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1.  Axial Black Blood Turbo Spin Echo Imaging of the Right Ventricle 
Black blood turbo spin echo (TSE) imaging of the right ventricle (RV) free wall is highly sensitive to cardiac motion, frequently resulting in non-diagnostic images. Temporal and spatial parameters of a black blood TSE pulse sequence were evaluated for visualization of the RV free wall. 74 patient studies were retrospectively evaluated for the effects of acquisition timing on image quality. Axial black blood TSE images were acquired on 10 healthy volunteers to assess the role of spatial misregistration on right ventricle visualization; increasing the double inversion recovery (DIR) slice thickness beyond 300% had no effect on image quality (p=0.2). 35 patient studies were prospectively evaluated with inversion times (TIs) corresponding to the mid-diastolic rest period and end-systole based on visual analysis of a four chamber cine. When TIs were chosen to be within the patients’ RV rest period, mean image quality score was significantly improved (2.3 vs. 1.86, p<0.001) and the number of clinically diagnostic images increased from 32% to 46%. Black blood TSE imaging of the RV free wall is highly sensitive to cardiac motion. Image quality can be improved by choosing TIs concordant with the rest period of the patient’s RV that may occur at mid-diastole or end-systole.
PMCID: PMC4301616  PMID: 19165884
cardiac MRI; black blood; turbo spin echo; right ventricle
2.  Impact of Nonischemic Scar Features on Local Ventricular Electrograms and Scar-Related Ventricular Tachycardia Circuits in Patients with Nonischemic Cardiomyopathy 
Circulation. Arrhythmia and electrophysiology  2013;6(6):10.1161/CIRCEP.113.000159.
The association of local electrogram features with scar morphology and distribution in nonischemic cardiomyopathy (NICM) has not been investigated. We aimed to quantify the association of scar on late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) with local electrograms and ventricular tachycardia (VT) circuit sites in patients with NICM.
Methods and Results
Fifteen patients with NICM underwent LGE-CMR before VT ablation. The transmural extent and intramural types (endocardial, mid-wall, epicardial, patchy, transmural) of scar were measured in LGE-CMR short axis planes. Electro-anatomic map (EAM) points were registered to LGE-CMR images. Myocardial wall thickness, scar transmurality, and intramural scar types were independently associated with electrogram amplitude, duration, and deflections in linear mixed effects multivariable models, clustered by patient. Fractionated and isolated potentials were more likely to be observed in regions with higher scar transmurality (P<0.0001 by ANOVA) and in regions with patchy scar (versus endocardial, mid wall, epicardial scar, P<0.05 by ANOVA). Most VT circuit sites were located in scar with >25% scar transmurality.
Electrogram features are associated with scar morphology and distribution in patients with NICM. Prior knowledge of electrogram image associations may optimize procedural strategies including the decision to obtain epicardial access.
PMCID: PMC3884514  PMID: 24235267
ventricular tachycardia; nonischemic cardiomiopathy; cardiac magnetic resonance imaging; electrophysiology mapping
3.  Mutation Positive Arrhyhmogenic Right Ventricular Dysplasia/Cardiomyopathy: The Triangle of Dysplasia Displaced 
The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes.
Methods and Results
We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation.
Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.
PMCID: PMC3971054  PMID: 23889974
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy; magnetic resonance imaging; electroanatomic mapping; ventricular tachcardia; phenotype; genetics; implantable cardioverter defibrillator
4.  Incremental Value of Cardiac Magnetic Resonance Imaging in Arrhythmic Risk Stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated Desmosomal Mutation Carriers 
To identify the incremental value and optimal role of Cardiac Magnetic Resonance (CMR) imaging in arrhythmic risk stratification of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) associated desmosomal mutation carriers without a prior history of sustained ventricular arrhythmia.
Risk stratification of ARVD/C mutation carriers is challenging.
We included 69 patients (age 27.0 ± 15.3 years, 42% male) harboring ARVD/C associated pathogenic mutations (83% PKP-2) without prior sustained ventricular arrhythmias. Electrocardiography (ECG) and 24-hours Holter monitoring closest to presentation were analyzed for electrical abnormalities as per revised Task Force Criteria. CMR studies were done to identify abnormal cardiac structure and function according to the revised Task Force Criteria.
Overall, 42 (61%) patients presented with electrical abnormalities based on their ECG and Holter monitor, of whom 20 (48%) had an abnormal CMR. Only 1 (4%) of 27 patients without electrical abnormalities at initial evaluation had an abnormal CMR. Over a mean follow-up of 5.8 ± 4.4 years, 11 (16%) patients experienced a sustained ventricular arrhythmia, exclusively in patients with both electrical abnormalities (ECG and/or Holter) and abnormal CMR.
Our results suggest that electrical abnormalities on ECG and Holter monitoring precede detectable structural abnormalities in ARVD/C mutation carriers. Therefore, evaluation of cardiac structure and function using CMR is probably not necessary in the absence of baseline electrical abnormalities. Among ARVD/C mutation carriers, the presence of both electrical and CMR abnormalities identifies patients at high risk of events and thus patients who might benefit from prophylactic implantable cardioverter-defibrillator implantation.
PMCID: PMC3971056  PMID: 23810894
cardiomyopathy; electrocardiography; magnetic resonance imaging; risk stratification; tachyarrhythmias
5.  Exercise Increases Age-Related Penetrance and Arrhythmic Risk in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated Desmosomal Mutation Carriers 
Journal of the American College of Cardiology  2013;62(14):10.1016/j.jacc.2013.06.033.
To determine how exercise influences penetrance of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) among patients with desmosomal mutations.
While animal models and anecdotal evidence suggest exercise is a risk factor for ARVD/C, there have been no systematic human studies.
Eighty-seven carriers (46 male, mean age 44±18) were interviewed about regular physical activity from age ten. The relationship of exercise with; 1) sustained ventricular arrhythmia (VT/VF), 2) stage C heart failure (HF), and 3) meeting diagnostic criteria for ARVD/C (TFC) was studied.
Endurance athletes (n=56) developed symptoms at a younger age (30.1±13.0 vs. 40.6±21.1 years, p=0.05), were more likely to meet TFC at last follow-up (82% vs. 35%, p<0.001), and had a lower lifetime survival free from VT/VF (p=0.013) and HF (p=0.004). Compared to those who did the least (lowest quartile) exercise per year prior to presentation, those in the second (OR=6.64, p=0.013), third (OR=16.7, p=0.001), and top (OR=25.3, p<0.0001) quartiles were increasingly likely to meet TFC. Among 61 who did not present with VT/VF, the 13 subjects experiencing a first VT/VF event over a mean 8.4±6.7 year follow-up were all endurance athletes (p=0.002). Survival from first VT/VF was lowest among those who exercised most (top quartile) both prior to (p=0.036) and after (p=0.005) clinical presentation. Among individuals in the top quartile, a reduction in exercise decreased VT/VF risk (p=0.04).
Endurance exercise and frequent exercise increase risk of VT/VF, HF, and ARVD/C in desmosomal mutation carriers. These findings support exercise restriction for these patients.
PMCID: PMC3809992  PMID: 23871885
Arrhythmogenic right ventricular dysplasia / cardiomyopathy; exercise; heart failure; ventricular arrhythmias; penetrance
6.  Prevalence and Pathophysiologic Attributes of Ventricular Dyssynchrony in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 
To study the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE).
ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilatation. These pathologic changes may result in electromechanical dyssynchrony.
Electrocardiography, conventional and TDE was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 controls. RV end-diastolic and end-systolic areas, RV fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (TSV) between the RV free wall, ventricular septum and LV lateral wall. RV dyssynchrony was defined as the difference in TSV between the RV free wall and the ventricular septum, >2 SD above the mean value for controls.
Mean difference in RV TSV was higher in ARVD/C compared to controls (55 ± 34 ms vs. 26 ± 15 ms, p<0.001). Significant RV dyssynchrony was not noted in any of the controls. Based on a cut-off value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had larger RV end-diastolic area (22 ± 5 vs. 19 ± 4 cm2, p=0.02), and lower RVFAC (29 ± 8 vs. 34 ± 8%, p=0.03) compared to ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes and function were present between the two groups.
RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.
PMCID: PMC4138506  PMID: 19628120
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy; Echocardiography; Ventricular dyssynchrony
7.  Feasibility of Image-Based Simulation to Estimate Ablation Target in Human Ventricular Arrhythmia 
Previous studies suggest that MRI with late gadolinium enhancement (LGE) may identify slowly conducting tissues in scar-related ventricular tachycardia (VT).
We tested the feasibility of image-based simulation based on LGE to estimate ablation targets in VT.
We conducted a retrospective study in 13 patients who had pre-ablation MRI for scar-related VT ablation. We used image-based simulation to induce VT and estimate target regions according to the simulated VT circuit. The estimated target regions were co-registered with the LGE scar map and the ablation sites from the electroanatomical map in the standard ablation approach.
In image-based simulation, VT was inducible in 12 patients (92.3%). All VTs showed macro-reentrant propagation patterns, and the narrowest width of estimated target region that an ablation line should span to prevent VT recurrence was 5.0 ± 3.4 mm. Out of 11 patients who underwent ablation, the results of image-based simulation and the standard approach were consistent in 9 patients (82%), where ablation within the estimated target region was associated with acute success (n=8) and ablation outside the estimated target region was associated with failure (n=1). In one case (9%), the results of image-based simulation and the standard approach were inconsistent, where ablation outside the estimated target region was associated with acute success.
The image-based simulation can be used to estimate potential ablation targets of scar-related VT. The image-based simulation may be a powerful noninvasive tool for pre-procedural planning of ablation procedures to potentially reduce the procedure time and complication rates.
PMCID: PMC3735782  PMID: 23608593
Image-guided intervention; Ventricular arrhythmia; Catheter ablation; Cardiac MRI; Computer simulation
8.  Arrhythmogenic right ventricular cardiomyopathy (ARVC): cardiovascular magnetic resonance update 
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the “Task Force” criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC.
PMCID: PMC4222825  PMID: 25191878
Arrhythmogenic right ventricular cardiomyopathy; Cardiovascular magnetic resonance; Diagnosis; Genetics; Treatment
9.  Myocardial Structural Associations with Local Electrograms: A Study of Post-Infarct Ventricular Tachycardia Pathophysiology and Magnetic Resonance Based Non-Invasive Mapping 
The association of scar on late-gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping (EAM) has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support post-infarct ventricular tachycardia (VT).
Methods and Results
LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and post-infarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. EAM points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations between left ventricular wall thickness, post infarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on EAM. Antero-posterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Anti-arrhythmic drug use was associated with electrogram duration. Critical sites of post-infarct VT were associated with >25% scar transmurality and slow conduction sites with >40 msec stimulus-QRS time were associated with >75% scar transmurality.
Critical sites for maintenance of post-infarct VT are confined to areas with >25% scar transmurality. Our data provides insights into the structural substrates for delayed conduction and VT, and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping due to sampling density, and enhance magnetic resonance based ablation by feature extraction from complex images.
PMCID: PMC3581804  PMID: 23149263
ischemic heart disease; magnetic resonance imaging; mapping; ventricular tachycardia; late gadolinium enhancement
10.  Right Ventricular Structure is Associated with the Risk of Heart Failure and Cardiovascular Death: The MESA-Right Ventricle Study 
Circulation  2012;126(14):1681-1688.
Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure (HF) or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants between 2000–2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (N = 4,144) was 61.4 ± 10.1 years old and 47.6 % male. The presence of RV hypertrophy (increased RV mass) was associated with a more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (HR = 2.52, 95%CI 1.55–4.10, p < 0.001) and a doubling of risk (or more) with left ventricular mass at the mean value or lower (p for interaction = 0.05).
RV hypertrophy was associated with the risk of heart failure or death in a multi-ethnic population free of clinical cardiovascular disease at baseline.
PMCID: PMC3532921  PMID: 22932258
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension; survival
11.  Right Ventricular Morphology and the Onset of Dyspnea: The MESA-Right Ventricle Study 
PLoS ONE  2013;8(2):e56826.
The association of right ventricular (RV) structure and function with symptoms in individuals without cardiopulmonary disease is unknown. We hypothesized that greater RV mass and RV end-diastolic volume (RVEDV), smaller RV stroke volume (RVSV), and lower RV ejection fraction (RVEF) measured by cardiac magnetic resonance imaging (MRI) in participants free of clinical cardiovascular disease at baseline would be associated with a greater risk of self-reported dyspnea.
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRIs on participants without clinical cardiovascular disease between 2000 and 2002. We excluded subjects who reported “prevalent” dyspnea at the first assessment (24 months). The presence of dyspnea was assessed at 24 months, 42 months, and 60 months from baseline. Cox proportional hazards models were used to examine the relationship between RV measures and incident dyspnea.
In the final study sample (N = 2763), there were significant interactions between RV measures and sex in terms of the risk of dyspnea (p<0.05). Among men (N = 1453), lower RV mass (p = 0.003), smaller RVEDV (p<0.001), smaller RV end-systolic volume (RVESV) (p = 0.03) and decreased RVSV (p<0.001) were associated with an increased risk of developing dyspnea after adjusting for covariates. Associations remained after adjusting for left ventricular function and lung function. However, there were no significant associations between RV measures and the risk of dyspnea in women.
Lower RV mass and smaller RV volumes were associated with an increased risk of dyspnea in men, but not in women.
PMCID: PMC3574101  PMID: 23457622
13.  Right Ventricular Volume Analysis by Angiography in Right Ventricular Cardiomyopathy 
Imaging of the right ventricle (RV) for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is commonly performed by echocardiography or magnetic resonance imaging (MRI). Angiography is an alternative modality, particularly when MRI cannot be performed. We hypothesized that RV volume and ejection fraction computed by angiography would correlate with these quantities as computed by MRI.
Methods and Results
RV volumes and ejection fraction were computed for subjects enrolled in the North American ARVC/D Registry, with both RV angiography and MRI studies. Angiography was performed in the 30° right anterior oblique (RAO) and 60° left anterior oblique (LAO) views. Angiographic volumes were computed by RAO view and two-view (RAO and LAO) formulae. 17 subjects were analyzed (11 men and 6 women), with 15 subjects classified as affected, and 2 as unaffected by modified Task Force criteria. The correlation coefficient of MRI to the two-view angiographic analysis was 0.76 for end-diastolic volume and 0.79 for ejection fraction. Angiographically derived volumes were larger than MRI derived volume (p=0.006) and with the slope in a linear relationship equal to 0.8 for end diastolic volume, and 0.9 for RV ejection fraction (p<0.001), computed by the two view formula. The RAO view formula was significantly related to the MRI derived quantities, but with lower correlation coefficients (0.36 for volume and 0.73 for ejection fraction).
End-diastolic volume and ejection fraction of the RV can be obtained by angiography and correlates with these quantities as obtained by MRI.
PMCID: PMC3488440  PMID: 21706146
cardiomyopathy; right ventricle; magnetic resonance imaging; angiography; right ventricular volume
14.  Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy 
Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a “false positive” case in which plakoglobin signal was reduced in a patient initially thought to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC, but has not previously been associated with altered desmosomal proteins.
Methods and Results
We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (non-granulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of IL-17, TNFα and IL-6, cytokines implicated in granulomatous myocarditis, caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in non-granulomatous myocarditis had no effect, even at much high concentrations. We also observed myocardial expression of IL-17 and TNFα, and elevated serum levels of inflammatory mediators including IL-6R, IL-8, MCP1 and MIP1β in ARVC patients (all p<0.0001 compared with controls).
These results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.
PMCID: PMC3203520  PMID: 21859801
plakoglobin; desmosome; sarcoidosis; giant cell myocarditis; cytokines
15.  Sex and Race Differences in Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
Circulation  2011;123(22):2542-2551.
Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease, however determinants of RV anatomy have not been well-studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants. RV volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived using an allometric approach. The study sample (N = 4123) was 61.5 ± 10.1 years old and 47.5% male. Older age was associated with lower RV mass (~5% lower mass per decade) with larger age-related decrements in men than in women (p for interaction < 0.05). Older age was also associated with higher RV ejection fraction (RVEF), an association which differed between races/ethnicities (p for interaction ≤ 0.01). Overall, men had greater RV mass (~8%) and larger RV volumes than women, but had lower RVEF (4% in absolute terms) (p < 0.001). African Americans had lower RV mass than Caucasians (p ≤ 0.002), whereas Hispanics had higher RV mass (p ≤ 0.02). Using the derived normative equations, 7.3% (95%CI, 6.5–8.1%) met criteria for RV hypertrophy and 5.9% (95%CI, 5.2–6.6%) had RV dysfunction.
In conclusion, age, sex, and race are associated with significant differences in RV mass, RV volumes and RVEF, potentially explaining distinct responses of the RV to cardiopulmonary disease.
PMCID: PMC3111939  PMID: 21646505
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension
16.  MR and CT imaging of Arrhythmogenic Cardiomyopathy 
PMCID: PMC3085887  PMID: 21552378
17.  Reversible Cardiac Conduction Block and Defibrillation with High-Frequency Electric Field 
Science Translational Medicine  2011;3(102):102ra96.
Electrical impulse propagation is an essential function in cardiac, skeletal muscle, and nervous tissue. Abnormalities in cardiac impulse propagation underlie lethal reentrant arrhythmias, including ventricular fibrillation. Temporary propagation block throughout the ventricular myocardium could possibly terminate these arrhythmias. Electrical stimulation has been applied to nervous tissue to cause reversible conduction block, but has not been explored sufficiently in cardiac tissue. We show that reversible propagation block can be achieved in cardiac tissue by holding myocardial cells in a refractory state for a designated period of time by applying a sustained sinusoidal high-frequency alternating current (HFAC); in doing so, reentrant arrhythmias are terminated. We demonstrate proof of concept using several models, including optically mapped monolayers of neonatal rat ventricular cardiomyocytes, Langendorff-perfused guinea pig and rabbit hearts, intact anesthetized adult rabbits, and computer simulations of whole-heart impulse propagation. HFAC may be an effective and potentially safer alternative to direct current application, currently used to treat ventricular fibrillation.
PMCID: PMC3328400  PMID: 21957174
18.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
19.  Physical Activity and Right Ventricular Structure and Function 
Rationale: Intense exercise in elite athletes is associated with increased left ventricular (LV) and right ventricular (RV) mass and volumes. However, the effect of physical activity on the RV in an older community-based population is unknown.
Objectives: We studied the association between levels of physical activity in adults and RV mass and volumes.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on community-based participants without clinical cardiovascular disease. RV volumes were determined from manually contoured endocardial margins. RV mass was determined from the difference between epicardial and endocardial volumes multiplied by the specific gravity of myocardium. Metabolic equivalent–minutes/day were calculated from the self-reported frequency, duration, and intensity of physical activity.
Measurements and Main Results: The study sample (n = 1,867) was aged 61.8 ± 10 years, 48% male, 44% white, 27% African American, 20% Hispanic, and 9% Chinese. Higher levels of moderate and vigorous physical activity were linearly associated with higher RV mass (P = 0.02) after adjusting for demographics, anthropometrics, smoking, cholesterol, diabetes mellitus, hypertension, and LV mass. Higher levels of intentional exercise (physical activity done for the sole purpose of conditioning or fitness) were nonlinearly associated with RV mass independent of LV mass (P = 0.03). There were similar associations between higher levels of physical activity and larger RV volumes.
Conclusions: Higher levels of physical activity in adults were associated with greater RV mass independent of the associations with LV mass; similar results were found for RV volumes. Exercise-associated RV remodeling may have important clinical implications.
PMCID: PMC3056232  PMID: 20813888
exercise; pulmonary heart disease; pulmonary hypertension; magnetic resonance imaging
20.  Matrix metalloproteinase-9 and plasminogen activator inhibitor-1 are associated with right ventricular structure and function: The MESA-RV Study 
Elevated resistance and reduced compliance of the pulmonary vasculature increase right ventricular (RV) afterload. Local and systemic inflammation and haemostatic abnormalities are prominent in pulmonary vascular diseases. We hypothesized that plasma biomarker levels indicating greater inflammation and coagulability associated with pulmonary vascular disease would be associated with RV structure and function measured by cardiac magnetic resonance imaging (MRI). The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI among participants aged 45–84 years without clinical cardiovascular disease. We assessed the associations of RV mass, RV end-diastolic volume (RVEDV), RV stroke volume (RVSV) and RV ejection fraction (RVEF) with plasma measures of inflammation (matrix metalloproteinase (MMP)-3 and -9, intercellular adhesion molecule (ICAM)-1, tumour necrosis factor receptor (TNF-R1), and E-selectin) and thrombosis (plasminogen activator inhibitor (PAI)-1, tissue factor, tissue factor pathway inhibitor and CD40 ligand).The study sample included 731 subjects. Higher MMP-9 levels were associated with lower RV mass before and after adjustment for left ventricular (LV) mass (p = 0.008 and p = 0.044, respectively). Higher levels of MMP-9 and PAI-1 were also associated with smaller RVEDV (p<0.05). Higher PAI-1 levels were associated with lower RVEF even after adjustment for LV ejection fraction (p = 0.017). In conclusion, MMP-9 and PAI-1 are associated with changes in RV structure and function which could be potentially related to a subclinical increase in pulmonary vascular resistance.
PMCID: PMC3045574  PMID: 20923324
Inflammation; thrombosis; hypertension; pulmonary
21.  Imaging Phenotype vs. Genotype in Non-Hypertrophic Heritable Cardiomyopathies: Dilated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy 
Advances in cardiovascular imaging increasingly afford unique insights into heritable myocardial disease. As clinical presentation of genetic cardiomyopathies may range from nonspecific symptoms to sudden cardiac death, accurate diagnosis has implications for individual patients as well as related family members. The initial consideration of genetic cardiomyopathy may occur in the imaging laboratory, where one must recognize the patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) among the many with ventricular arrhythmia referred to define myocardial substrate. Accurate diagnosis of the patient presenting with dyspnea and palpitations whose first-degree relatives have lamin A/C cardiomyopathy may warrant genetic testing1, 2 plus imaging of diastolic function and myocardial fibrosis3. As advances in cardiac imaging afford detection of subclinical structural and functional changes, the imaging specialist must be attuned to signatures of specific genetic disorders. With increased availability of both advanced imaging as well as genotyping techniques, this review seeks to provide cardiovascular imaging specialists and clinicians with the contemporary information needed for more precise diagnosis and treatment of heritable myocardial disease. A companion paper in this series covers imaging phenotype and genotype considerations in hypertrophic cardiomyopathy (HCM). This review details clinical features, imaging phenotype and current genetic understanding for two of the most common non-HCM conditions that prompt myocardial imaging - dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). While all modalities are considered herein, considerable focus is given to CMR with its unique capabilities for myocardial tissue characterization.
PMCID: PMC3065294  PMID: 21081743
imaging; cardiomyopathy; genetics
22.  Shared Desmosome Gene Findings in Early and Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited form of cardiomyopathy with low penetrance and variable expressivity. Dominant mutations and rare polymorphisms in desmosome genes are frequently identified. We reasoned that individuals with earlier onset disease would have more frequent desmosome gene mutations and rare polymorphisms. Three groups were compared: Young with symptoms attributable to ARVD/C or a diagnosis of ARVD/C at age of 21 years or earlier, Middle with first symptoms or diagnosis age of 22–49 years, and Late with first symptoms or diagnosis at age of 50 or more years. deoxyribonucleic acid (DNA) sequence analysis was performed on five cardiac desmosome genes, and the presence of mutations and rare missense polymorphisms was compared among the three groups. In the entire Young cohort, 20 (67%) had one or more cardiac desmosome gene mutations. The prevalence of cardiac desmosome gene mutations was similar in the Middle (48%) and Late (53%) cohorts (P=0.23). Similar numbers of individuals in each cohort had more than one desmosome gene mutation, although the numbers are too small for statistical comparisons. The prevalence of certain rare missense DNA variants was not different among the cohorts (P=0.71), yet these rare missense alleles were more prevalent in the overall study cohort of 112 ARVD/C participants compared to 100 race-matched controls (P=0.027). The presence of these variants did not associate with the age of onset of ARVD/C or ventricular tachycardia. These findings highlight the complex interplay of environmental and genetic factors contributing to this condition.
PMCID: PMC3138067  PMID: 20857253
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C); Genetics; Sudden cardiac death; Desmosome
23.  Epidemiology of Sudden Cardiac Death in Rural South India - Insights From The Andhra Pradesh Rural Health Initiative 
Sudden cardiac death (SCD) is a common initial presentation of coronary artery disease (CAD). Despite the growing epidemic of CAD in India, the epidemiology of SCD is largely unknown.
The objective of the study was to define the prevalence and determinants of sudden cardiac deaths in rural South India.
Prospective mortality surveillance was conducted in 45 villages (180,162 subjects) in rural South India between January 2006 and October 2007. Trained multipurpose health workers sought to do verbal autopsies within 4 weeks of any death. Detailed questionnaires including comorbidities and circumstances surrounding death were recorded. SCD was adjudicated using the modified Hinkle-Thaler classification.
A total of 1916 deaths occurred in the study population over the 22 month time period and verbal autopsy was obtained in 1827 (95%) subjects. Overall mean age of the deceased was 62 ± 20 years and 1007 (55%) were men. Cardiovascular and cerebrovascular diseases together accounted for 559 deaths (31%), followed by infectious disease (163 deaths, 9%), cancer (126 deaths, 7%) and suicide (93 deaths, 5%).
Of the 1827 deaths, after excluding accidental deaths (89 deaths), 309 deaths (17%) met criteria for SCD. Cardiovascular disease was the underlying causes in the majority of the SCD events (231/309 (75%)). On multivariate analyses, previous MI/CAD (p < 0.001, OR 14.25), hypertension (p < 0.001, OR 1.84), and age groups between 40-60 yrs (p=0.029) were significantly associated with SCD.
Sudden cardiac death accounted for up to half of the cardiovascular deaths in rural Southern India. Traditional cardiovascular risk factors were strongly associated with SCD.
PMCID: PMC3128815  PMID: 21760680
Epidemiology; Sudden Cardiac Death; Rural South India; Andhra Pradesh
24.  Relation of Cardiovascular Risk Factors to Right Ventricular Structure and Function as Determined by Magnetic Resonance Imaging (Results from the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2010;106(1):110-116.
The impact of cardiovascular risk factors on the left ventricle is well known but their impact on right ventricle has not been studied using advanced imaging techniques. The purpose of this study was to determine the relation between cardiovascular risk factors and right ventricular (RV) structure and function and its interaction with the left ventricle. Cardiac magnetic resonance images were analyzed in 4204 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression models were used to study the cross sectional association between individual RV parameters and risk factors. All RV parameters except ejection fraction decreased with age (p<0.0001). RV mass was positively associated with systolic blood pressure (+0.4g, p<0.0001) and high density lipoprotein (HDL) cholesterol (+0.2g, p<0.0001); inversely with diastolic blood pressure (−0.3g, p<0.0001) and total cholesterol (−0.2g, p<0.01). RV end diastolic volume was positively associated with systolic blood pressure (+1.6ml, p<0.01) and HDL cholesterol (+1.8ml, p<0.0001); and inversely with diastolic blood pressure (−2.2 ml, p<0.0001), total cholesterol (−1.4ml, p<0.0001), current smoking (−2.7ml, p<0.05) and diabetes mellitus (−3.1ml, p<0.01). RV ejection fraction was positively related with systolic blood pressure (+1.0%, p<0.0001), HDL cholesterol (+0.4%, p<0.0001) and inversely with diastolic blood pressure (−0.7%, p<0.0001). In conclusion, the mass and volumes of the right ventricle decrease with age. Cardiovascular risk factors, especially blood pressure and HDL cholesterol are associated with subclinical changes in RV mass and volumes.
PMCID: PMC2901248  PMID: 20609657

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