Ventricular Chamber Dimensions Research Articles

A Novel Histone Deacetylase (HDAC) Inhibitor Attenuates Cardiac Dysfunction in the Setting of Pressure Overload Heart Failure

Background: Histone deacetylases (HDACs) are a family of epigenetic regulator enzymes responsible for chromatin conformation and reversible protein acetylation. HDAC inhibitors have previously been shown to be cardioprotective in acute myocardial infarction and heart failure. HDAC inhibition is thought to attenuate cardiac remodeling and improve cardiac function by enhancing acetylation of sarcomeric proteins, suppressing autophagy and apoptosis, bolstering protective genes and inhibiting pro-inflammatory genes. Objective: We investigated the efficacy of a novel, orally active HDAC class I inhibitor, MRL-003, in a murine model of pressure overload induced heart failure. Methods and Results: All studies were performed in a fully blinded manner, data analysis was performed off site by independent statisticians, and data was only unblinded following completion of statistical analysis of all parameters. Mice (C57 BL6J) at age 8-10 weeks were subjected to transverse aortic constriction (TAC) to induce pressure overload heart failure. Cardiac function was monitored sequentially using echocardiography and terminal hemodynamic measurements were taken. At 3 weeks post-TAC 3 doses (10, 30, and 100 mg/kg/day) of MRL-003 were provided to the mice in a blinded manner in chow ad libitum for 13 weeks. MRL-003 (100 mg/kg/d) significantly improved left ventricular (LV) ejection fraction and LV chamber dimensions compared to TAC-vehicle. LV end-diastolic pressure (LVEDP) was significantly increased in the vehicle treated group compared to sham and there was no significant difference in LVEDP in mice treated with MRL-003 (100 mg/kg/d) compared to sham. Conclusion: HDAC inhibition with MRL-003 significantly improves cardiac function and remodeling in the setting of pressure overload heart failure. Further studies are warranted to assess the molecular changes associated with these functional improvements.

Abstract 41: Cardiomyocyte-specific Conditional Deletion of GSK-3β Leads to Cardiac Dysfunction in a High Fat Diet Induced Obesity Model

Introduction: Previous studies from our group have demonstrated that cardiac myocyte glycogen synthase kinase-3’s (GSK-3) are required to maintain normal cardiac physiology. Adult mice lacking both isoforms of GSK-3 (α and β) in cardiac myocytes exhibit excessive dilatative remodeling and ventricular dysfunction ultimately leading to death. While high fat diet (HFD) induced obesity is associated with increased risk of cardiovascular disease, the specific role of cardiac GSK-3α or GSK-3β in obesity-associated cardiac dysfunction is unknown. Objective: The primary goal of the present study was to investigate the role of cardiomyocyte GSK-3β in cardiac homeostasis in HFD-induced chronic obesity model. Method: Cardiomyocyte specific-GSK-3β knock out (CM-GSK-3βKO) and wild type (WT) mice were fed either a chow (11.5% calories from fat) or high-fat (60% calories from fat) for 24 weeks. Cardiac function was accessed by non-invasive transthoracic echocardiography. Results: HFD significantly increased body weight, lean and fat mass in the WT and CM-GSK-3βKO compared to chow. However, there was no difference in body weights, lean and fat mass between the two genotypes fed either a chow or HFD. Furthermore, ventricular chamber dimensions and cardiac function were comparable between the WT and CM-GSK-3βKO mice fed a chow diet. In contrast, high fat fed CM-GSK-3βKO hearts exhibit significant cardiac hypertrophy (heart weight/tibia length ratio) and ventricular dysfunction (reduced ejection fraction (EF) and fractional shortening (FS)) compared to the WT. Interestingly cardiomyocytes from HF fed CM-GSK-3βKO exhibit structural abnormalities and increased expression of pro-apoptotic protein Bax and reduced expression of Bcl-2, an anti-apoptotic protein. Conclusion: In summary, these data suggests that cardiac GSK-3β is important in the setting of HFD-induced chronic obesity to maintain cardiac function. In the absence of GSK-3β, cardiomyocytes undergo morphometric abnormalities, excessive fat infiltration and apoptosis leading to cardiac dysfunction.

Sustained Improvement in Right Ventricular Chamber Dimensions 10 Years Following Xenograft Pulmonary Valve Replacement.

The goals following pulmonary valve replacement (PVR) are to optimize right ventricular hemodynamics and minimize the need for subsequent reoperations on the right ventricular outflow tract. We hypothesized PVR using a xenograft valved conduit would result in superior freedom from reoperation with sustained improvement in right ventricular chamber dimensions. Xenograft valved conduits placed in patients aged >16 years were reviewed from 2000 to 2010 to allow for a 5-year minimum follow-up. Preoperative, one-year, and the most recent echocardiograms quantified right ventricular chamber dimensions, corresponding Z scores, and prosthetic valve function. Magnetic resonance imaging (MRI) studies compared preoperative and follow-up right ventricular volumes. A total of 100 patients underwent PVR at 24 (19-34) years. Freedom from reintervention was 100% at 10 years. At most recent follow-up, only one patient had greater than mild pulmonary insufficiency. The one-year (17.3 ± 7.2 mm Hg; P < .01) and most recent follow-up (18.6 ± 9.8 mm Hg; P < .01) Doppler-derived right ventricular outflow tract gradients remained significantly lower than preoperative measurements (36.7 ± 27.0 mm Hg). Similarly, right ventricular basal diameter, basal longitudinal diameter, and the corresponding Z scores remained lower at one year and follow-up from preoperative measurements. From 34 MRI studies, the right ventricular end-diastolic indexed volume (161.7 ± 58.5 vs 102.9 ± 38.3; P < .01) and pulmonary regurgitant fraction (38.0% ± 15.9% vs 0.8% ± 3.3%; P < .01) were significantly lower at 7.1 ± 3.4 years compared to the preoperative levels. Use of a xenograft valved conduit for PVR results in excellent freedom from reoperation with sustained improvement in right ventricular dimensions at an intermediate-term follow-up.

Effects of pericardiectomy on training- and myocardial infarction-induced left ventricular hypertrophy, chamber dimensions and gene expression.

The primary purpose of the study was to evaluate whether a pericardiectomy (PERI) alters training- or myocardial infarction (MI)-induced left ventricular hypertrophy (LVH), chamber geometry, gene expression and/or running performance. Mice were randomized into 6 groups: naïve control (CONT)-sedentary (Sed), CONT-trained (Tr), PERI-Sed, PERI-Tr, MI-Sed and MI-Tr. MI mice also received a pericardiectomy as part of the MI surgical procedure. 10 weeks of treadmill running resulted in enhanced running performance-to-exhaustion in all 3 trained groups (CONT-Tr, PERI-Tr, MI-Tr) compared to sedentary cohorts (P<0.001). Training also resulted in similar increases in normalized LVH (LV/BW) in CONT-Tr and PERI-Tr mice. 2D-echocardiographic evaluation of LV internal chamber dimensions revealed that stroke diameter (SD) was larger in PERI compared to MI (P<0.01) but not CONT mice. Ventricular B-type natriuretic peptide mRNA (BNP) was elevated only in the 2 MI groups. Left ventricle β1-adrenergic receptor (β1-AR) and melusin transcripts both demonstrated an overall increase in trained compared to sedentary mice (both P<0.05). Additionally long-term pericardiectomy did not further enhance running performance or increase LV/BW in either sedentary or trained mice.

Right ventricular involvement in feline hypertrophic cardiomyopathy

ObjectivesTo evaluate right ventricular (RV) wall thickness and chamber dimensions in cats with hypertrophic cardiomyopathy (HCM). AnimalsOne hundred fifty-one healthy control cats and 200 cats with HCM. MethodsRetrospective, observational, clinical cohort study. Two-dimensional echocardiograms from all cats were analyzed. Right atrial diameter, RV free wall thickness, and RV chamber diameter were quantified using multiple imaging views. Conventional (mean ± 2 standard deviations) and allometrically scaled (Y = a × Mb) reference values were determined in normal cats and compared to values found in cats with HCM. Linear and logistic regression, multivariate regression, and mixed model analysis were performed to identify associations between RV wall thickness and severity of left ventricular (LV) hypertrophy, clinical severity of HCM, and presence of pleural effusion. ResultsMean RV wall thickness was increased in HCM (p<0.001). Considering increased RV wall thickness in at least one segment, 94 (47%) and 112 (56%) cats with HCM had RV hypertrophy using upper reference limits based on mean + 2 standard deviations or allometric scaling, respectively. There was an association between severity of LV and RV hypertrophy (p<0.05). Left-sided congestive heart failure (n = 58) was associated with increased RV wall thickness in all segments compared to cats with preclinical HCM (p<0.001). Body weight had negligible effects on RV wall thickness (R2 0.08–0.17, p<0.001), whereas age and breed had no effect (p>0.05) in control cats. ConclusionsIncreased RV wall thickness is common in cats with HCM and relates to severity of LV hypertrophy and clinical status.

Abstract 82: Reduction of SHP2’s Phosphatase Activity Improves Cardiac Adaptation to Pressure and Volume Overload

Since the inability of the heart to adapt to pathological stress results in heart failure, supporting cardiac stress adaptation may improve clinical outcome. We hypothesized that the protein tyrosine phosphatase SHP2 controls adaptation by modulating several signaling pathways involved. To test whether SHP2 plays an active role in stress adaptation, we generated transgenic (TG) mice with cardiomyocyte-specific overexpression of Q510E-SHP2, which is a dominant-negative mutant (dnSHP2). Under unstressed conditions, TG mice do not exhibit a cardiac phenotype. TG and nonTG (NTG) mice were subjected to pressure overload by transverse aortic constriction (TAC) or to volume overload by inducing large myocardial infarction (MI) via coronary artery ligation. Expression of dnSHP2 significantly improved stress adaptation after TAC (n=17 TG, n=13 NTG). Twelve weeks after banding, TG mice exhibited well preserved contractile function with significantly higher fractional shortening (FS) [TG 33.2±1.7 vs. NTG 22.2±1.5 %, p&lt;0.001] and ejection fraction (EF) [TG 67.7±2.7 vs. NTG 50.3±3.0 %, p&lt;0.001]. dnSHP2 TGs also had smaller left ventricular (LV) chamber dimensions [LV inner diameter at end-diastole (LVIDd) TG 4.4±0.2 vs. NTG 5.1±0.2 mm, p=0.02]. There were no significant differences in ventricular wall thickness or heart weights, indicating that the degree of hypertrophy in response to TAC was not affected by dnSHP2 expression. In response to volume overload induced by large MI (n=22 TG, n=24 NTG), TG hearts displayed only a trend towards improved contractile function [FS TG 21.3±1.5 vs. NTG 18.9±1.1%, EF TG 48.4±2.7 vs. NTG 44.2±2.1%]. However, chamber dimensions were better preserved in TGs [LVIDd TG 5.1±0.1 vs. NTG 5.7±0.2 mm, p=0.03]. In summary, dnSHP2 expression ameliorated LV chamber dilation and increased contractile function under pressure overload. In TGs subjected to volume overload, reduced LV dimensions were observed but with only a trend towards improved contractile function. Taken together, it is evident that reducing SHP2’s phosphatase activity indeed improves cardiac stress adapation, making SHP2 a potential novel therapeutic target.

Cardiovascular Abnormalities in Egyptian Children with Mucopolysaccharidoses.

The Mucopolysaccharidoses (MPS) are rare inherited metabolic disorders. They are characterized by the progressive systemic deposition of Glycosaminoglycans (GAGs). GAGs accumulate in the myocardium and the cardiac valves. Enzyme Replacement Therapy (ERT) is available for MPS I, II, and VI. However, ERT does not appear to improve cardiac valve disease in patients with valve disease present at the start of ERT. To evaluate the cardiac involvement in Egyptian children with MPS. Echocardiograms (ECG) were done for 34 patients. Both quantitative and qualitative Glycosaminoglycans (GAGs) in urine and enzyme assay confirmed the diagnosis. Mitral, tricuspid and aortic valves were evaluated for increased thickness, regurgitation and/or stenosis, left ventricular chamber dimensions, septal and posterior wall thicknesses. The patients' age ranged from 0.9-16 years (median age 4 years). They included 19 cases of MPS I (55.9%), 3 cases of MPS II (8.8%), 2 cases of MPS III (5.9%), 6 cases of MPS IV (17.6%) and 4 cases of MPS VI (11.8%). Heart murmur was heard in 9 of the participants (9/34) (26%). However, 15 patients (15/34) (44%) revealed cardiac lesions on ECG examinations. Mitral regurge (47%), followed by pulmonary hypertension (40%), were the most frequent findings. The absence of Cardiac murmurs does not exclude the heart involvement. Cardiac valve dysfunction may not be reversible. Regular ECG should be routinely warranted in children with MPS and early ERT are recommended.

Heart-rate adjustment of transcatheter haemodynamics improves the prognostic evaluation of paravalvular regurgitation after transcatheter aortic valve implantation.

Paravalvular aortic regurgitation (PVAR) after balloon-expandable transcatheter aortic valve implantation (TAVI) remains difficult to quantify, and the utility of the AR index (ARi) to create a composite aortic insufficiency (CAI) score was an important advance. Heart rate (HR) influences the ARi but the clinical relevance of this phenomenon remains poorly appreciated. We sought to validate a new composite heart-rate-adjusted haemodynamic-echocardiographic aortic insufficiency (CHAI) score in the prognostic evaluation of PVAR after balloon-expandable TAVI. The severity of PVAR was assessed immediately post TAVI by transoesophageal echocardiography (TOE) with simultaneous assessment of transcatheter haemodynamics. A total of 303 patients were studied. The CHAI score, incorporating the HR-adjusted diastolic-delta (HRA-DD, the difference between left ventricular and aortic diastolic pressures/HR*80), had a greater discriminatory value for one-year mortality than both PVAR by TOE (p=0.0018) and the previously proposed CAI score, based on the ARi without HR adjustment (p=0.0029). The CHAI score also better stratified percentage increases in left ventricular systolic chamber dimensions at one month and serum natriuretic peptide levels at one to three months. Prognostication of PVAR in the intermediate range of echocardiographic severity remains unreliable and is greatly enhanced by the integration of heart-rate-adjusted transcatheter haemodynamics.

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.

Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts.

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.

Discoidin domain receptor 2 germline gene deletion leads to altered heart structure and function in the mouse.

Discoidin domain receptor 2 (DDR2) is a fibrillar collagen receptor that is expressed in mesenchymal cells throughout the body. In the heart, DDR2 is selectively expressed on cardiac fibroblasts. We generated a germline DDR2 knockout mouse and used this mouse to examine the role of DDR2 deletion on heart structure and function. Echocardiographic measurements from null mice were consistent with those from a smaller heart, with reduced left ventricular chamber dimensions and little change in wall thickness. Fractional shortening appeared normal. Left ventricular pressure measurements revealed mild inotropic and lusitropic abnormalities that were accentuated by dobutamine infusion. Both body and heart weights from 10-wk-old male mice were ~20% smaller in null mice. The reduced heart size was not simply due to reduced body weight, since cardiomyocyte lengths were atypically shorter in null mice. Although normalized cardiac collagen mass (assayed by hydroxyproline content) was not different in null mice, the collagen area fraction was statistically higher, suggesting a reduced collagen density from altered collagen deposition and cross-linking. Cultured cardiac fibroblasts from null mice deposited collagen at a slower rate than wild-type littermates, possibly due to the expression of lower prolyl 4-hydroxylase α-isoform 1 enzyme levels. We conclude that genetic deletion of the DDR2 collagen receptor alters cardiac fibroblast function. The resulting perturbations in collagen deposition can influence the structure and function of mature cardiomyocytes.

Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy.

EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI). The EphA2-receptor (EphA2-R) potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-κB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT) and EphA2-R-mutant (EphA2-R-M) mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2-R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-κB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF-κB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post-MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy.

Diastolic function in Olympic athletes versus controls: Stiffness-based and relaxation-based echocardiographic comparisons

Physiologic hypertrophy of the athlete heart, compared to the heart of nonathletic controls, is characterized by an increase in the left ventricular (LV) chamber dimension, mass, and wall thickness. Comparisons of the diastolic function (DF) between athletes and controls have employed conventional echocardiographic transmitral flow (Doppler E-wave)-derived indexes such as the peak flow velocity and deceleration time (which are load-dependent) and obscure the mechanistic determinants (e.g., stiffness, relaxation, load) of E-wave. With a focus on stiffness and relaxation chamber properties, conventional kinematic model-derived and load-independent indexes of the DF were compared between athletes and controls in this study. Echocardiographic and magnetic resonance imaging (MRI) data from 22 master athletes (whose sport was canoeing) and 21 sedentary controls were analyzed (1290 Doppler E-waves; 702 from athletes and 588 from the controls; on average, there were 30 pieces of data per subject). The LV mass and chamber size were determined from the MRI data. Quantitative DF assessment utilized an established kinematic model of filling that used the digitized Doppler E-wave contour as the input and characterized the DF on the basis of the chamber stiffness (k), relaxation/viscoelasticity (c), load (xo). We observed significant chamber stiffness (k), load (xo), and E-wave duration differences between the two groups. Concordant with the findings of previous studies, we also noted significant group differences in LV mass and dimension. These results indicated that physiological LV remodeling of the athlete heart at rest generates numerically quantifiable alterations in specific chamber properties. Assessment of the DF by using these methods during exercise will further elucidate the dynamic interplay between relaxation and stiffness as DF determinants.

Clinical and echocardiographic determinants of diastolic dysfunction among Nigerian hypertensive subjects

Background: Diastolic dysfunction can occur either as an early marker or in late stages of hypertensive heart disease. Knowledge about its determinants is crucial to its management. Reports about clinical and echocardiographic determinants of diastolic dysfunction among Nigerian hypertensive subjects are few. This study aimed at describing the main clinical and echocardiographic determinants of diastolic dysfunction among Nigerian hypertensive subjects. Methods: Two hundred and forty-five hypertensive subjects and 68 age and sex-matched normotensives that had echocardiography were used for this study. Diastolic function was assessed by a combination using the ratio of early and late mitral flow velocity E/A ratio, isovolumic relaxation time (IVRT) and deceleration time (DT). Statistical analysis was carried out with the SPSS 16.0. Correlation and stepwise regression analysis were used for univariate and multivariate analysis respectively. Results: Mean age of the hypertensive subjects was similar with that of the controls (56.8±12.2 vs. 55.0±7.9 respectively, P>0.05). Diastolic dysfunction was commoner among hypertensive subjects than controls. Age, systolic and diastolic blood pressure (BP), and left ventricular chamber dimensions generally showed the greatest correlation with indices of diastolic function among the study population. Using the multivariate analysis, age was the strongest determinant of DT and IVRT followed by left ventricular chamber dimension for DT and systolic BP for IVRT. Left ventricular internal chamber dimension was the strongest determinant of mitral E/A ratio followed by diastolic BP. Conclusion: Age, systolic BP, and left ventricular volume and dimension are the major determinants of the diastolic dysfunction among hypertensive Nigerians. They affect different aspect of the diastolic parameters.

Predictors of response to cardiac resynchronization therapy on pre-implantation cardiovascular magnetic resonance imaging

Background Cardiac resynchronization therapy (CRT) is an established treatment for severe heart failure. However, up to 40% of patients do not respond. While regional scar distribution has received focused attention, the predictive utility of global markers of remodeling and irreversible injury has not been well explored. Methods Sixty-eight patients receiving CRT underwent pre-implant cardiovascular MRI followed by serial echocardiography at 3 and 6 months. Blinded measurement of Left Ventricular (LV) and Right Ventricular (RV) chamber dimensions, volumes and mass were performed from short axis cine datasets. LV dysynchrony was measured by septal to lateral wall delay. Total LV scar burden was determined from Late Gadolinium Enhancement (LGE) images using manual contour tracing of endocardial and epicardial borders with application of a signal threshold ≥5SD above reference myocardium. Response to CRT was defined as a reduction in LV end-systolic volume (ESV) ≥15% at 6 months. Results The mean age was 66.3 ± 8.9 years with a mean LV Ejection fraction (EF) of 25.2 ± 7.2%. Overall, 47 patients (69%) responded. Among all baseline measures LVEDV (p=0.03), LVESV (p=0.045), RV EF (p=0.0349) and total scar burden (p=0.018) were the only significant predictors of CRT response. Multivariate analysis showed total scar burden to be the only independent predictor of CRT response (p=0.015). Conclusions Pre-implantation MRI offers markers for the prediction of response to CRT. Of these, total scar burden appears to be an independent predictor of response and may be of assistance in the selection of optimal candidates. Funding None

Assessing the Athlete’s Heart

The initial report of the athlete’s heart dates back to the late 1890s. The concept that endurance-based exercise and strength-based exercise lead to distinctly different changes in left ventricular (LV) structure was proposed in the 1970s and has been confirmed by more recent studies. Advances in cardiac imaging, particularly echocardiography and cardiac magnetic resonance imaging, have allowed for more precise characterization of the structural changes that develop in the hearts of athletes engaged in different sporting disciplines. Despite our improved understanding of exercise-induced cardiac remodeling, the findings of: 1) increased LV chamber dimension, 2) increased LV wall thickness, and 3) increased right ventricular (RV) chamber dimension continue to be accompanied by significant diagnostic uncertainty in clinical practice. Determining whether these entities arise from exercise-induced cardiac remodeling or represent pathologic cardiomyopathy requires the integration of a number of diagnostic techniques, including evaluations with echocardiography and/or cardiac magnetic resonance imaging. Ambiguous cases require additional testing, such as cardiopulmonary exercise testing and assessing the response to a period of prescribed detraining. Novel imaging techniques coupled with physiologic provocation that assess regional LV and RV function may make the distinction between physiologic adaptation and pathology more clear in the future.

Left ventricular chamber dimensions and wall thickness by cardiovascular magnetic resonance: comparison with transthoracic echocardiography

Cardiovascular magnetic resonance (CMR) is a reference standard imaging technique in assessment of cardiomyopathies due to the accurate measurement of cardiac volumes and mass. In clinical routine, transthoracic echocardiography (TTE) is the standard first-line technique and is commonly used for follow-up. In this study we examined how CMR-derived measurement of left ventricular (LV) chamber dimensions and wall thickness correspond to TTE. A total of 101 subjects underwent TTE and CMR (men, n = 67, mean age 62 ± 9 years) and formed a normal group (n = 44), a group with dilated LV cavity (n = 33; LV internal dimensions in end-diastole ≥ 52 mm) and a group with increased LV wall thickness (n = 24; interventricular septum ≥ 12 mm, inferolateral wall both in end-diastole ≥ 12 mm). Standard TTE measurements of LV chamber and wall thickness were compared to CMR-derived values in the basal short-axis slice and the 3-chamber (3-CH) view. Interstudy reproducibility for CMR was done in 23 subjects. In all groups, there was a better agreement between TTE and 3-CH for all dimensions. The intraobserver and interobserver agreements were superior for 3-CH view. In addition, both CMR approaches showed sound interstudy reproducibility for all dimensions and in all groups. We demonstrate a good agreement between CMR and TTE in LV chamber dimension and wall thickness measurements. We propose that with CMR using a 3-CH approach is superior in reproducibility and closer in concordance with TTE-derived values.

The time-course changes of NT-proBNP and tissue Doppler indices in patients undergoing mitral valve replacement

In severe mitral regurgitation, a subset of patients who are asymptomatic may develop left ventricular decompensation before changes in echocardiographic parameters become evident. Since N-terminal brain natriuretic peptide (NT-proBNP) is used to detect early heart failure, we hypothesised that NT-proBNP would be activated in patients with mitral regurgitation. Patients submitted to surgery were prospectively evaluated over eight months in the Department of Cardiology at Inkosi Albert Luthuli Central Hospital. Control patients with severe mitral regurgitation were obtained from the outpatient clinic. In order to define their value in identifying left ventricular decompensation, NT-proBNP levels and tissue Doppler imaging (TDI) indices were simultaneously measured and compared with conventional echocardiographic indices at baseline and this was repeated at one week and at six weeks after valve replacement. Mean NT-proBNP levels were markedly elevated pre-operatively in all surgical cases compared to controls (p = 0.0001). The diastolic E-mitral/E-annulus ratio, measured using TDI, was higher in the study group, indicating higher left ventricular filling pressure present in the study group. NT-proBNP levels increased further at one week after surgery and subsided at the six-week follow-up visit to levels similar to the control group. The TDI diastolic ratio also decreased at one week, and increased slightly again at the six-week follow up. These changes were accompanied by significant reduction in left atrium and left ventricular chamber dimensions with an increase in the ejection fraction from one to six weeks. Marked differences in mean NT-proBNP levels and TDI ratios between the study and control groups suggest that using TDI and NT-proBNP assays may detect covert left ventricular decompensation.

Increased Potency of Cardiac Stem Cells Compared with Bone Marrow Mesenchymal Stem Cells in Cardiac Repair

Whereas cardiac-derived c-kit(+) stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p < .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p < .05). Whereas 1 × 10(6) MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit(+)CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.

Benefits of PDE5 inhibition in patients with diastolic heart failure

The occurrence of signs and symptoms of heart failure (HF) with normal left ventricular ejection fraction and predominant anomalies of left ventricular (LV) relaxation and stiffness (i.e. diastolic HF) is increasingly recognized. Notably, in recent years survival rate of systolic HF has improved, whereas the prognosis for diastolic HF remains unchanged. This may be in part attributable to the lack of additional benefits by treatments’ options used as standard care of systolic HF. PDE5 inhibition is an emerging therapy proposed for HF treatment that enhances NO signaling by increasing the cyclic guanosine monophosphate (cGMP) availability. This pharmacological property seems especially attractive for patients with left ventricular hypertrophy and diastolic HF [1]. In experimental models of failing hearts due to pressure overload and diastolic dysfunction, PDE5 inhibition has been shown to promote a reverse left ventricular (LV) chamber remodeling by modulating LV hypertrophy and fibrosis [2]. Preliminary observations in humans confirm the ability of long-term PDE5 inhibition administration by sildenafil to improve cardiac geometry, LV mass and diastolic function [3]. Recent community based studies [4] have highlighted that a considerable number of patients with diastolic HF present with left-sided Group 2 pulmonary hypertension suggesting a tight pathophysiological relationship between LV hypertrophy, increasing LV filling pressures and abnormalities of pulmonary vascular tone and permeability. Interestingly, development of pulmonary hypertension strongly discriminates survival rate. Although in these patients alterations of many signaling pathways may be unique to the heart or pulmonary vasculature, downregulation of the NO-cGMP pathway seems to be a common finding in both locations. Accordingly, in an effort to better understand the combined role of this pathway in both the heart and the lung vasculature, we recently performed a study aimed at testing the hypothesis that diastolic HF patients at higher risk for the unfavorable upstream effects of an increased left atrial pressure would benefit of chronic PDE5 inhibition with sildenafil. Specifically, we hypothesized that sildenafil would modulate pulmonary vascular tone and RV hemodynamic burden. A significant improvement in pulmonary hemodynamics, right ventricular contractility and chamber dimensions were observed at 6 and 12 months of follow-up. These effects were paralleled by an improvement in quality of life and clinical status [5]. Although the available experimental and clinical data seem promising, further large-scale morbidity and mortality studies are necessary to provide a definitive appreciation onto whether PDE5 inhibition may effectively impact the natural history of HF due to diastolic origin.