± 4.7 kg/m 2 (32%, P < .004) during 17 months of observation. The LV mass decreased from 120 ± 23 g to 82 ± 11 g (32%, P < .004), with a linear relationship between the decrease in BMI and decrease in LV mass ( P = .008) for the duration of the observation period. After adjustment for systolic and/or diastolic blood pressure, the relationship remained significant ( P < .001). The right ventricular (RV) mass declined from 31.7 ± 6.7 g preoperatively to 26.6 ± 4.5 g at 3 months (16%, P < .001) but without additional changes at 17 months. No change was found in the LV or RV end-diastolic volume or ejection fraction. Conclusion In morbidly obese women, substantial weight loss was associated with a reduction of LV and RV mass. The decrease in LV mass was linearly related to the reduction in BMI, independent of changes in blood pressure, and might partially explain the reduction in cardiovascular mortality associated with substantial weight loss. The BMI was a predictor of LV mass in this population.

Impact of alcohol septal ablation on left anterior descending coronary artery blood flow in hypertrophic obstructive cardiomyopathy

The aim of this study was to evaluate the effects of alcohol septal ablation (ASA) on coronary blood flow in symptomatic hypertrophic obstructive cardiomyopathy (HOCM) using cardiac MR (CMR) coronary flow measurements. Background CMR flow mapping enables quantification of coronary blood flow in a noninvasive way. Both left ventricular outflow tract (LVOT) gradient reduction and myocardial scarring after ASA are expected to influence left anterior descending (LAD) coronary blood flow. Cine, contrast-enhanced (CE) imaging and breath-hold CMR phase contrast velocity mapping were performed at baseline and 1 and 6 months after ASA in seven patients. Changes of coronary blood flow were related to left ventricular (LV) mass reduction, enzyme release, volume of ethanol administered, LVOT gradient reduction, and LV rate pressure product (LVRPP). A significant mass reduction was observed both in the target septal myocardium and in the total myocardium (both P < 0.01). Mean myocardial infarct size was 23 +/- 12 g (range 7.3-41.6 g). LVRPP decreased from 13,268 +/- 2,212 to 10,685 +/- 3,918 at 1 month (P = 0.05) and 9,483 +/- 2,496 mmHg beats/min at 6 months' follow-up (P < 0.01). LAD coronary blood flow decreased from 100 +/- 37 ml/min at baseline to 84 +/- 54 ml/min (P = 0.09) at 1 month and 67 +/- 33 ml/min at 6 months follow-up (P < 0.01). A significant correlation was found between the change in LVRPP and LAD coronary flow at 1 month follow-up (r = 0.83, P = 0.02). CE-infarct size tended to modulate the blood flow changes over time (P = 0.12); no correlation was observed between enzyme release, volume of ethanol or both septal and total mass reduction and coronary blood flow. The reduction in coronary blood flow is primarily associated with diminished LV loading conditions, whereas the induction of metabolically inactive myocardial scar tissue by ASA did not significantly influence the changes in coronary blood flow.

Effect of the Direct Renin Inhibitor Aliskiren, the Angiotensin Receptor Blocker Losartan, or Both on Left Ventricular Mass in Patients With Hypertension and Left Ventricular Hypertrophy

Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients. We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups. Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.

Long-Term Effects of Enzyme Replacement Therapy on Fabry Cardiomyopathy

Enzyme replacement therapy with recombinant alpha-galactosidase A reduces left ventricular hypertrophy and improves regional myocardial function in patients with Fabry disease during short-term treatment. Whether enzyme replacement therapy is effective in all stages of Fabry cardiomyopathy during long-term follow-up is unknown. We studied 32 Fabry patients over a period of 3 years regarding disease progression and clinical outcome under enzyme replacement therapy. Regional myocardial fibrosis was assessed by magnetic resonance imaging late-enhancement technique. Echocardiographic myocardial mass was calculated with the Devereux formula, and myocardial function was quantified by ultrasonic strain-rate imaging. In addition, exercise capacity was measured by bicycle stress test. All measurements were repeated at yearly intervals. At baseline, 9 patients demonstrated at least 2 fibrotic left ventricular segments (severe myocardial fibrosis), 11 had 1 left ventricular segment affected (mild fibrosis), and 12 were without fibrosis. In patients without fibrosis, enzyme replacement therapy resulted in a significant reduction in left ventricular mass (238+/-42 g at baseline, 202+/-46 g at 3 years; P for trend <0.001), an improvement in myocardial function (systolic radial strain rate, 2.3+/-0.4 and 2.9+/-0.6 seconds(-1), respectively; P for trend=0.045), and a higher exercise capacity obtained by bicycle stress exercise (106+/-14 and 122+/-26 W, respectively; P for trend=0.014). In contrast, patients with mild or severe fibrosis showed a minor reduction in left ventricular hypertrophy and no improvement in myocardial function or exercise capacity. These data suggest that treatment of Fabry cardiomyopathy with recombinant alpha-galactosidase A should best be started before myocardial fibrosis has developed to achieve long-term improvement in myocardial morphology and function and exercise capacity.

Switch From Conventional to Every Other Day Hemodialysis: A Comparison Pilot Study

Fluid and solute fluctuations during the week are the main drawbacks of conventional hemodialysis (cHD) in patients' outcomes. The aim of our study was to evaluate the influence of every other day hemodialysis (eodHD) on clinical and laboratory parameters and to compare to that of cHD. Eighteen patients on cHD were included in the study. Nine patients (group I) were randomly switched to eodHD, while the rest (group II) remained on their regular cHD. By the end of the study (12 months) we observed a reduction in body weight followed by a parallel reduction in predialysis mean blood pressure by 7 mm Hg in group I (p<0.05) and the number of antihypertensives. Moreover, a reduction in left ventricular mass and an increment of ejection fraction was observed in group I. Hemoglobin levels remained stable in both groups, but erythropoietin dose was reduced in eodHD group. Dialysis delivered dose (dpKt/V) was higher and urea rebound phenomenon was less in group I. Finally, an improvement in uremia related and postdialysis symptoms was observed in the same group of patients. Our results showed that eodHD improved patients' clinical and biochemical status and therefore might have advantages in patients' outcomes compared with cHD.

Aortic Valve Replacement for Aortic Stenosis During Orthotopic Cardiac Transplant

Although concomitant coronary bypass, and mitral and tricuspid valve surgery have been used to expand the donor pool for cardiac transplantation, aortic valve disease is considered an absolute contraindication for use of an offered organ. A case is presented with the successful use of an organ requiring concomitant aortic valve replacement for calcific aortic stenosis on a congenitally bicuspid valve. Eighteen-month follow-up documented excellent allograft function with a normally functioning mechanical aortic prosthesis. Aortic valve disease in offered organs can be successfully treated with aortic valve replacement at the time of transplantation and should not preclude the use of the organ in the setting of a recipient who is a candidate for a marginal allograft.

Prosthesis-Patient Mismatch in the Elderly: Survival, Ventricular Mass Regression, and Quality of Life

Evaluation of the impact of prosthesis-patient mismatch (PPM) on long-term outcome and quality of life (QOL) in elderly patients who underwent implantation of small size bileaflet prostheses for aortic stenosis. Between September 1988 and September 2006, 377 patients aged greater than 70 years underwent aortic valve replacement with a small size bileaflet prosthesis (17, 19, and 21 mm) in one Institution. The study population's survivors (345 patients) were divided into three groups according to the indexed effective orifice area (EOAI): Group A included patients with EOAI less than 0.60 cm(2)/m(2); group B included patients with EOAI ranging between 0.61 and 0.84 cm(2)/m(2); and group C included patients with EOAI 0.85 cm(2)/m(2) or greater. Cumulative and comparative analyses of long-term outcomes and of left ventricular mass regression were performed. The QOL was evaluated with the 36-Item Short Form Health Survey (SF-36) questionnaire. Overall hospital mortality was 8.5% (32 patients). Group A included 33 patients (9.6%), group B 175 (50.7%), and group C 137 (39.7%). Actuarial survival was 88.8% +/- 0.016 at 1 year, 82.1% +/- 0.022 at 5 years, and 76.7% +/- 0.032 at 10 years. No difference emerged among the three groups. A significant reduction in left ventricular mass was observed in all groups and in all patient subsets of prosthetic size. The scores obtained in the SF-36 test were similar in the three groups and significantly higher than those of the general population (p < 0.001 in all domains). Incidence of severe PPM is low after aortic valve replacement. Presence of severe or moderate PPM, did not influence long-term outcome, left ventricular mass regression and QOL in a population of septuagenarians.

Abstract 2954: Short-term Effects of High Dose Idebenone on Left Ventricular Mass and Function in a Pediatric Cohort with Friedreich’s Ataxia

Background: Early mortality in Friedreich’s Ataxia (FA) is believed to commonly result from an underlying hypertrophic cardiomyopathy which may be caused by increases in reactive oxygen species. Antioxidant therapy could result in slowing of disease progression or regression of left ventricular mass (LVM). Methods: We tested the hypothesis that high dose idebenone could lead to regression of LVM and LV functional improvement in 48 pediatric subjects with genetically-confirmed FA (23 females, 25 males, mean age=13.4 years) randomly assigned to weight-stratified low (4 – 8 mg/kg), medium (10–20 mg/kg) or high (30–50 mg/kg) doses of idebenone or placebo. Cardiac magnetic resonance imaging (MRI) and echocardiographic (echo) two-dimensional and Doppler analysis blinded to treatment assignment were performed at baseline and after 6 months of therapy. Results: At baseline, increased LVM indexed by height 2.7 was observed in 44%, LV concentric remodeling (relative wall thickness &gt;0.39) in 83% and impaired early relaxation by Doppler tissue velocity (E’) in 88% of subjects as determined by age-adjusted, normative echo data. MRI-determined LVM (n=45 subjects) was inversely related to measures of LV relaxation including E’ (p&lt;0.0001), color Doppler flow propagation (p&lt;0.007) and isovolumic relaxation time (p&lt;0.005) but not mitral deceleration time. LVM also correlated with peak lateral systolic tissue velocity (p=0.002) but not LV ejection fraction. At 6 months combined, idebenone-assigned subjects demonstrated a 1.3 ± 1.6 % reduction of LVM vs. baseline which compared to an 8.9 ± 4.0% LVM increase in placebo subjects (p=.007). By Fisher’s test, LVM regression was observed only in the high and intermediate dose groups (p≤0.05 and p≤0.01) with a trend toward regression in the low dose group (p=0.056). No effects on diastolic relaxation or systolic functional parameters were observed after 6 months of idebenone treatment. Conclusions: Hypertrophic cardiomyopathy and associated diastolic functional impairment is highly prevalent in pediatric FA patients with moderate neurologic impairment. Short term treatment with high dose idebenone appears to result primarily in blunting of LV mass progression but not to detectable improvements in LV function.

Abstract 5930: The Effect of Spironolactone on Myocardial Structure and Function Measured by Echocardiography in Patients with Early Stage Chronic Kidney Disease

Introduction Early stage chronic kidney disease (CKD) is associated both with a high rate of adverse cardiovascular events and abnormal myocardial structure and function. Activation of the renin-angiotensin-aldosterone system is common in CKD and may result in adverse inflammatory, fibrotic and hypertrophic effects upon the heart and vasculature. Treatment with ACE inhibitors and ARBs frequently fails to suppress aldosterone production. We hypothesized that addition of the aldosterone antagonist spironolactone to ACE Inhibitors and ARB’s might reduce left ventricular (LV) mass and improve systolic and diastolic function measured by echocardiography. Methods One hundred and seventeen patients with stage 2 and 3 CKD, controlled hypertension (&lt;130/85mmHg) and no history of cardiovascular disease or diabetes were recruited in to a double blind placebo controlled trial. After an active 4 week run in of spironolactone 25mg daily, patients were randomized to continue this treatment or receive placebo for a further 36 weeks. Echocardiographic assessment of LV mass, systolic and diastolic LV function was performed before run in and after 40 weeks of treatment. Results Compared to placebo, spironolactone reduced LV mass (mean (SD) −10g ± 10 vs.+3g ± 13, p&lt;0.01). There was an improvement in LV Tei Index (−0.08 ± 0.1 vs. −0.001 ± 0.1, p&lt;0.01) and mean basal long axis annular systolic velocities (Sm +1.4cm/s ± 1.9 vs. +0.1cm/s ± 1.1, p&lt;0.01) but no difference in ejection fraction (+3% ± 5 vs.+2% ± 7). Transmitral E/A filing ratio (E/A +0.3 ± 0.3 vs −0.02 ± 0.2, p&lt;0.05), basal annular early myocardial diastolic velocities (Ea +0.5cm/s ± 2.1 vs. −0.3cm/s ± 2.1, p&lt;0.05), E/Ea ratio (−0.7 ± 1.9 vs. 0.1 ± 2.0, p&lt;0.05), and colour flow propogation velocities (+8.7 ± 16.3 vs. −0.1 ± 16.6, p&lt;0.05) were all improved. Systolic blood pressure was reduced with spironolactone but was not an independent predictor of change in any echocardiographic parameters. Conclusion Treatment with spironolactone reduced LV mass and improved both systolic and diastolic LV function. These data suggest that aldosterone plays an important role in cardiovascular disease in CKD and provides support for a clinical outcome trial investigating the use of aldosterone inhibitors to reduce cardiovascular risk.

Distinct genomic replacements from Lewis correct diastolic dysfunction, attenuate hypertension, and reduce left ventricular hypertrophy in Dahl salt-sensitive rats

Hypertension and diastolic heart failure are two common cardiovascular diseases that inflict heavy morbidity and mortality, yet relatively little is understood about their pathophysiology. The identification of quantitative trait loci for blood pressure is important in unveiling the causes of polygenic hypertension. Although Dahl salt-sensitive strain is also an excellent model for the study of diastolic heart failure, virtually nothing is known about the quantitative trait loci determining diastolic heart failure. Diastolic dysfunction often represents the onset of diastolic heart failure. We first characterized the cardiac phenotype of Dahl salt-sensitive strain and normotensive Lewis control rats by echocardiography to ascertain diastolic function. We then analyzed corresponding features of four newly developed and two existing congenic strains, each of which carries a specific chromosome substitution of Dahl salt-sensitive strain by its Lewis homologue and each lowering blood pressure. Dahl salt-sensitive strain displayed diastolic dysfunction that was rectified in two of six congenic strains, designated as positive congenic strains, which represent the first rodent models exhibiting functional normalization of diastolic dysfunction caused by naturally occurring genetic variants. The two positive congenic strains also showed a reduction in left ventricular mass. In contrast, four of six congenic strains did not change diastolic function despite their blood pressure-lowering effects. Genes present in the replaced chromosome segments of the two positive congenic strains are not commonly known to affect blood pressure, diastolic function or left ventricular mass. Consequently, novel prognostic, diagnostic and therapeutic strategies for hypertensive diastolic heart failure likely emerge from this work.

Arrhythmias in patients receiving enzyme replacement therapy for infantile Pompe disease

PurposeEnzyme replacement therapy in infants with Pompe disease prolongs survival, decreases cardiomegaly, and improves muscle function. Because ectopy has been previously described in these patients, we sought to determine the prevalence and types of arrhythmias. MethodsThirty-eight children with infantile Pompe disease received enzyme replacement therapy in two open-label, multicenter, international, clinical trials. Data were reviewed on a retrospective basis. The corrected QT interval, ejection fraction, and indexed left ventricular mass were measured on a scheduled basis from electrocardiograms and echocardiograms. Arrhythmias were identified and characterized from electrocardiograms, ambulatory electrocardiograms, and point-of-care monitoring. Electrocardiogram and echocardiogram measurements were compared in children with and without arrhythmias. ResultsSeven children (18%) experienced arrhythmias. The QT interval, ejection fraction, indexed left ventricular mass, and rate of reduction of indexed left ventricular mass were not statistically different in those seven versus the other 31 children. Two children with life-threatening arrhythmias had among the highest combined baseline maximum indexed left ventricular mass and QT interval. Their arrhythmias occurred during severe metabolic stress from noncardiac illness. ConclusionsThere was a high incidence of arrhythmias in our cohort. The relationship of arrhythmias with enzyme replacement therapy, myocardial fibrosis, or simply longer survival is unknown. Therefore, further characterization of specific arrhythmia risk factors and continued vigilance regarding screening for arrhythmias in children receiving enzyme replacement therapy is warranted.

Mechanical unloading of the rat heart involves marked changes in the protein kinase–phosphatase balance

Mechanical unloading of failing hearts by left ventricular (LV) assist devices is regularly used as a bridge to transplantation and may lead to symptomatic improvement. The latter has been associated with altered phosphorylation of cardiac regulatory proteins, but the underlying mechanisms remained unknown. Here, we tested whether cardiac unloading alters protein phosphorylation by affecting the corresponding kinase–phosphatase balance. Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation in rats for two weeks ( n = 8). Native in situ hearts from the recipient animals were used as controls ( n = 8). The steady-state protein kinase A (PKA) and/or Ca 2+-calmodulin-dependent protein kinase II (CaMKII) phosphorylation levels of phospholamban (PLB, Ser 16 and Thr 17) and troponin I (TnI, Ser 23/24) were decreased by 40–60% in unloaded hearts. Consistently, in these hearts PKA activity was decreased by ∼ 80% and the activity of protein phosphatase 1 and 2A was increased by 50% and 90%, respectively. In contrast, CaMKII activity was ∼ 60% higher, which may serve as a partial compensation. These data indicate that unloading shifts the kinase–phosphatase balance towards net dephosphorylation of PLB and TnI. This shift may also contribute to the reduction in phosphorylation levels of cardiac phosphoproteins observed in diseased human hearts after LVAD.

Coronary Microvascular Dysfunction in Patients with Cardiomyopathies

Anginal symptoms and electrocardiographic changes suggestive of myocardial ischemia, despite angiographically normal coronary arteries, are common in patients with cardiomyopathies and those with left ventricular hypertrophy secondary to pressure overload. Studies using positron-emission tomography (PET) to measure regional myocardial blood flow have demonstrated that maximum myocardial blood flow and coronary flow reserve are severely blunted in patients with hypertrophic as well as dilated cardiomyopathy.1,2 In the absence of epicardial stenoses, blunted maximum myocardial blood flow and coronary flow reserve are suggestive of coronary microvascular dysfunction.3,4 Furthermore, it has been demonstrated that in both hypertrophic and dilated cardiomyopathy, the severity of coronary microvascular dysfunction, assessed by measuring myocardial blood flow with PET, is an independent predictor of prognosis.2,5 In patients with cardiomyopathies, coronary microvascular dysfunction can be sustained by a number of different pathogenetic mechanisms. These include structural and functional abnormalities of the intramural arterioles as well as extravascular mechanisms (eg, increased extramural compression).4 Article 161 Anderson-Fabry disease (AFD) is an X-linked deficiency of lysosomal α-galactosidase A.6 This deficiency results in multiorgan damage from glycosphingolipid deposition, leading to renal, cardiac, and cerebrovascular disease and premature death. Patients with AFD complain of angina despite angiographically normal coronary arteries. Recent studies have also shown that there is progressive deterioration in left ventricular systolic function and myocardial scarring in patients with AFD cardiomyopathy. A number of mechanisms may contribute to microvascular dysfunction in these patients. AFD cardiomyopathy is characterized by globotriaosyl-ceramide (Gb3) and related glycosphingolipid deposition in myocytes, conduction tissue, vascular endothelium, and valvular tissue. This is accompanied by secondary changes, such as myocyte hypertrophy and fibrosis, often mimicking hypertrophic cardiomyopathy.7 In the vasculature, Gb3 accumulates in endothelial and smooth muscle cells, possibly causing structural abnormalities that may be responsible for vascular dysfunction. In addition, it …

State of the science conference: Initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary.

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …