Dilated Cardiomyopathy Subjects Research Articles

Dysregulation of iron metabolism-linked genes at myocardial tissue and cell levels in dilated cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Fondazione Gigi & Pupa Ferrari ONLUS Italian Ministry of Health-Ricerca Corrente. Background Heart failure (HF) is defined as one of the main clinical and public health burdens with multifactorial symptoms and high worldwide prevalence. Dilated cardiomyopathy (DCM) is one of the leading causes of HF and is responsible for over half of all left ventricular assist device implantations and heart transplantations. DCM is regarded as a multiple disease entity linked to a number of genetic, nutritional, inflammatory, infective, metabolic, and environmental causes. Among the metabolic processes associated with HF, iron metabolism disorders, ranging from iron deficiency to iron overload, are gaining attention. However, the understanding of iron mechanisms, at cardiac level, involved in HF and particularly in DCM, remains elusive. Purpose We aim to evaluate the possible dysregulation of iron metabolism-linked genes in DCM, through a quantitative analysis of public myocardial gene expression data at tissue and cell levels. Methods Bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq) datasets, respectively of 436 and 38 left ventricle samples from adult non-failed (NF) and DCM subjects, were retrieved from public studies. We defined a list of 272 genes directly related to intramyocardial iron metabolism and performed the differential gene expression analysis both at whole cardiac tissue level and in cardiomyocytes, fibroblasts, myeloid, endocardial, and endothelial cells. Results In the overall myocardial tissue, we found 44 iron-linked genes differentially expressed between DCM and NF subjects. To better understand iron genes abnormalities in the myocardium of DCM patients we deepened the analysis from tissue to single-cell level. Among the five considered cell types (cardiomyocytes, fibroblasts, myeloid, endocardial, and endothelial cells) at least 9% of iron-linked expressed genes were significantly regulated in DCM when compared to NF. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels (Figure 1), including: 1) imbalance of Fe3+ internalization (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), 2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), 3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), 4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and 5) positive regulation of hepcidin (BMP6 up-regulation). Conclusions In conclusion, the present study provides significant progress in knowledge of iron metabolism changes in DCM disease, which likely have a clinical meaning. Indeed, our data show that regulation of intracellular iron homeostasis is dysfunctional in DCM patients’ cardiac tissues, supporting, but not providing, the hypothesis of a direct effect of iron in the disease progression.

Dysregulation of Iron Metabolism-Linked Genes at Myocardial Tissue and Cell Levels in Dilated Cardiomyopathy.

In heart failure, the biological and clinical connection between abnormal iron homeostasis, myocardial function, and prognosis is known; however, the expression profiles of iron-linked genes both at myocardial tissue and single-cell level are not well defined. Through publicly available bulk and single-nucleus RNA sequencing (RNA-seq) datasets of left ventricle samples from adult non-failed (NF) and dilated cardiomyopathy (DCM) subjects, we aim to evaluate the altered iron metabolism in a diseased condition, at the whole cardiac tissue and single-cell level. From the bulk RNA-seq data, we found 223 iron-linked genes expressed at the myocardial tissue level and 44 differentially expressed between DCM and NF subjects. At the single-cell level, at least 18 iron-linked expressed genes were significantly regulated in DCM when compared to NF subjects. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels, including: (1) imbalance of Fe3+ internalization (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), (2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), (3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), (4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and (5) positive regulation of hepcidin (BMP6 up-regulation).

Genomic findings of hypertrophic and dilated cardiomyopathy characterized in a Thai clinical genetics service.

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common referrals in the Inherited Cardiovascular Condition (ICC) Genetics Service. Several issues must be discussed with patients and their families during the genetic consultation session, including the options for genetic testing and cardiovascular surveillance in family members. We developed an ICC registry and performed next-generation-based DNA sequencing for all patients affected by non-syndromic HCM and idiopathic DCM in our joint specialist genetics service. The target gene sequencing panel relied on the Human Phenotype Ontology with 237 genes for HCM (HP:0001639) and 142 genes for DCM (HP:0001644). All subjects were asked to contact their asymptomatic first-degree relatives for genetic counseling regarding their risks and to initiate cardiovascular surveillance and cascade genetic testing. The study was performed from January 1, 2014, to December 31, 2020, and a total of 62 subjects (31-HCM and 31-DCM) were enrolled. The molecular detection frequency was 48.39% (32.26% pathogenic/likely pathogenic, 16.13% variant of uncertain significance or VUS for HCM, and 25.81% (16.13% pathogenic/likely pathogenic, 9.68% VUS) for DCM. The most prevalent gene associated with HCM was MYBPC3. The others identified in this study included ACTN2, MYL2, MYH7, TNNI3, TPM1, and VCL. Among the DCM subjects, variants were detected in two cases with the TTN nonsense variants, while the others were missense and identified in MYH7, DRSP3, MYBPC3, and SCN5A. Following the echocardiogram surveillance and cascade genetic testing in the asymptomatic first-degree relatives, the detection rate of new cases was 8.82% and 6.25% in relatives of HCM and DCM subjects, respectively. Additionally, a new pre-symptomatic relative belonging to an HCM family was identified, although the genomic finding in the affected case was absent. Thus, ICC service is promising for the national healthcare system, aiming to prevent morbidity and mortality in asymptomatic family members.

Toward a diagnostic CART model for Ischemic heart disease and idiopathic dilated cardiomyopathy based on heart rate total variability

Diagnosis of etiology in early-stage ischemic heart disease (IHD) and dilated cardiomyopathy (DCM) patients may be challenging. We aimed at investigating, by means of classification and regression tree (CART) modeling, the predictive power of heart rate variability (HRV) features together with clinical parameters to support the diagnosis in the early stage of IHD and DCM. The study included 263 IHD and 181 DCM patients, as well as 689 healthy subjects. A 24 h Holter monitoring was used and linear and non-linear HRV parameters were extracted considering both normal and ectopic beats (heart rate total variability signal). We used a CART algorithm to produce classification models based on HRV together with relevant clinical (age, sex, and left ventricular ejection fraction, LVEF) features. Among HRV parameters, MeanRR, SDNN, pNN50, LF, LF/HF, LFn, FD, Beta exp were selected by the CART algorithm and included in the produced models. The model based on pNN50, FD, sex, age, and LVEF features presented the highest accuracy (73.3%). The proposed approach based on HRV parameters, age, sex, and LVEF features highlighted the possibility to produce clinically interpretable models capable to differentiate IHD, DCM, and healthy subjects with accuracy which is clinically relevant in first steps of the IHD and DCM diagnostic process.Graphical abstract

Interpretable machine learning models to support differential diagnosis between Ischemic Heart Disease and Dilated Cardiomyopathy

The differential diagnosis between Ischemic Heart Disease (IHD) and Dilated Cardiomyopathy (DCM), particularly in the early stages of the diseases, can often be difficult. Left ventricular ejection fraction (LVEF) and heart rate variability (HRV) analysis are shown to be helpful tools for diagnosing several cardiac diseases. There is a growing interest in application of machine learning techniques to guide the diagnosis. However, often black-box machine learning models create dissatisfaction among clinicians due to the lack of a model interpretability. The aim of our study was to compare the classification performance of interpretable and clinically plausible models applied for early differential diagnosis between DCM and IHD (NYHA ≤ 1) based on LVEF and HRV features. The study encompassed 196 IHD and 117 DCM subjects. The models were produced by classification tree, logistic regression and naïve Bayes algorithms considering the set of selected HRV and LVEF features, chosen with the information gain method. The results showed that the most informative features for classification between IHD and DCM were LVEF, LF, NN50, pNN50, and meanRR. The naive Bayes model with classification accuracy of 73.5% outperformed classification tree and logistic regression models with 67.4% and 67.1% accuracies, respectively. We also demonstrated that the produced models together with nomograms allow probabilistic interpretation of the classification output between IHD and DCM, which is an important factor to guide the clinical decision making in differential diagnosis.

Machine-learning–based exploration to identify remodeling patterns associated with death or heart-transplant in pediatric-dilated cardiomyopathy

We investigated left ventricular (LV) remodeling, mechanics, systolic and diastolic function, combined with clinical characteristics and heart-failure treatment in association to death or heart-transplant (DoT) in pediatric idiopathic, genetic or familial dilated cardiomyopathy (DCM), using interpretable machine-learning. Echocardiographic and clinical data from pediatric DCM and healthy controls were retrospectively analyzed. Machine-learning included whole cardiac-cycle regional longitudinal strain, aortic, mitral and pulmonary vein Doppler velocity traces, age and body surface area. We used unsupervised multiple kernel learning for data dimensionality reduction, positioning patients based on complex conglomerate information similarity. Subsequently, k-means identified groups with similar phenotypes. The proportion experiencing DoT was evaluated. Pheno-grouping identified 5 clinically distinct groups that were associated with differing proportions of DoT. All healthy controls clustered in groups 1 to 2, while all, but one, DCM subjects, clustered in groups 3 to 5; internally validating the algorithm. Cluster-5 comprised the oldest, most medicated patients, with combined systolic and diastolic heart-failure and highest proportion of DoT. Cluster-4 included the youngest patients characterized by severe LV remodeling and systolic dysfunction, but mild diastolic dysfunction and the second-highest proportion of DoT. Cluster-3 comprised young patients with moderate remodeling and systolic dysfunction, preserved apical strain, pronounced diastolic dysfunction and lowest proportion of DoT. Interpretable machine-learning, using full cardiac-cycle systolic and diastolic data, mechanics and clinical parameters, can potentially identify pediatric DCM patients at high-risk for DoT, and delineate mechanisms associated with risk. This may facilitate more precise prognostication and treatment of pediatric DCM.

Pediatric and adult dilated cardiomyopathy are distinguished by distinct biomarker profiles.

Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls. We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured 1310 plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1-14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1-13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46-63). Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics. These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease. Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics and outcomes. Our findings suggest that pediatric DCM may be a heterogeneous disease with various sub-phenotypes, including differing biomarker profiles and clinical findings. These data provide prerequisite information for future prospective studies that validate the identified pediatric DCM biomarkers, address their diagnostic accuracy and prognostic significance, and explore the full extent of heterogeneity amongst pediatric DCM patients.

Abstract 13179: Distinct Biomarker Profiles for Pediatric and Adult Dilated Cardiomyopathy

Introduction: Pediatric and adult dilated cardiomyopathy (DCM) represent distinct entities with divergent gene expression, histopathology, and response to medical therapies. Prognostically important serum biomarkers identified in adults have failed to provide similar diagnostic and prognostic information for children with DCM. We hypothesized that pediatric and adult DCM populations display different biomarker profiles. Methods: Pediatric control (≤18y), pediatric DCM, and adult DCM plasma samples were analyzed using the SOMAscan biomarker platform to simultaneously measure over 1300 known protein analytes. Pediatric control and DCM subjects were age- and gender-matched. Most samples were obtained within 2 years of diagnosis. Biomarkers were compared between groups with p-value <0.05 (false discovery rate) and fold change (ratio of means) >2 considered significant. Principal component analysis was used to visualize differences in proteomic data. Results: The study included 39 pediatric control (mean age 3y, IQR 1-14), 39 pediatric DCM (median age 2.7y, IQR 1-13), and 40 adult DCM (median age 53y, IQR 46-63) subjects. Twenty plasma peptides were upregulated in pediatric DCM compared to controls. Plasma renin and 6-phosphogluconate dehydrogenase represented potential pediatric-specific biomarkers. Pediatric DCM subjects clustered into 4 distinct subgroups with unique biomarker profiles and distinguishing clinical characteristics suggesting the pediatric DCM phenotype may represent a heterogeneous group of diseases. Conclusions: This feasibility study provides important evidence that distinct biomarker profiles are present in pediatric and adult DCM patients. These findings provide preliminary data to inform the design of larger prospective studies to validate pediatric DCM specific biomarkers and investigate their prognostic value.

Association of S100B 3'UTR polymorphism with risk of chronic heart failure in a Chinese Han population.

To study the correlation between single nucleotide polymorphism (SNP) of the 3′ untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84–6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.

Intraventricular Flow Patterns in Patients Treated with Left Ventricular Assist Devices.

The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

Whole-Exome Sequencing Reveals Novel Genetic Variation for Dilated Cardiomyopathy in Pediatric Chinese Patients.

Dilated cardiomyopathy (DCM) is characterized by left or bilateral ventricular dilation and systolic dysfunction without rational conditions, which can lead to progressive heart failure and sudden cardiac death. Most of the pathogenic genes have been reported in adult population by locus mapping in familial cases and animal model studies. However, it still remains challenging to decipher the role of genetics in the etiology of pediatric DCM. We applied whole-exome sequencing (WES) for 30 sporadic pediatric DCM subjects and 100 non-DCM local controls. We identified the pathogenic mutations using bioinformatics tools based on genomic strategies synergistically and confirmed mutations by Sanger sequencing. We identified compound heterozygous nonsense mutations in DSP (c.3799C > T, p.R1267X; c.4444G > T, p.E1482X). In sporadic cases, the two heterozygous mutations in XIRP2 were identified. Then we performed an exome-wide association study with 30 case and 100 control subjects. Interestingly, we could not identify TTN truncating variants in all cases. Collectively, we observed a significant risk signal between carriers of TTN deleterious missense variants and DCM risk (odds ratio 4.0, 95% confidence interval 1.1-22.2, p = 3.12 × 10-2). Our observations expanded the spectrum of mutations and were valuable in the pre- and postnatal screening and genetic diagnosis for DCM.

Respiratory Sinus Arrhythmia Quantified with Linear and Non-Linear Techniques to Classify Dilated and Ischemic Cardiomyopathy.

In congestive heart failure (CHF), dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) are two highly related pathologies that are not fully characterized. The aim of this study is to assess respiratory sinus arrhythmia (RSA) index of the parasympathetic system, in order to discriminate between both pathologies, DCM and ICM. For this, ECG-signals of 49 subjects (12 DCM patients, 21 ICM patients, 6 ICM patients with diabetes mellitus (DM) type II and 10 control subjects) from the database HERIS II and of 173 subjects (50 DCM, 50 ICM, 15 DCM with DM type II, 15 ICM with DM type II and 47 control subjects) from the database MUSIC2 were analyzed. The RSA was quantified using linear and non-linear analysis methods (fractal dimension and entropy). The results showed a significant difference between ICM and DCM subjects (p=0.013) with a sensitivity of 83% and specificity of 90%. Decreasing RSA values were present in CHF patients, especially in ICM patients, in comparison with healthy subjects. Alterations in the parasympathetic system due to DM were also identified.

Exercise cardiac magnetic resonance to differentiate athlete's heart from structural heart disease.

The distinction between left ventricular (LV) dilation with mildly reduced LV ejection fraction (EF) in response to regular endurance exercise training and an early cardiomyopathy is a frequently encountered and difficult clinical conundrum. We hypothesized that exercise rather than resting measures would provide better discrimination between physiological and pathological LV remodelling and that preserved exercise capacity does not exclude significant LV damage. We prospectively included 19 subjects with LVEF between 40 and 52%, comprising 10 ostensibly healthy endurance athletes (EA-healthy) and nine patients with dilated cardiomyopathy (DCM). In addition, we recruited five EAs with a region of subepicardial LV. Receiver operating characteristic fibrosis (EA-fibrosis). Cardiac magnetic resonance (CMR) imaging was performed at rest and during supine bicycle exercise. Invasive afterload measures were obtained to enable calculations of biventricular function relative to load (an estimate of contractility). In DCM and EA-fibrosis subjects there was diminished augmentation of LVEF (5 ± 6% vs. 4 ± 3% vs. 14 ± 3%; P = 0.001) and contractility [LV end-systolic pressure-volume ratio, LVESPVR; 1.4 (1.3-1.6) vs. 1.5 (1.3-1.6) vs. 1.8 (1.7-2.7); P < 0.001] during exercise relative to EA-healthy. Receiver-operator characteristic curves demonstrated that a cut-off value of 11.2% for ΔLVEF differentiated DCM and EA-fibrosis patients from EA-healthy [area under the curve (AUC) = 0.92, P < 0.001], whereas resting LVEF and VO2max were not predictive. The AUC value for LVESPVR ratio was similar to that of ΔLVEF. Functional cardiac evaluation during exercise is a promising tool in differentiating healthy athletes with borderline LVEF from those with an underlying cardiomyopathy. Excellent exercise capacity does not exclude significant LV damage.

Ischemic vs. Non-Ischemic Dilated Cardiomyopathy: a Comparative Study in Stem Cell Therapy Efficacy

Background: Ischemic (ICM) versus dilated cardiomyopathy (DCM) have different pathogenesis and outcomes with standard medical therapy. Mesenchymal stem cell (MSC) therapy has produced improvements in both diseases. However, whether the efficacy of MSCs between ICM and DCM subjects is comparable, remains undetermined. Hypothesis: Subjects with DCM respond better than those with ICM. Methods: We analysed the effects of transendocardial MSC injections in patients with ICM vs. DCM from three single-institution, randomized, double-blinded, clinical trials: TAC-HFT, POSEIDON and POSEIDON-DCM. Cardiac structure, function and subject quality of life data were compared between ICM and DCM groups at baseline and one year follow-up. Results: Ejection fraction improved in DCM 7% (2.9, 11.0, p=0.002) vs. ICM 1.5% (-0.2, 3.2, p=0.08) subjects with a significant difference between groups (p=0.005). Similarly, stroke-volume increased in DCM 10.59mL (0.2, 21, p=0.046) vs. ICM -0.16mL (-4.6, 4.3, p=0.94) subjects with a significant difference between groups (p=0.02). End-diastolic volume improved only in ICM subjects, -10.68mL (-21, -0.1, p=0.047), and end-systolic volume improved only in DCM subjects, -17.8mL (-54.5, 17.0, p=0.049). Sphericity index only decreased in ICM, -0.04 (-0.06, -0.02, p=0.0002), subjects. End-diastolic mass increased in ICM, 3.57g (-3.1, 28, p=0.004), vs. DCM subjects, -4.1g (-15, 7, p=0.45), with a significant difference between groups (p=0.007). Six-minute walk test improved in DCM, 34m (18, 53, p=0.009), and ICM, 30m (-16, 89, p=0.0007), subjects with a difference between groups (p=0.03) favoring ICM subjects. NYHA class improved in both DCM (p=0.005) and ICM (p=0.02) subjects (between group p=0.20). Similarly, the Minnesota Heart Failure Questionnaire improved in DCM, -19 (-31, -7.1, p=0.003), and ICM, -9.3 (-16, -2.7, p=0.007), subjects (between group difference p=0.12). Conclusion: MSC therapy exerts distinct effects in ICM vs DCM. It improves functionality in DCM, cardiac remodelling in ICM, and enhances quality of life parameters in both disease processes.

Phase analysis of gated blood pool SPECT for multiple stress testing assessments of ventricular mechanical dyssynchrony in a tachycardia-induced dilated cardiomyopathy canine model

BackgroundStress-induced dyssynchrony has been shown to be independently correlated with clinical outcomes in patients with dilated cardiomyopathy (DCM) and narrow QRS complexes. However, the extent to which stress levels affect inter- and intraventricular dyssynchrony parameters remains unknown. MethodsTen large dogs were submitted to tachycardia-induced DCM by pacing the right ventricular apex for 3–4 weeks to reach a target ejection fraction (EF) of 35% or less. Stress was then induced in DCM dogs by administering intravenous dobutamine up to a maximum of 20 μg·kg−1·min−1. Hemodynamic and ventricular dyssynchrony data were analyzed by left ventricular (LV) pressure measurements and gated blood pool SPECT (GBPS) imaging. In order to assess mechanical dyssynchrony in DCM subjects and compare it with that of 8 normal counterparts, we extracted the following data: count-based indices of LV contraction homogeneity index (CHI), entropy and phase standard deviation, and interventricular dyssynchrony index. ResultsA significant LV intraventricular dyssynchrony (CHI: 96.4 ± 1.3% in control vs 78.6% ± 10.9% in DCM subjects) resulted in an intense LV dysfunction in DCM subjects (EF: 49.5% ± 8.4% in control vs 22.6% ± 6.0% in DCM), compared to control subjects. However, interventricular dyssynchrony did not vary significantly between the two groups. Under stress, DCM subjects showed a significant improvement in ventricular functional parameters at each level (EF: 22.6% ± 6.0% at rest vs 48.1% ± 5.8% at maximum stress). All intraventricular dyssynchrony indices showed a significant increase in magnitude of synchrony from baseline to stress levels of greater than or equal to 5 μg·kg−1·min−1 dobutamine. There were individual differences in the magnitude and pattern of change in interventricular dyssynchrony during the various levels of stress. ConclusionsBased on GBPS analyses, different levels of functional stress, even in close intervals, can have a significant impact on hemodynamic and intraventricular dyssynchrony parameters in a DCM model with narrow QRS complex.

Patterns of Mechanical Inefficiency in Pediatric Dilated Cardiomyopathy and Their Relation to Left Ventricular Function and Clinical Outcomes

Pediatric dilated cardiomyopathy (DCM) is associated with death or transplantation and is typically considered a homogeneous process affecting global left ventricular (LV) function. However, assessment of regional abnormalities that contribute to pumping inefficiencies is lacking. The aim of this study was to define regional strain patterns of mechanical inefficiency in the broader context of LV discoordination (dysfunction and timing abnormalities) and to evaluate their associations with LV function and clinical outcomes. Multiplanar apical LV echocardiographic images from patients with pediatric DCM (n=56) and control subjects (n=20) were analyzed by two-dimensional longitudinal speckle-tracking strain analysis to identify segmental strain patterns and global contraction groups. Clinical outcome (death or transplantation vs transplantation-free survival) and echocardiographic data were evaluated. Outcome groups were compared using the Fisher exact test, the χ(2) test, or analysis of variance (with P values≤.05 considered to indicate statistical significance). Of 56 patients with DCM, 29 (52%) progressed to death or transplantation. Five segmental strain patterns were observed that were used to define seven contraction groups by regional contractility and/or timing discoordination. The group(s) with the most discoordination had the most LV dysfunction (P=.0004) and a trend toward the highest frequency of death or transplantation (P=.069). Interreader reproducibility of segmental strain patterns agreed in 165 or 180 (92%) segments tested (κ=0.90). Control subjects had normal strain patterns. A heterogeneous mixture of abnormalities in the regional wall mechanics that lead to inefficient pump mechanics through functional and timing abnormalities were seen in this cohort and were categorized into natural subgroups. More severe LV discoordination was associated with increased LV dysfunction and a trend toward death or transplantation.

Coronary microcirculation changes in non-ischemic dilated cardiomyopathy identified by novel perfusion CT.

Intramyocardial microvessels demonstrate functional changes in cardiomyopathies. However, clinical computed tomography (CT) does not have adequate spatial resolution to assess the microvessels. Our hypothesis is that these functional changes manifest as altered heterogeneity of the spatial distribution of arteriolar perfusion territories. Our goal was to determine whether the spatial analysis of perfusion CT could clinically detect changes in the function and structure of the intramyocardial microcirculation in a non-ischemic dilated cardiomyopathy (DCM). Two groups were studied: (1) a Control group (12 male plus 12 female) with no risk factors nor evidence of coronary artery disease, and (2) a DCM group (12 male plus 12 female) with left ventricular ejection fraction ≤40% and no evidence of coronary artery disease. Using the CT scan, the LV free wall thickness and its radius of curvature were measured. The DCM group was sub divided into those with LV free wall thickness <11.5 mm and those with thickness ≥11.5 mm. In the myocardial opacification phase of the CT scan sequence, myocardial perfusion (F) and intramyocardial blood volume (Bv) for multiple intramyocardial regions were computed. No significant differences between the groups were demonstrable in overall myocardial F or Bv. However, the myocardial regional data showed significantly increased spatial heterogeneity in the DCM group when compared to the Control group. The findings demonstrate that altered function of the subresolution intramyocardial microcirculation can be quantified with myocardial perfusion CT and that significant changes in these parameters occur in the DCM subjects with LV wall thickness greater than 11.5 mm.

Beta blockers prevent correlation of plasma ACE2 activity with echocardiographic parameters in patients with idiopathic dilated cardiomyopathy.

Plasma angiotensin-converting enzyme (ACE) 2 activity has been demonstrated to be an independent prognostic marker in Chagas' disease, equally potent as B-type natriuretic peptide. This study aimed to investigate the prognostic potency of circulating ACE2 activity in patients with idiopathic dilated cardiomyopathy (DCM). Blood samples were withdrawn from patients with idiopathic DCM and healthy control subjects. The DCM patients were subdivided into 2 groups according to their New York Heart Association classification. The plasma ACE2 activity was measured by a fluorescence method. Plasma ACE2 activity was significantly increased in DCM patients, correlating with clinical severity. It was correlating with echocardiographic parameters in patients with DCM. Furthermore, plasma ACE2 activity had the potency to predict cardiac death and heart transplantation. However, compared with patients with Chagas' disease, the correlation and predictive value of ACE2 activity in patients with DCM was much less pronounced. Beta blocker treatment in patients with DCM was identified to prevent the association between circulating ACE2 activity and echocardiographic parameters. Although ACE2 activity in blood samples of patients with DCM without beta blockers is potent in correlating with the severity of disease and in predicting death and heart transplantation, its correlation and prediction potency are significantly diminished by beta blocker treatment.

Hypotension rather than hypertension is more correlated with lower exercise capacity in idiopathic dilated cardiomyopathy

Background: Exercise Capacity has been reported as an important prognostic marker in patients with idiopathic dilated cardiomyopathy (DCM). We evaluated the relationship of resting systolic blood pressure (rSBP) with cardiopulmonary exercise parameters in patients with idiopathic DCM and control subjects. Methods: We consecutively enrolled 44 idiopathic DCM patients (28 males, 51±11 years, mean LVEF=29%) and 70 control subjects without medical history (31 males, 51±11 years, mean LVEF=67%). We classified all study population into 3 groups according to rSBP (hypotensive: ∼110, normotensive 111∼140, hypertensive, 141∼) Results: Hypotensive group had significantly lower percent achieved of peak oxygen uptake than normotensive or hypertensive groups in idiopathic DCM (67.8 vs. 86.6 vs 90.5%, p=0.004). On the other hand, hypertensive group had lowest exercise capacity in controls (96.5 vs. 96.6 vs. 84.3%, p=0.36). Pearson Correlation demonstrated that rSBP had significant correlation with percent achieved of pVO2 in patients with idiopathic DCM (r=0.513, p<0.001), but not in control (r=-0.035, p=0.772). Multivariate analysis revealed that resting SBP was an independent predictor of percent achieved of pVO2 in idiopathic DCM group after controlling age, gender, BMI and renal function, increment of SBP during exercise. ![Figure][1] Exercise Capacity according to SBP Conclusions: Hypotension rather than hypertension is more correlated with lower exercise capacity in idiopathic DCM. [1]: pending:yes

Comparative numerical study on left ventricular fluid dynamics after dilated cardiomyopathy

IntroductionThe role of flow on the progression of left ventricular (LV) remodeling has been presumed, although measurements are still limited and the intraventricular flow pattern in remodeling hearts has not been evaluated in a clinical setting. Comparative evaluation of intraventricular fluid dynamics is performed here between healthy subjects and dilated cardiomyopathy (DCM) patients. MethodsLV fluid dynamics is evaluated in 20 healthy young men and 8 DCM patients by combination of 3D echocardiography with direct numerical simulations of the equation governing blood motion. Results are analyzed in terms of quantitative global indicators of flow energetics and blood transit properties that are representative of the qualitative fluid dynamics behaviors. ResultsThe flow in DCM exhibited qualitative differences due to the weakness of the formed vortices in the large LV chamber. DCM and healthy subjects show significant volumetric differences; these also reflect inflow properties like the vortex formation time, energy dissipation, and sub-volumes describing flow transit. Proper normalization permitted to define purely fluid dynamics indicators that are not influenced by volumetric measures. ConclusionCardiac fluid mechanics can be evaluated by a combination of imaging and numerical simulation. This pilot study on pathological changes in LV blood motion identified intraventricular flow indicators based on pure fluid mechanics that could potentially be integrated with existing indicators of cardiac mechanics in the evaluation of disease progression.