Right ventricular function in dilated cardiomyopathy and ischemic heart disease: assessment with non-invasive imaging

Background

Dilated cardiomyopathy and ischaemic heart disease can both lead to right ventricular (RV) dysfunction. Direct comparisons of the two entities regarding RV size and function using state-of-the-art imaging techniques have not yet been performed. We aimed to determine RV function and volume in dilated cardiomyopathy and ischaemic heart disease in relation to left ventricular (LV) systolic and diastolic function and systolic pulmonary artery pressure.

Methods and results

A well-characterised group (cardiac magnetic resonance imaging, echocardiography, coronary angiography and endomyocardial biopsy) of 46 patients with dilated cardiomyopathy was compared with LV ejection fraction (EF)-matched patients (n = 23) with ischaemic heart disease. Volumes and EF were determined with magnetic resonance imaging, diastolic LV function and pulmonary artery pressure with echocardiography.After multivariable linear regression, four factors independently influenced RVEF (R² = 0.51, p < 0.001): LVEF (r = 0.54, p < 0.001), ratio of peak early and peak atrial transmitral Doppler flow velocity as measure of LV filling pressure (r = − 0.52, p < 0.001) and tricuspid regurgitation flow velocity as measure of pulmonary artery pressure (r = − 0.38, p = 0.001). RVEF was significantly worse in patients with dilated cardiomyopathy compared with ischaemic heart disease: median 48 % (interquartile range (IQR) 37–55 %) versus 56 % (IQR 48–63 %), p < 0.05.

Conclusions

In patients with dilated cardiomyopathy and ischaemic heart disease, RV function is determined by LV systolic and diastolic function, the underlying cause of LV dysfunction, and pulmonary artery pressure. It was demonstrated that RV function is more impaired in dilated cardiomyopathy.     

Association of Arterial Stiffness and Electrocardiography-Determined Left Ventricular Hypertrophy with Left Ventricular Diastolic Dysfunction

Objectives

Increased arterial stiffness is associated with left ventricular diastolic dysfunction (LVDD), but this association may be influenced by left ventricular (LV) performance. Left ventricular hypertrophy (LVH) is not only a significant determinant of LV performance, but is also correlated with LVDD. This study is designed to compare LV diastolic function among patients divided by brachial-ankle pulse wave velocity (baPWV) and electrocardiography (ECG)-determined LVH and to assess whether increased baPWV and ECG-determined LVH are independently associated with LVDD.

Methods

This cross-sectional study enrolled 270 patients and classified them into four groups according to the median value of baPWV and with/without ECG-determined LVH. The baPWV was measured using an ABI-form device. ECG-determined LVH was defined by Sokolow-Lyon criterion. LVDD was defined as impaired relaxation, pseudonormal, and restrictive mitral inflow patterns. Groups 1, 2, 3, and 4 were patients with lower baPWV and without ECG-determined LVH, lower baPWV but with ECG-determined LVH, higher baPWV but without ECG-determined LVH, and higher baPWV and with ECG-determined LVH respectively.

Results

Early diastolic mitral velocity (Ea) was gradually decreased from group 1 to group 4 (p≦0.027). Patients in group 4 had the highest prevalence of LVDD (all p<0.001). After multivariate analysis, both baPWV and ECG-determined LVH were independent determinants of Ea (β = −0.02, P<0.001; β = −1.77, P<0.001 respectively) and LVDD (odds ratio = 1.02, P = 0.011 and odds ratio = 3.53, P = 0.013 respectively).

Conclusion

Our study showed the group with higher baPWV and ECG-determined LVH had the lowest Ea and highest prevalence of LVDD. In addition, both baPWV and ECG-determined LVH were independently associated with Ea and LVDD. Hence, assessment of arterial stiffness by baPWV and LVH by ECG may be useful in identifying the high risk group of LVDD.     

Right ventricular dysfunction following acute myocardial infarction in the absence of pulmonary hypertension in the mouse

Background

Cardiac remodelling after AMI is characterized by molecular and cellular mechanisms involving both the ischemic and non-ischemic myocardium. The extent of right ventricular (RV) dilatation and dysfunction and its relation to pulmonary hypertension (PH) following AMI are unknown. The aim of the current study was to evaluate changes in dimensions and function of the RV following acute myocardial infarction (AMI) involving the left ventricle (LV).

Methods

We assessed changes in RV dimensions and function 1 week following experimental AMI involving the LV free wall in 10 mice and assessed for LV and RV dimensions and function and for the presence and degree of PH.

Results

RV fractional area change and tricuspidal annular plane systolic excursion significantly declined by 33% (P = 0.021) and 28% (P = 0.001) respectively. Right ventricular systolic pressure measured invasively in the mouse was within the normal values and unchanged following AMI.

Conclusion

AMI involving the LV and sparing the RV induces a significant acute decline in RV systolic function in the absence of pulmonary hypertension in the mouse indicating that RV dysfunction developed independent of changes in RV afterload.     

ACE2 improves right ventricular function in a pressure overload model

Background

Right ventricular (RV) dysfunction is a complication of pulmonary hypertension and portends a poor prognosis. Pharmacological therapies targeting RV function in pulmonary hypertension may reduce symptoms, improve hemodynamics, and potentially increase survival. We hypothesize that recombinant human angiotensin-converting enzyme 2 (rhACE2) will improve RV function in a pressure overload model.

Results

rhACE2 administered at 1.8 mg/kg/day improved RV systolic and diastolic function in pulmonary artery banded mice as measured by in vivo hemodynamics. Specifically, rhACE2 increased RV ejection fraction and decreased RV end diastolic pressure and diastolic time constant (p<0.05). In addition, rhACE2 decreased RV hypertrophy as measured by RV/LV+S ratio (p<0.05). There were no significant negative effects of rhACE2 administration on LV function. rhACE2 had no significant effect on fibrosis as measured by trichrome staining and collagen1α1 expression. In pulmonary artery banded mice, rhACE2 increased Mas receptor expression and normalized connexin 37 expression.

Conclusion

In a mouse RV load-stress model of early heart failure, rhACE2 diminished RV hypertrophy and improved RV systolic and diastolic function in association with a marker of intercellular communication. rhACE2 may be a novel treatment for RV failure.     

Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity

Background

Patients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function.

Methods

Patients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension.

Results

In total 31 patients with diabetes and 31 controls were included. Mean age was 58 ± 12 years, mean LVEF was 51 ± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 ± 2.9 vs. 17.7 ± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 ± 1.1 vs. 6.4 ± 1.1 cm/s, p = 0.02 and 6.1 ± 1.7 vs. 7.7 ± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively.

Conclusion

In patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis.     

Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

Background

Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice.

Methods

Mice were held either at normoxia (N; 21% O₂) or at hypobaric hypoxia (H; 0.5 atm; ~10% O₂). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy.

Results

Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H ± RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined.

Conclusion

Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.     

Two-Dimensional Echocardiography in the Assessment of Long-Term Prognosis in Patients with Pulmonary Arterial Hypertension

Objective

To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH.

Methods

Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis.

Results

Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (r_LVDD  = −0.699; r_RVDD  = −0.818, both P<0.001) and at last follow-up (r_LVDD  = −0.701; r_RVDD  = −0.666, both P<0.001). Furthermore, bi-ventricular (LVDD+RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r = −0.831; r = −0.771, both P<0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD+RVDD) scores were 0.823 (P<0.0001), 0.737 (P = 0.0002), and 0.825 (P<0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH.

Conclusion

LVDD score, RVDD score and (LVDD+RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.     

Real-Time 3-Dimensional Echocardiographic Assessment of Ventricular Volume,Mass, and Function in Human Fetuses

Objectives

We sought to determine the feasibility and reproducibility of real-time 3-dimensional echocardiography (RT3DE) for evaluation of cardiac volume, mass, and function and to characterize maturational changes of these measurements in human fetuses.

Methods

Eighty pregnant women in the 2^nd and 3^rd trimesters (59 with normal fetuses and 21 with fetuses with congenital heart disease [CHD]) were enrolled. We acquired RT3DE images using a matrix-array transducer. RT3DE measurements of volume, mass, stroke volume (SV), combined cardiac output (CCO), and ejection fraction (EF) were obtained. Images were scored and analyzed by two blinded independent observers. Inter- and intraobserver variabilities and correlations between fetal cardiac indices and gestational age were determined.

Results

Fifty-two of 59 normal data sets (88%) and 9 of 21 CHD data sets (43%) were feasible for analysis. In normal fetuses, the right ventricle (RV) is larger than the left ventricle (LV) (P<0.05), but no difference exists between the LV and RV in mass, SV, CO, and CO/CCO. The EFs for the LV and RV were diminished; the RVSV/LVSV was reduced in CHD fetuses compared with normal fetuses (P<0.05). Fetal ventricular volumes, mass, SV, and CCO fit best into exponential curves with gestational age, but LVEF, RVEF, and RVSV/LVSV remain relatively constant.

Conclusions

RT3DE is feasible and reproducible for assessment of LV and RV volume, mass, and function, especially in normal fetuses. Gestational growth of these measures, except for EF, is exponential in normal and CHD fetuses. CHD fetuses exhibit diminished LV and RV EFs.     

Assessing Right Ventricular Function in Patients with Hypertrophic Cardiomyopathy with Cardiac MRI: Correlation with the New York Heart Function Assessment (NYHA) Classification

Purpose

To determine whether 3.0-T magnetic resonance imaging (MRI) could assess right ventricular (RV) function in patients with hypertrophic cardiomyopathy (HCM), and if this assessment is correlated with the New York Heart Function Assessment (NYHA) classification.

Materials and Methods

Forty-six patients with HCM and 23 normal individuals were recruited. Left and right ventricular function parameters including end-diastolic and end-systolic volumes (EDV, ESV), stroke volume (SV) and ejection fraction (EF) and dimensions were measured and compared using 3.0-T MRI. RV function parameters between HCM patients and controls were compared using independent sample t tests. A one way ANOVA test with Bonferroni correction was used to determine significant differences among different NYHA groups. Receiver operating characteristic analyses calculated the sensitivity and specificity of RV dysfunction on MRI for the prediction of HCM severity.

Results

Statistical analysis revealed significant differences of left ventricular (LV) and RV volumetric values and masses between the HCM patients and controls (all p<0.05). Within the HCM group, the simultaneously decreased maximum RVEDD correlated well with the LVEDD (r = 0.53; p<0.001). The function and dimension parameters among Class I to III were not determined to be significantly different (all p>0.05). However, significant differences between the Class IV and I-III groups (all P<0.0167) indicated that the diastolic and systolic function in both the RV and LV were impaired in Class IV patients. ROC analyses identified the EDV, ESV and EDD of both the LV and RV with a high sensitivity cutoff value to predict the HCM patients with severe heart failure (Class IV) with high sensitivity and specificity.

Conclusions

RV involvements were comparable to those of LV global function impairments in patients with HCM. The presence of RV dysfunction and decreased dimension on the MRI helped to predict the severe symptomatic HCM with high sensitivity and specificity.     

Phenotyping of Left and Right Ventricular Function in Mouse Models of Compensated Hypertrophy and Heart Failure with Cardiac MRI

Background

Left ventricular (LV) and right ventricular (RV) function have an important impact on symptom occurrence, disease progression and exercise tolerance in pressure overload-induced heart failure, but particularly RV functional changes are not well described in the relevant aortic banding mouse model. Therefore, we quantified time-dependent alterations in the ventricular morphology and function in two models of hypertrophy and heart failure and we studied the relationship between RV and LV function during the transition from hypertrophy to heart failure.

Methods

MRI was used to quantify RV and LV function and morphology in healthy (n = 4) and sham operated (n = 3) C57BL/6 mice, and animals with a mild (n = 5) and a severe aortic constriction (n = 10).

Results

Mice subjected to a mild constriction showed increased LV mass (P<0.01) and depressed LV ejection fraction (EF) (P<0.05) as compared to controls, but had similar RVEF (P>0.05). Animals with a severe constriction progressively developed LV hypertrophy (P<0.001), depressed LVEF (P<0.001), followed by a declining RVEF (P<0.001) and the development of pulmonary remodeling, as compared to controls during a 10-week follow-up. Myocardial strain, as a measure for local cardiac function, decreased in mice with a severe constriction compared to controls (P<0.05).

Conclusions

Relevant changes in mouse RV and LV function following an aortic constriction could be quantified using MRI. The well-controlled models described here open opportunities to assess the added value of new MRI techniques for the diagnosis of heart failure and to study the impact of new therapeutic strategies on disease progression and symptom occurrence.     

Lipids and carotid plaque in the Northern Manhattan Study (NOMAS)

Background

Heterogeneity in B-type natriuretic peptide (BNP) levels, especially among individuals with acute heart failure with normal left ventricular ejection fraction (HFNEF), can cause confusion in interpreting results. We investigated the characteristics of cases of acute HFNEF with only modestly elevated BNP.

Methods

One hundred forty-two patients with acute or acute exacerbation of chronic HFNEF were divided into two groups by BNP level: BNP < 100 pg/ml (NB group, n = 45) and BNP ≥ 100 pg/ml (B group, n = 97). We compared clinical findings, echocardiography results, and neurohormonal factors between these two groups.

Results

In the NB group, a history of open-heart surgery (OHS) was more frequent (71% vs. 22%, p < 0.0001) and hypertension was less frequent (p = 0.0005). Left atrial diameter (LAd) was higher (p = 0.0026), while interventricular septal thickness, posterior wall thickness, relative wall thickness, left ventricular mass index were lower (p = 0.0005, p = 0.0225, p = 0.0114, p = 0.0051, respectively) in the NB group. In patients with HFNEF, a history of OHS remained an independent predictor of BNP level (< 100 pg/ml) after adjustment for hypertension, age, LAd, and interventricular septal thickness (odds ratio 3.6, p = 0.0252).

Conclusion

We found associations between acute HFNEF with less elevated BNP and a history of OHS. In a patient suspected of HFNEF, a history of OHS is considered diagnostic evidence of presence of diastolic heart failure when plasma levels of BNP are less elevated.     

Cardiac Impairment Evaluated by Transesophageal Echocardiography and Invasive Measurements in Rats Undergoing Sinoaortic Denervation

Background

Sympathetic hyperactivity may be related to left ventricular (LV) dysfunction and baro- and chemoreflex impairment in hypertension. However, cardiac function, regarding the association of hypertension and baroreflex dysfunction, has not been previously evaluated by transesophageal echocardiography (TEE) using intracardiac echocardiographic catheter.

Methods and Results

We evaluated exercise tests, baroreflex sensitivity and cardiovascular autonomic control, cardiac function, and biventricular invasive pressures in rats 10 weeks after sinoaortic denervation (SAD). The rats (n = 32) were divided into 4 groups: 16 Wistar (W) with (n = 8) or without SAD (n = 8) and 16 spontaneously hypertensive rats (SHR) with (n = 8) or without SAD (SHRSAD) (n = 8). Blood pressure (BP) and heart rate (HR) did not change between the groups with or without SAD; however, compared to W, SHR groups had higher BP levels and BP variability was increased. Exercise testing showed that SHR had better functional capacity compared to SAD and SHRSAD. Echocardiography showed left ventricular (LV) concentric hypertrophy; segmental systolic and diastolic biventricular dysfunction; indirect signals of pulmonary arterial hypertension, mostly evident in SHRSAD. The end-diastolic right ventricular (RV) pressure increased in all groups compared to W, and the end-diastolic LV pressure increased in SHR and SHRSAD groups compared to W, and in SHRSAD compared to SAD.

Conclusions

Our results suggest that baroreflex dysfunction impairs cardiac function, and increases pulmonary artery pressure, supporting a role for baroreflex dysfunction in the pathogenesis of hypertensive cardiac disease. Moreover, TEE is a useful and feasible noninvasive technique that allows the assessment of cardiac function, particularly RV indices in this model of cardiac disease.     

Differential right and left ventricular diastolic tolerance to acute afterload and NCX gene expression in Wistar rats

This study evaluated right ventricular (RV) and left ventricular (LV) diastolic tolerance to afterload and SERCA2a, phospholamban and sodium-calcium exchanger (NCX) gene expression in Wistar rats. Time constant tau and end diastolic pressure-dimension relation (EDPDR) were analyzed in response to progressive RV or LV afterload elevations, induced by beat-to-beat pulmonary trunk or aortic root constrictions, respectively. Afterload elevations decreased LV- tau, but increased RV-tau. Whereas LV- tau analyzed the major course of pressure fall, RV- tau only assessed the last fourth. Furthermore, RV afterload elevations progressively upward shifted RV EDPDR, whilst LV afterload elevations did not change LV-EDPDR. SERCA2a and phospholamban mRNA were similar in both ventricles. NCX-mRNA was almost 50 % lower in RV than in LV. Left ventricular afterload elevations, therefore, accelerated the pressure fall and did not induce diastolic dysfunction, indicating high LV diastolic tolerance to afterload. On the contrary, RV afterload elevations decelerated the late RV pressure fall and induced diastolic dysfunction, indicating small RV diastolic tolerance to afterload. These results support previous findings relating NCX with late Ca(2+) reuptake, late relaxation and diastolic dysfunction.     

High Prevalence of Left Ventricle Diastolic Dysfunction in Severe COPD Associated with A Low Exercise Capacity: A Cross-Sectional Study

Background

A subclinical left ventricle diastolic dysfunction (LVDD) has been described in patients with chronic obstructive pulmonary disease (COPD).

Objectives

To evaluate the prevalence of LVDD in stable severe COPD patients, to analyze its relationship with exercise capacity and to look for its possible causes (lung hyperinflation, ventricular interdependence or inflammatory mechanisms).

Methods

We evaluated 106 consecutive outpatients with severe COPD (FEV₁ between 30–50%). Thirty-three (31%) were excluded because of previous heart disease. A pulmonary function test, a 6-minute walking test (6MWT), a Doppler echocardiography test, including diastolic dysfunction parameters, and an analysis of arterial blood gases, NT-proBNP and serum inflammatory markers (CRP, leucocytes), were performed in all patients.

Results

The prevalence of LVDD in severe stable COPD patients was 90% (80% type I, n=57, and 10% type II, n=7). A significant association between a lower E/A ratio (higher LVDD type I) and a lower exercise tolerance (6-minute walked distance (6MWD)) was found (r=0.29, p<0.05). The fully adjusted multivariable linear regression model demonstrated that a lower E/A ratio, a DLCO in the quartile 4^th and a higher tobacco consumption were associated with a lower 6MWD (76, 57 and 0.7 metres, respectively, p<0.05). A significant correlation between E/A ratio and PaO₂ was observed (r=0.26, p<0.05), but not with static lung hyperinflation, inflammation or right ventricle overload parameters.

Conclusion

In stable severe COPD patients, the prevalence of LVDD is high and this condition might contribute in their lower exercise tolerance. Hypoxemia could have a concomitant role in their pathogenesis.     

Coronary microcirculatory dysfunction is associated with left ventricular dysfunction during follow-up after STEMI

Background

Coronary microvascular resistance is increased after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), which may be related in part to changed left ventricular (LV) dynamics. Therefore we studied the coronary microcirculation in relation to systolic and diastolic LV function after STEMI.

Methods

The study cohort consisted of 12 consecutive patients, all treated with primary PCI for a first anterior wall STEMI. At 4 months, we assessed pressure-volume loops. Subsequently, we measured intracoronary pressure and flow velocity and calculated coronary microvascular resistance. Infarct size and LV mass were assessed using magnetic resonance imaging.

Results

Patients with an impaired systolic LV function due to a larger myocardial infarction showed a higher baseline average peak flow velocity (APV) than the other patients (26?±?7 versus 17?±?5 cm/s, p?=?0.003, respectively), and showed an impaired variable microvascular resistance index (2.1?±?1.0 versus 4.1?±?1.3 mmHg?cm^?1?s^?1, p?=?0.003, respectively). Impaired diastolic relaxation time was inversely correlated with hyperaemic APV (r?=??0.56, p?=?0.003) and positively correlated with hyperaemic microvascular resistance (r?=?0.48, p?=?0.01). LV dilatation was associated with a reduced variable microvascular resistance index (r?=?0.78, p?=?0.006).

Conclusion

A larger anterior myocardial infarction results in impaired LV performance associated with reduced coronary microvascular resistance variability, in particular due to higher coronary blood flow at baseline in these compromised left ventricles.     

Anodal stimulation: an underrecognized cause of nonresponders to cardiac resynchronization therapy

Objective

The purpose of this study was to determine if anodal stimulation accounts for failure to benefit from cardiac resynchronization therapy (CRT) in some patients.

Background

Approximately 30-40% of patients with moderate to severe heart failure do not have symptomatic nor echocardiographic improvement in cardiac function following CRT. Modern CRT devices allow the option of programming left ventricular (LV) lead pacing as LV tip to right ventricular (RV) lead coil to potentially improve pacing thresholds. However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode).

Methods

Patients enrolled in our center''s CRT registry had an echocardiogram, 6-minute walk (6MW), and Minnesota Living with HF Questionnaire (MLHFQ) pre-implant and 6 months after CRT. Electrocardiograms (12 lead) during RV, LV, and biventricular (BiV) pacing were obtained at the end of the implant in 102 patients. Anodal stimulation was defined as LV pacing QRS morphology on EKG being identical to RV pacing or consistent with fusion with RV and LV electrode capture. LV end systolic volume (LVESV) was measured by echo biplane Simpson''s method and CRT responder was defined as 15% or greater reduction in LVESV.

Results

Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring). 3 of the 46 subjects (6.5%) had EKG findings consistent with anodal stimulation, not corrected intraoperatively. All anodal stimulation patients were nonresponders to CRT by echo criteria (reduction in LVESV 13.3 ± 0.6%, increase in EF 5.0 ± 1.4%) compared to 46% responders for those without anodal stimulation, (change in LVESV 18.7 ± 25.6%, EF 7.6 ±10.9%). None of the anodal stimulation patients were responders for the 6 minute walk, compared to 32 of 66 (48%) of those without anodal stimulation.

Conclusion

Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT.     

Haptoglobin genotype predicts development of coronary artery calcification in a prospective cohort of patients with type 1 diabetes

Background

Soluble ST2, a member of the of the Toll/IL-1 superfamily, is a novel biomarker with exceptional predictive value in heart failure and myocardial infarction- related mortality as well as in acute dyspneic states. Soluble ST2 is considered a decoy receptor of IL 33 that blocks the protective effects of the cytokine in atherosclerosis and cardiac remodeling. In the present study we investigated the differences in the levels of soluble ST2, BNP and hs-CRP between healthy controls and patients with type 2 diabetes with and without left ventricular diastolic dysfunction. A secondary aim was to investigate correlations between sST2 and other biomarkers of type 2 diabetes, such as HbA1c.

Methods

158 volunteers were recruited and underwent a complete Doppler-echocardiographic evaluation of both systolic & diastolic cardiac function. All subjects with ejection fraction < 50% were excluded. The study population was divided in 4 groups as follows: A: 42 healthy controls, B: 18 subjects without diabetes with LVDD, C: 48 patients with type 2 diabetes without LVDD & D: 50 patients with type 2 diabetes & LVDD. ELISA technique was performed to measure sST2 levels. Statistical analysis was performed with Kruskal-Wallis & Mann-Whitney test (continuous variables), chi squared & Fischer exact test (discrete variables), Spearman coefficient (univariate analysis) and step-wise backward method (multivariate analysis).

Results

Patients with type 2 diabetes with (p < 0.001) or without LVDD (p = 0.007) had higher serum ST2 levels compared to healthy controls, state found also for hs-CRP levels but not for the corresponding BNP levels (p = 0.213 & p = 0.207 respectively). Patients with type 2 diabetes & LVDD had higher serum ST2 in relation to diabetic patients without LVDD (p = 0.001). In multivariate analysis HbA1c positively and independently correlated with sST2 levels in both groups of patients with type 2 diabetes.

Conclusions

Patients with type 2 diabetes exhibit higher sST2 levels compared to healthy controls. The presence of LVDD in patients with type 2 diabetes is associated with even higher sST2 levels. A significant correlation between glycemic control and sST2 levels was also revealed.     

Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice

Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle (RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca(2+) removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.     

In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy

Aims

The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice.

Methods and Results

Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy.

Conclusions

MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.     

Left Ventricular Mechanics in Repaired Tetralogy of Fallot with and without Pulmonary Valve Replacement: Analysis by Three-Dimensional Speckle Tracking Echocardiography

Background

Altered septal curvature and left ventricular (LV) geometry secondary to right ventricular (RV) dilation render two-dimensional assessment of LV mechanics difficult in repaired tetralogy of Fallot (TOF) patients. The novel three-dimensional (3D) speckle tracking echocardiography enables comprehensive evaluation of true 3D LV mechanics.

Methods and Results

Seventy-six patients aged 23.6±8.3 years, 55 with isolated repair (group I) and 21 with subsequent pulmonary valve replacement (group II), and 34 healthy controls were studied. Three-dimensional volume datasets were acquired for assessment of LV global and regional 3D strain, systolic dyssynchrony index (SDI), twist, twist gradient (twist/LV length), and ejection fraction. A global performance index was calculated as (global 3D strain•twist gradient)/SDI. The septal curvature and LV eccentricity were determined from the mid-ventricular short-axis. Compared with controls, group I and II patients had significantly reduced LV global 3D strain, LV twist, twist gradient, septal curvature, and global performance index, and greater LV systolic and diastolic eccentricity and SDI (all p<0.05). All but the four apical LV segments in patients had reduced regional 3D strain compared with controls (all p<0.05). Septal curvature correlated with LV global 3D strain (r = 0.41, p<0.001), average septal strain (r = 0.38, p<0.001), twist (r = 0.32, p<0.001), twist gradient (r = 0.33, p<0.001), and global performance index (r = 0.43, p<0.001).

Conclusions

Adverse 3D LV mechanics as characterized by impaired global and regional 3D systolic strain, mechanical dyssynchrony, and reduced twist is related to reduced septal curvature in repaired TOF patients with and without pulmonary valve replacement.