Normal Left Ventricular Wall Thickness Research Articles

Quality of Life and Exercise Capacity in Early Stage and Subclinical Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial.

The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being. VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort. Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P=0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P=0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P=0.01) but did not significantly impact CPET performance. Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.

Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including abnormal ECG, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.

Prognostic utility and characterization of left ventricular hypertrophy using global thickness

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects having undergone CMR were studied (cardiac patients, n = 2543; healthy volunteers, n = 100). A new measure, global wall thickness (GT, GTI if indexed to body surface area) was accurately calculated from LV mass and end-diastolic volume. Among patients with follow-up (n = 1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12–1.20], p < 0.001), followed by GTI (HR 1.14[1.09–1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35–1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease).

Abstract 12588: A Hyperactive Heart: A Case of Adderall-Induced Cardiomyopathy

Introduction: Stimulants are commonly used in the treatment of attention deficit hyperactivity disorder (ADHD). Cardiomyopathy is a rare but serious potential side effect of long-term stimulant use, even when done so for therapeutic purposes. Case: We present a 56-year-old female with ADHD and long-term high dose Adderall use who presented for progressively worsening dyspnea over the course of 1 year. Labs were notable for peak hs-troponin 246ng/L and pro-BNP 6598pg/mL. On admission, echocardiogram was notable for reduced left ventricular (LV) ejection fraction (EF) of 20-25% with normal LV wall thickness and mild-moderate valvular disease. ECG showed sinus rhythm 97 bpm, bi-atrial enlargement, normal voltage and no evidence of conduction delay. A left heart catheterization demonstrated no evidence of coronary artery disease. Cardiac MRI at 1.5T was notable for LVEF 18%, severe LV dilation (EDV 189mL/m2), severe right ventricular (RV) dilation (EDV 131mL/m2) with RVEF 26%, native T1 1099 msec, ECV 41%, normal T2*, and a very thin circumferential subendocardial late gadolinium enhancement involving the apical and mid segments (6% of LV mass). TSH, Vitamin B1, and selenium levels were normal, and there was no evidence of tachyarrhythmia throughout her admission. She denied significant alcohol use, illicit substance use, or family history of cardiomyopathy. The absence of paraprotein gap and other stigmata lowered suspicion for amyloidosis. Due to the results of her workup, her Adderall was discontinued as this was thought to be the likely cause of her newly discovered cardiomyopathy. She was discharged home on GDMT with close follow up with advanced heart failure. Discussion: The association between long-term stimulant use and cardiomyopathy is known, but not well described. Common cardiac effects of stimulants include tachycardia, hypertension and increased risk of arrhythmias, all of which are associated with increased workload on the heart and therefore contribute to the development of cardiomyopathy. Although generally rare, long-term use of prescription stimulant medications can contribute to the development of cardiomyopathy and should therefore be used sparingly and for the shortest period possible when necessary for the treatment of ADHD.

Chronic troponin elevation assessed by myocardial T1 mapping in patients with stable coronary artery disease.

Cardiac troponin detected with sensitive assays can be chronically elevated, in the absence of unstable coronary syndromes. In patients with chronic coronary artery disease, clinically silent ischemic episodes may cause chronic troponin release. T1 mapping is a cardiovascular magnetic resonance technique useful in quantitative cardiac tissue characterization. We selected patients with anatomically and functionally normal hearts to investigate associations between chronic troponin release and myocardial tissue characteristics assessed by T1 mapping. We investigated the relationship between cardiac troponin I concentrations and cardiovascular magnetic resonance T1 mapping parameters in patients with stable coronary artery disease enrolled in MASS V study before elective revascularization. Participants had no previous myocardial infarction, negative late gadolinium enhancement, normal left ventricular function, chamber dimensions and wall thickness. A total of 56 patients were analyzed in troponin tertiles: nativeT1 and extracellular volume (ECV) values (expressed as means ± standard deviations) increased across tertiles: nativeT1 (1006 ± 27 ms vs 1016 ± 27 ms vs 1034 ± 37 ms, ptrend = 0.006) and ECV (22 ± 3% vs 23 ± 1.9% vs 25 ± 3%, ptrend = 0.007). Cardiac troponin I concentrations correlated with native T1(R = 0.33, P = .012) and ECV (R = 0.3, P = .025), and were independently associated with nativeT1 (P = .049) and ventricular mass index (P = .041) in multivariable analysis. In patients with chronic coronary artery disease and structurally normal hearts, troponin I concentrations correlated with T1 mapping parameters, suggesting that diffuse edema or fibrosis scattered in normal myocardium might be associated with chronic troponin release.

Circulating MicroRNAs Identify Early Phenotypic Changes in Sarcomeric Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM. We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320. Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups. Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome.

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in ABCC9, which encodes cardiovascular KATP (ATP-sensitive potassium) channel subunits. We studied the cardiovascular phenotype longitudinally in 31 subjects with CS with confirmed ABCC9 variants (median [interquartile range] age 8 years [3-32 years], body mass index 19.9 [16.5-22.9], 16 male subjects). Subjects with CS presented with significant left ventricular hypertrophy (left ventricular mass index 86.7 [57.7-103.0] g/m2 in CS, n=30; 26.6 [24.1-32.8] g/m2 in controls, n=17; P<0.0001) and low blood pressure (systolic 94.5 [90-103] mm Hg in CS, n=17; 109 [98-115] mm Hg in controls, n=17; P=0.0301; diastolic 60 [56-66] mm Hg in CS, n=17; 69 [65-72] mm Hg in control, n=17; P=0.0063). Most (21/31) subjects with CS exhibited eccentric hypertrophy with normal left ventricular wall thickness. Congestive heart failure symptoms were evident in 4 of the 5 subjects with CS aged >40 years on long-term follow-up. Conclusions The data define the natural history of high-output cardiac hypertrophy resulting from decreased systemic vascular resistance in subjects with CS, a defining population for long-term consequences of high-output hypertrophy caused by low systemic vascular resistance, and the potential for progression to high-output heart failure.

Cardiomyocyte stretch mediates the relation between left ventricular amyloid burden and adverse outcomes in light chain amyloidosis: a 18F-florbetapir positron emission tomography study

Abstract Background Patients with light chain (AL) amyloidosis and cardiac involvement have poor prognosis. Mayo stage accounts for severity of plasma cell dyscrasia and cardiac biomarker release, and provides powerful risk stratification. Myocardial amyloid burden can be quantified by 18F-florbetapir positron emission tomography (PET), but its prognostic value is not known. Purpose To test our hypothesis that (1) myocardial amyloid burden predicts adverse outcomes and (2) the relationship between amyloid burden and adverse outcomes is mediated by cardiomyocyte stretch and injury. Amyloid burden was estimated by left ventricular 18F-florbetapir retention index (RI) and cardiomyocyte stretch and injury by NT proBNP and troponin T respectively. Methods We performed 18F-florbetapir PET (median dose 9.05 mCi) in prospectively enrolled subjects with newly diagnosed AL amyloidosis with abnormal cardiac biomarkers or with normal cardiac biomarkers and normal left ventricular wall thickness (NCT02641145). Left ventricular RI was calculated as the activity concentration between 10 and 30 min. after injection divided by the integral of the left atrial blood time-activity curve from 0 to 20 min. RI was categorized as normal (&amp;lt;0.06/min, based on controls), increased (0.06–0.12/min), or high risk (&amp;gt;0.12/min, based on log-rank statistic maximization). Mayo stages I–IV were based on elevated serum cardiac biomarkers: NT-proBNP ≥1800 pg/ml, troponin T ≥0.025 ng/ml, and difference in free light chains ≥180 mg/l. Adverse outcomes of all-cause death or heart failure hospitalization were evaluated. Survival analysis was performed using Kaplan-Meier and Cox regression including Mayo stage and RI. Mediation analysis was used to elucidate the role of cardiomyocyte stretch (as NT-proBNP) and injury (as troponin T) in the association between amyloid burden estimated by RI and adverse outcomes. Results We studied 80 subjects with median age 62 years (IQR 57–67), 46 men (57%), 60 with abnormal cardiac biomarkers (75%), and median RI of 0.10/min (IQR 0.06–0.16). At follow-up (median 15 months), adverse outcomes occurred in 34 subjects (42%), with 17 deaths (21%) and 23 heart failure hospitalizations (29%). The incidence of adverse outcomes increased across Mayo stages from 9% to 44% (log-rank p&amp;lt;0.001), and across RI levels from 29% to 57% (log-rank p=0.037, Figure 1). In multivariable Cox regression, only Mayo stage independently predicted adverse outcomes (HR 2.0 [95% CI 1.4–3.0], p&amp;lt;0.001). Multivariable mediation analysis showed that 83% of the association between RI and adverse outcomes was mediated by NT-proBNP (p&amp;lt;0.001, Figure 2), without contribution from troponin T. Conclusion Myocardial amyloid burden estimated by F-18 florbetapir RI predicts adverse outcomes in AL amyloidosis, but not independently of Mayo stage. Cardiomyocyte stretch mediates the relationship between myocardial amyloid burden and adverse outcomes in AL amyloidosis. Funding Acknowledgement Type of funding sources: Private company.

Cardiac Amyloidosis with a Dilated Phenotype: Participant or Bystander?

<h3>Purpose</h3> Transthyretin amyloidosis (ATTR) is an increasingly recognized cause of cardiomyopathy (CMY). Both genetic variant (v-ATTR) and wild-type (wt-ATTR) amyloidosis present with a restrictive phenotype characterized by thick ventricular walls, small ventricular cavity, and left atrial enlargement. We present a series of 4 patients (pts) with non-restrictive phenotypes that were identified to have cardiac amyloidosis at heart transplant (HT). <h3>Methods</h3> Between 11/2019 to 10/2020, 4/121 heart explants were identified with a non-restrictive phenotype and amyloid deposition. All 4 pts were male, 3 were black, and only Case 1 had a history of coronary artery disease. Pre-HT transthoracic echocardiograms (TTE) were reviewed. Explants were evaluated by gross examination, light microscopy, immunohistochemical staining (kappa light chains, lamba light chains, beta-2-microglobulin, amyloid A, transthyretin), and mass spectrometry. <h3>Results</h3> Pre-HT TTE demonstrated low EF, normal left ventricular (LV) wall thickness, and LV dilation in all cases (>95^th percentile for height and gender). The mean LV end diastolic internal diameter (LVIDd) was 69 mm (range 61-80) and LVIDd adjusted for body surface area was 36 mm/m² (range 28-48). There was no evidence of ventricular wall thickening. Mean LV EF was 19% (range 15-25) and 3 pts had moderate right ventricular dysfunction. Explant pathology was notable for interstitial and perivascular Congo Red positive deposits. Mass spectrometry confirmed presence of v-ATTR (3 cases) and amyloidosis leukocyte chemotactic factor 2 (ALECT2) (1 case). In 2 cases, amyloid deposits were found diffusely throughout the myocardium. <h3>Conclusion</h3> Amyloid CMY can present with a dilated phenotype composed of marked LV dilation and normal wall thickness. Further research is needed to determine the contribution of amyloidosis to the development of dilated cardiomyopathy as seen in these cases. Additionally, the relationship of non-ATTR genetics to typical and atypical cardiac amyloid phenotypes is unknown.

Cardiac manifestations of fabry disease in female patients: a single centre experience

Abstract Introduction Fabry disease is a lysosomal storage disorder resulting in multisystemic effects due to deposition and accumulation of glycosphingolipids. Although an X linked disorder, it is recognised that female heterozygotes can express clinical manifestations. Cardiac expression in the female Fabry population remains incompletely understood. Data from the Fabry Outcome Survey suggests that up to a quarter of female patients demonstrate left ventricular hypertrophy (LVH) on echocardiography. Although LVH is the most commonly cited cardiac finding, other abnormalities from clinical surveillance can include electrocardiographic abnormalities, fibrosis and elevated troponin levels. Purpose To establish the prevalence and extent of cardiac involvement amongst our cohort of female Fabry patients. Methods Heterozygous females, confirmed by genetic testing, were identified in our single centre Fabry database. Data was collected retrospectively on their 12 lead ECG, high sensitivity troponin I level and echocardiography performed at their most recent cardiac Fabry clinic visit, along with the most recent cardiac magnetic resonance imaging (CMR). Values are expressed as mean ± SD. Results 51 female heterozygotes were identified, ranging from 23 to 83 years (mean age 49.3±15.4). 28 (54.9%) were established on enzyme replacement therapy. On echocardiography LVH of ≥13mm was identified in 14 (27.5%) patients (mean 14.6±1.9 mm). 44 patients had CMR and of these, 17 (38.6%) had findings in keeping with a Fabry cardiomyopathy (34.1% had fibrosis, 15.9% hypertrophy, 13.6% both). Of the 17 patients with abnormalities on CMR, 8 had normal left ventricular wall thickness on echocardiography. All patients had a high sensitivity troponin I measurement and this was above upper reference limits (&amp;gt;40ng/L) in 21 (41.1%) patients in the absence of chest pain. Of 21 patients with abnormal troponin I levels, 9 had normal left ventricular wall thickness on echocardiography. Abnormalities identified on 12 lead ECG are summarised in Table 1. All patients with ECG abnormalities listed in Table 1 had an abnormal troponin and/or abnormal imaging, except for 5 patients who had an isolated short PR interval. 6 patients had a permanent pacemaker and 1 had a primary prevention implantable cardioverter defibrillator. 25 (49%) of the 51 patients were classed as having cardiac involvement based on raised troponin levels and/or abnormal imaging findings. Conclusion Although Fabry disease is traditionally thought to be a male predominant disease, in our cohort nearly half of our female heterozygotes showed evidence of cardiac involvement. The use of CMR, cardiac biomarkers and 12 lead ECG are helpful adjuncts to identify cardiac involvement, which could otherwise be missed if stand-alone echocardiography was used. Timely identification and monitoring of cardiac involvement has clinical implication, especially with regards to prognosis and treatment. Funding Acknowledgement Type of funding sources: None.

Prognostic Significance of Nonischemic Myocardial Fibrosis in Patients With Normal LV Volumes and Ejection-Fraction

ObjectivesThis study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction. BackgroundNonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain. MethodsPatients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD). ResultsOf 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001). ConclusionsThere was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia.

Basal Segmental Longitudinal Strain: A Marker of Subclinical Myocardial Involvement in Anderson-Fabry Disease

Cardiac involvement in Anderson-Fabry disease (AFD) is associated with increased left ventricular (LV) wall thickness. The aim of this study was to evaluate if two-dimensional global and regional strain in patients with AFD can identify early myocardial involvement (when LV wall thickness and function are normal). Additionally, the association of altered strain with adverse cardiovascular events was evaluated. In a retrospective cross-sectional study, 43 patients with AFD, before enzyme replacement therapy (mean age, 44±12years; 58.1% men), were compared with age- and gender-matched healthy control subjects. The mean follow-up duration among patients with AFD for major adverse cardiovascular events (MACE) was 82months. LV ejection fraction was similar between groups (patients with AFD vs control subjects, 61±8% vs 61±6%; P=.89). However, global longitudinal strain (LS) was impaired in patients with AFD compared with control subjects (-16.5±3.8% vs -20.2±1.7%, P<.001), with greater impairment in patients with AFD with increased LV wall thickness (-15.4±3.9% vs -18.7±2.3%, P<.006). Additionally, LS was most impaired in the basal segments in patients with AFD (-14.8±3.7% vs -20.3±1.1%, P<.001). MACE occurred in 19 of 43 patients (four women, 15 men), and Kaplan-Meier analysis demonstrated that MACE were associated with impaired basal LS. In patients with AFD, altered basal LS is present even in those with normal LV wall thickness and is associated with MACE. Therefore, basal LS should be considered when screening for cardiac involvement inAFD, particularly in female patients with AFD with normal LV wall thickness.

Pathological changes of myocardium in the model of chronic renal insufficiency at application of low-protein diet

Myocardial damage in patients with chronic renal failure histologically manifests as hypertrophy of cardiomyocytes, intramyocardial artery walls, development of diffuse sclerosis and a change in the number of capillaries. One of the components in the complex treatment of this category of patients is a low-protein diet, however, to date there is no data on the effect of a low-protein diet on structural changes in the myocardium. The aim of the work was to assess the effect of low protein diet on myocardial structural changes in the experimental model of chronic renal failure. To reproduce the experiment of chronic renal failure, a standardized 5/6 nephrectomy model was used in wistar rats. To determine the effect of a low-protein diet on structural changes in the myocardium, two types of diet were used - a standard one and a low-protein diet (Ketosteril). The animals were sacrificed 4 months after nephrectomy. For a comparative assessment of the effect of low-protein diet on structural changes in the myocardium, histological methods of investigation and morphometry were used. The use of low-protein diet was accompanied by a less pronounced violation of biochemical blood parameters (creatinine, urea, calcium, phosphorus), as well as maintaining normal blood pressure, myocardial mass and left ventricular wall thickness. Histologically, this was manifested by a decrease in the severity of dystrophic changes in cardiomyocytes, the degree of their hypertrophy, a decrease in the area of nuclei, and a decrease in the nuclear-cytoplasmic ratio. Indices of perivascular and diffuse sclerosis were lower compared with the control group. Also, when using low-protein diet in animals with a chronic renal failure model, a decrease in the total cross-sectional area of capillaries was noted with an increase in their number in comparison with animals of the control group. Thus, the use of a low-protein diet in an experimental model of chronic renal failure has a cardioprotective effect by reducing the severity of uremia and stabilizing biochemical parameters.

Oral delivery of xenon for cardiovascular protection

Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.

An Update on Pediatric Cardiomyopathy.

This review summarizes the clinical characteristics and updated outcomes of primary pediatric cardiomyopathies including dilated (DCM), hypertrophic (HCM), and restrictive cardiomyopathy (RCM), and briefly discusses left ventricular non-compaction (LVNC) and arrhythmogenic cardiomyopathy (ACM), primarily arrythmogenic right ventricular cardiomyopathy (ARVC). Pediatric cardiomyopathies are diseases of the heart muscle with an estimated annual incidence of 1.1-1.5 cases per 100,000. They are progressive in nature and are frequently caused by a genetic mutation causing a structural abnormality in the myocyte. Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with normal left ventricular wall thickness, accounts for about 50-60% of all pediatric cardiomyopathy cases. This is followed by hypertrophic cardiomyopathy accounting for about 40%, characterized by abnormally thickened myocardium in the absence of another cause of hypertrophy with non-dilated left ventricle. Left ventricular non-compaction and restrictive cardiomyopathy each account for about 5% of the cases. Genetic mutations play a dominant role in the development of pediatric cardiomyopathies. While treatment for congestive heart failure and arrhythmias alleviates symptoms, it has not been shown to reduce the risk of sudden death. The 5-year transplant-free survival of DCM, HCM, RCM, and LVNC are 50%, 90%, 30%, and 60% respectively. Pediatric cardiomyopathies while not common they are a significant cause of morbidity and mortality in afflicted children. Dilated forms are the most common followed by hypertrophic, left ventricular non-compaction, and restrictive cardiomyopathies. Arrhythmogenic cardiomyopathies tend to be diagnosed later in the teenage years. Treatment typically follows adult recommendations for which there is significantly more data on treatment benefits, although the indications for ICD placement in children remain even less clear, other than for secondary prevention.

Intrinsic mitral valve alterations in hypertrophic cardiomyopathy sarcomere mutation carriers.

Mitral valve (MV) abnormalities are recognized features of hypertrophic cardiomyopathy (HCM), and there is preliminary evidence suggesting they are intrinsic phenotypic manifestations of sarcomere mutations, present in mutation carriers without left ventricular (LV) hypertrophy (subclinical HCM). However, further study is required to characterize the nature of these changes and their functional impact. Thus, we performed comprehensive echocardiographic analysis of MV structure and function on a genotyped population. MV and papillary muscle echocardiographic parameters were measured in 192 genotyped individuals, including 50 overt HCM, 79 subclinical HCM, and 63 mutation-negative, healthy relatives as normal controls. Compared to controls, subclinical HCM subjects had elongated anterior MV leaflets relative to LV end-diastolic volume index (0.57 ± 0.02 vs. 0.51 ± 0.02 mm/mL/m2, P = 0.013) and anteriorly displaced papillary muscles [decreased papillary-septal separation (31.1 ± 0.7 vs. 34.2 ± 0.9 mm, P = 0.004) and relative antero-posterior position ratio of the papillary muscles (0.67 ± 0.01 vs. 0.71 ± 0.01, P = 0.011]. Similar findings were identified comparing overt HCM to controls. These MV changes were associated with an increased prevalence of systolic anterior motion (SAM) of the MV amongst subclinical HCM subjects. Sarcomere mutations are associated with primary abnormalities of the MV apparatus, specifically excess anterior leaflet length relative to LV cavity size and anterior displacement of the papillary muscles; both features predisposing to SAM. These abnormalities appear to be early phenotypic consequences of sarcomere mutations, observed in mutation carriers with normal LV wall thickness.

Right ventricular involvement in transthyretin amyloidosis

Background: The extent of right ventricular (RV) involvement in transthyretin amyloidosis (ATTR) is unknown.Objectives: This study sought to establish the degree of RV involvement in ATTR amyloidosis, and compare findings with RV involvement in hypertrophic cardiomyopathy (HCM).Methods: Forty-two patients with ATTR amyloidosis and echocardiographic evidence of cardiac amyloidosis (cardiac ATTR), 19 ATTR patients with normal left ventricular (LV) wall thickness (non-cardiac ATTR), 25 patients with diagnosed HCM and 30 healthy controls were included in this study. Echocardiographic measurements for conventional parameters, as well as RV global and segmental strain, were recorded.Results: When comparing RV structure and function between cardiac ATTR amyloidosis and HCM patients, only segmental strain differed between the two groups. In cardiac ATTR amyloidosis, we found an RV apex-to-base strain gradient with highest deformation in the apex. This pattern was reversed in patients with HCM.Conclusions: RV involvement is common in cardiac ATTR patients. The present study also detected an RV apical sparing pattern in patients with ATTR cardiomyopathy, similar to what has previously been described for the left ventricle in these patients. This pattern was not seen in HCM patients. Further studies are needed to assess the clinical importance of these findings.

Abnormal stress echocardiography findings in cardiac amyloidosis

Background: Cardiac involvement in immunoglobulin light chain (amyloid light chain, AL) amyloidosis is characterized by myocardial interstitial deposition but can also cause obstructive deposits in the coronary microvasculature.Methods: We retrospectively identified 20 patients who underwent stress echocardiography within 1 year prior to the histologic diagnosis of AL amyloidosis. Only patients with cardiac amyloidosis and no known obstructive coronary disease were included.Results: Stress echocardiograms (13 exercise; 7 dobutamine) were performed for evaluation of dyspnea and/or chest pain. Stress-induced wall motion abnormalities (WMAs) occurred in 11 patients (55%), 4 of whom had normal left ventricular wall thickness. Coronary angiogram was performed in 9 of 11 patients and demonstrated no or mild epicardial coronary artery disease. Seven (54%) patients had an abnormal exercise blood pressure which occurred with similar likelihood between those with and without stress-induced WMAs.Conclusions: Stress-induced WMAs and abnormal exercise blood pressure may occur in patients with cardiac AL amyloidosis despite the absence of significant epicardial coronary artery disease. This finding should raise the possibility of cardiac amyloidosis even in the absence of significant myocardial thickening.

Abstract 15554: Heart Failure-Related Hyperphosphorylation of Ser199 on Cardiac Troponin I Causes Divergent Effects on Cardiac Function at Baseline and During Ischemia-Reperfusion

Background: Phosphorylation of cardiac troponin I (cTnI) on Ser199 is significantly increased in human heart failure (HF), however its cardiac impact in vivo remains unknown. In addition, selective proteolysis of cTnI is a marker of myocardial injury and contributes to cardiac dysfunction in ischemia/reperfusion (I/R), and Ser199 phosphorylation affects cTnI proteolysis in vitro, thus whether Ser199 phosphorylation affects cardiac performance during I/R is of great interest. Methods and Results: We generated transgenic mice (TgS200D) carrying cTnI S200D mutation to mimic the site-specific hyperphosphorylation of murine Ser200 (equivalent to human Ser199). Cardiac function was first assessed in vivo using echocardiography. TgS200D mice demonstrated unaltered ejection fraction (EF), significantly prolonged isovolumic relaxation time, and normal left ventricular (LV) chamber size and wall thickness (n=10). LV pressure-volume studies showed preserved dp/dtmax, significantly decreased -dp/dtmin and increased relaxation time constant in TgS200D when compared to non-transgenic (NTg) control group at baseline (n=10). With increasing heart rates, the two groups showed similar enhancement in both systolic and diastolic function, suggesting the positive force-frequency relation is preserved in TgS200D (n=5). After isoproterenol injection (i.v. 40ng/min/kg), although a comparable increase in dp/dtmax was observed in both groups, there was no enhancement of -dp/dtmin in TgS200D in contrast to 15% of increase in NTg (n=5, p=0.019). After ischemia (30 min)/reperfusion (60 min), LV developed pressure was recovered by ~90% in isolated TgS200D hearts but only ~40% in NTg (n=5, p=0.003). Immunoblotting detected cTnI cleavage only in NTg hearts. Conclusions: Our results indicate that hyperphosphorylation of cTnI Ser199 1) impairs basal diastolic function but preserves systolic function, without LV hypertrophy or dilation; 2) blunts cardiac lusitropic response to β-adrenergic stimulation with isoproterenol; 3) protects heart against I/R injury, likely via preventing cTnI degradation. We propose a dual role of cTnI Ser199 hyperphosphorylaiton: contributing to HF with preserved EF but protecting heart during I/R.

Hypertrophic cardiomyopathy: still connecting the dots between genotype and phenotype.

The current era of cardiac magnetic resonance (CMR) imaging has resulted in a resurgence of interest in hypertrophic cardiomyopathy (HCM). We are now much more aware of the various phenotypic expressions of this disease, which can manifest with typical septal thickening or other variants of hypertrophy, such as apical, midwall or concentric. Additionally, CMR has enabled us to appreciate the wide variety of abnormalities in papillary muscle morphology, which in some cases can contribute to left ventricular outflow tract or mid-cavitary level obstruction (1). In some subjects, mitral valve elongation, myocardial crypts, prominent apical trabeculation, papillary muscle thickening (with or without apical displacement) and abnormal chordal attachments may be subtle phenotypic HCM variants, despite normal left ventricular wall thickness. These abnormalities may be symptomatic to varying degrees or remain subclinical and be noted incidentally or on HCM familial screening programs. Whether these subjects will go on to develop progressive left ventricular hypertrophy (LVH) or whether they are manifesting incomplete phenotypic penetrance of the disease process remains unclear.