Publications by authors named "Chris Semsarian"

18 Publications

  • Page 1 of 1

Harmonizing the Collection of Clinical Data on Genetic Testing Requisition Forms to Enhance Variant Interpretation in Hypertrophic Cardiomyopathy (HCM): A Study from the ClinGen Cardiomyopathy Variant Curation Expert Panel.

J Mol Diagn 2021 Feb 22. Epub 2021 Feb 22.

Invitae Corporation, San Francisco, California; Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.

Diagnostic laboratories gather phenotypic data through requisition forms but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic dataset for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal dataset. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50 case pilot showed that while demographics and assertion of a clinical diagnosis of HCM had 86-98% completion, specific phenotypic features such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease were completed only 24-44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group such as the ClinGen Program in order to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.
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http://dx.doi.org/10.1016/j.jmoldx.2021.01.014DOI Listing
February 2021

Can post-mortem coronary artery calcium scores aid diagnosis in young sudden death?

Forensic Sci Med Pathol 2021 Mar 14;17(1):27-35. Epub 2020 Nov 14.

Victorian Institute of Forensic Medicine, 65 Kavanagh St, Southbank, VIC, 3006, Australia.

This study sought to explore the feasibility and utility of post-mortem coronary artery calcium (CAC) scoring in identifying patients with ischemic heart disease as cause of sudden death. 100 deceased patients aged 18-50 years underwent post-mortem examination in the setting of sudden death. At post-mortem, fifty cases were determined to have ischemic heart disease, and fifty had death attributed to trauma or unascertained causes. The CAC score was calculated in a blinded manner from post-mortem CTs performed on all cases. CAC scores were assessable in 97 non-decomposed cases (feasibility 97%). The median CAC score was 88 Agatston units [IQR 0-286] in patients deceased from ischemic heart disease vs 0 [IQR 0-0] in patients deceased from other causes (p < 0.0001). Presence of any coronary calcification differed significantly between ischemic heart disease and non-ischemic groups (adjusted odds ratio 10.7, 95% CI 3.2-35.5). All cases with a CAC score > 100 (n = 22) had ischemic heart disease as the cause of death. Fifteen cases had a CAC score of zero but severe coronary disease at post-mortem examination. Post-mortem CAC scoring is highly feasible. An elevated CAC score in cases 18-50 years old with sudden death predicts ischemic heart disease at post-mortem examination. However, a CAC score of zero does not exclude significant coronary artery disease. Post-mortem CAC score may be considered as a further assessment tool to help predict likely cause of death when there is an objection to or unavailability of post-mortem examination.
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http://dx.doi.org/10.1007/s12024-020-00335-zDOI Listing
March 2021

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions.

Genet Med 2021 Jan 13;23(1):69-79. Epub 2020 Oct 13.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene-disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance.

Methods: We developed a disease-specific variant classifier, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias. We assessed CardioBoost's ability to discriminate known pathogenic from benign variants, prioritize disease-associated variants, and stratify patient outcomes.

Results: CardioBoost has high global discrimination accuracy (precision recall area under the curve [AUC] 0.91 for cardiomyopathies; 0.96 for arrhythmias), outperforming existing tools (4-24% improvement). CardioBoost obtains excellent accuracy (cardiomyopathies 90.2%; arrhythmias 91.9%) for variants classified with >90% confidence, and increases the proportion of variants classified with high confidence more than twofold compared with existing tools. Variants classified as disease-causing are associated with both disease status and clinical severity, including a 21% increased risk (95% confidence interval [CI] 11-29%) of severe adverse outcomes by age 60 in patients with hypertrophic cardiomyopathy.

Conclusions: A disease-specific variant classifier outperforms state-of-the-art genome-wide tools for rare missense variants in inherited cardiac conditions ( https://www.cardiodb.org/cardioboost/ ), highlighting broad opportunities for improved pathogenicity prediction through disease specificity.
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http://dx.doi.org/10.1038/s41436-020-00972-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790749PMC
January 2021

Prevalence of Anderson-Fabry disease in a cohort with unexplained late gadolinium enhancement on cardiac MRI.

Int J Cardiol 2020 04 30;304:122-124. Epub 2019 Dec 30.

Royal Prince Alfred Hospital, Sydney, Australia; The University of Sydney, Australia.

Introduction: Fabry disease is a rare X-linked genetic disorder in which cardiac manifestations include LVH, contractile dysfunction, and fibrosis, visible on cardiac MRI (cMRI) as late gadolinium enhancement (LGE) of the myocardium. Fabry's disease is an important diagnosis to make as treatment is available as lifelong replacement of the deficient enzyme.

Aim: To define the prevalence of Fabry disease in a cohort of patients with unexplained LGE on cMRI.

Methods: The study population was recruited from patients aged >16 years who had cMRI performed between 2010 and 2018 to investigate LVH, idiopathic LV dysfunction and/or idiopathic ventricular arrhythmia. Patients with 'unexplained' LGE i.e. without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid, were tested for Fabry disease by either genetic testing or the Dried Blood Spot test (Sanofi-Genzyme).

Results: Of the 79 patients with unexplained LGE on cMRI, 2 patients tested positive for Fabry disease, both using genetic sequencing techniques. The prevalence of Fabry disease in this selected cohort was 2.5%. Specifically, 1 patient was a 65 year old male and the other patient a 75 year old female. In both cases, the pattern and distribution of LGE on cMRI was of patchy mid-wall enhancement in the inferoseptum.

Conclusion: Unexplained LGE on cMRI may be an isolated manifestation of late-onset Fabry disease. This finding should prompt testing for Fabry disease given this is a potentially treatable condition.
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http://dx.doi.org/10.1016/j.ijcard.2019.12.059DOI Listing
April 2020

Audit of a cardiac screening policy for elite Australian cricketers.

J Sci Med Sport 2020 Jun 28;23(6):541-547. Epub 2019 Dec 28.

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute and The University of Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

Objectives: To report the compliance and results of an electrocardiogram (ECG) cardiac screening program in male and female elite Australian cricketers.

Design: cross-sectional study.

Methods: Elite cricketers were offered screening in accordance with Cricket Australia policy. Players who consented provided a personal and family history, physical examination and resting 12-lead ECG. An audit (1 February 2019) examined all cardiac screening records for male and female players in all Australian Cricket state squads from 16 years upwards. Data extracted from the Cricket Australia database included the number of players who underwent screening; signed waivers opting out; and had follow-up tests. ECGs were re-reviewed according to the International Criteria.

Results: 710 players were included in the cohort (mean age 20.4±4.9 years, 62% male). 692 (97.5%) players underwent recommended cardiac screening or signed a waiver opting out (1.1%). 173 (24.4%) players were screened (or signed a waiver) more than once. Follow-up testing was conducted for 59 (6.9%) cases. No players were excluded from sport due to a cardiac problem and no major cardiac incidents occurred to any player in the audit cohort. Review of 830 ECGs showed benign athlete heart changes, including sinus bradycardia (33.5%), left ventricular hypertrophy (16.3%), and incomplete/partial right bundle branch block (8.4%), were common but abnormal screening ECGs were uncommon (2.0%).

Conclusions: An audit of a cardiac screening program in elite Australian cricketers found excellent compliance. A small proportion required follow-up testing and no player was excluded from sport due to a cardiac problem. ECG analysis suggested cricket is a sport of moderate cardiac demands, with benign athlete heart changes common.
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http://dx.doi.org/10.1016/j.jsams.2019.12.025DOI Listing
June 2020

The Cardiac Society of Australia and New Zealand Position Statement on the Diagnosis and Management of Arrhythmogenic Right Ventricular Cardiomyopathy (2019 Update).

Heart Lung Circ 2020 Jan 23;29(1):40-48. Epub 2019 Apr 23.

The Prince Charles Hospital, University of Queensland, Brisbane, Qld, Australia.

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http://dx.doi.org/10.1016/j.hlc.2019.02.194DOI Listing
January 2020

Assessment of myocardial oxygenation, strain, and diastology in MYBPC3-related hypertrophic cardiomyopathy: a cardiovascular magnetic resonance and echocardiography study.

Eur Heart J Cardiovasc Imaging 2019 Aug;20(8):932-938

Flinders Medical Centre, 1 Flinders Drive, Bedford Park, Adelaide, Australia.

Aims: Myocardial oxygenation is impaired in hypertrophic cardiomyopathy (HCM) patients with left ventricular hypertrophy (LVH), and possibly also in HCM gene carriers without LVH. Whether these oxygenation changes are also associated with abnormalities in diastolic function or left ventricular (LV) strain are unknown.

Methods And Results: We evaluated 60 subjects: 20 MYBPC3 gene positive patients with LVH (G+LVH+), 18 MYBPC3 gene positive without LVH (G+LVH-), 11 gene negative siblings (G-), and 11 normal controls (NC). All subjects underwent 2D transthoracic echocardiography and cardiovascular magnetic resonance imaging for assessment of ventricular volumes, mass, and myocardial oxygenation at rest and adenosine stress using the blood oxygen level dependent (BOLD) technique. Maximal septal thickness was 20 mm in the G+LVH+ group, vs. 9 mm for the G+LVH- group. As expected, the G+LVH+ group had a more blunted myocardial oxygenation response to stress when compared with the G+LVH- group (-5% ± 3% vs. 2% ± 4%, P < 0.05), G- siblings (-5% ± 3% vs. 11% ± 4%, P < 0.0001) and NC (-5% ± 3% vs. 15% ± 4%, P < 0.0001). A blunted BOLD response to stress was also seen in G+LVH- subjects when compared with gene negative siblings (2% ± 4% vs. 11% ± 4%, P < 0.05) and NC (15% ± 4%, P < 0.050). G+LVH+ patients exhibited abnormal diastolic function including lower E', higher E to E' ratio and greater left atrial area compared with the G+LVH- subjects who all had normal values for these indices.

Conclusion: Myocardial deoxygenation during stress is observed in MYBPC3 HCM patients, even in the presence of normal LV diastolic function, LV global longitudinal strain, and LV wall thickness.
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http://dx.doi.org/10.1093/ehjci/jey220DOI Listing
August 2019

Long-Term Outcomes of Hypertrophic Cardiomyopathy Diagnosed During Childhood: Results From a National Population-Based Study.

Circulation 2018 07 28;138(1):29-36. Epub 2018 Feb 28.

Royal Children's Hospital, Melbourne, Australia (P.M.A.A., A.M.D., R.G.W.).

Background: Late survival and symptomatic status of children with hypertrophic cardiomyopathy have not been well defined. We examined long-term outcomes for pediatric hypertrophic cardiomyopathy.

Methods: The National Australian Childhood Cardiomyopathy Study is a longitudinal population-based cohort study of children (0-10 years of age) diagnosed with cardiomyopathy between 1987 and 1996. The primary study end point was time to death or cardiac transplantation.

Results: There were 80 patients with hypertrophic cardiomyopathy, with a median age at diagnosis of 0.48 (interquartile range, 0.1, 2.5) years. Freedom from death/transplantation was 86% (95% confidence interval [CI], 77.0-92.0) 1 year after presentation, 80% (95% CI, 69.0-87.0) at 10 years, and 78% (95% CI, 67.0-86.0) at 20 years. From multivariable analyses, risk factors for death/transplantation included symmetrical left ventricular hypertrophy at the time of diagnosis (hazard ratio, 4.20; 95% CI, 1.60-11.05; =0.004), Noonan syndrome (hazard ratio, 2.88; 95% CI, 1.02-8.08; =0.045), higher posterior wall thickness score (hazard ratio, 1.45; 95% CI, 1.22-1.73; <0.001), and lower fractional shortening score (hazard ratio, 0.84; 95% CI, 0.74-0.95; =0.005) during follow-up. Nineteen (23%) subjects underwent left ventricular myectomy. At a median of 15.7 years of follow-up, 27 (42%) of 63 survivors were treated with β-blocker, and 13 (21%) had an implantable cardioverter-defibrillator.

Conclusions: The highest risk of death or transplantation for children with hypertrophic cardiomyopathy is within 1 year after diagnosis, with low attrition rates thereafter. Many subjects receive medical, surgical, or device therapy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028895DOI Listing
July 2018

NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy.

J Cardiovasc Electrophysiol 2015 Dec 13;26(12):1346-51. Epub 2015 Oct 13.

Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand.

Introduction: The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM.

Methods And Results: This HCM registry-based study included patients with an ECG, medical history, first SCD event data, and DNA available. Each individual SNP was assessed using logistic regression for associations with 2 outcomes: a prolonged QTc ( ≥440 milliseconds), and first SCD event (SCD, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock for ventricular fibrillation/ventricular tachycardia (VF/VT). In 272 HCM patients, there were 31 SCD events (8 SCD, 9 resuscitated cardiac arrest, 14 ICD shocks for VF/VT; 11%). A QTc ≥ 500 milliseconds was associated with SCD events on multivariate analysis (odds ratio [OR] = 4.0, 95% confidence interval [CI], 1.19-12.02, P = 0.016). In 228 Caucasian patients, 2 SNPs in the NOS1AP gene (rs10494366 and rs12143842) were associated with a prolonged QTc after correction for multiple testing. This remained significant after adjustment for current age, sex, and ≥1 SCD risk factor (OR 1.59 per copy of the minor allele, 95% CI 1.08-2.39, P = 0.022, and OR 1.63, 95% CI 1.09-2.49, P = 0.020, respectively). No SNPs were directly associated with SCD events.

Conclusion: SNPs in the NOS1AP gene influence QTc interval duration but we have not demonstrated a direct association with the risk of SCD.
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http://dx.doi.org/10.1111/jce.12827DOI Listing
December 2015

Surgery for hypertrophic cardiomyopathy.

Biophys Rev 2015 Mar 10;7(1):117-125. Epub 2015 Jan 10.

Sydney Medical School, The University of Sydney, Sydney, Australia.

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2 %, excellent long-term survival that matches the general population, and durable relief of symptoms.
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http://dx.doi.org/10.1007/s12551-014-0153-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418425PMC
March 2015

Impact of new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Int J Cardiol 2014 Feb 4;171(2):179-83. Epub 2013 Dec 4.

Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that can lead to sudden cardiac death. The diagnostic criterion has recently been revised and through the use of cardiac magnetic resonance (CMR) imaging this study aimed to assess the clinical impact of comparing the original 1994 task force (TF) criterion to the revised 2010 criterion.

Methods: We evaluated 173 consecutive CMR scans of patients referred with clinical suspicion of ARVC between 2008 and 2011. We then compared the prevalence of major and minor CMR criteria by applying the two criteria.

Results: Using the 1994 TF criterion, 13 (7.5%) patients had definite, 11 (6.4%) had borderline, and 39 (22.5%) had possible ARVC. Using the 2010 TF criterion, 10 (5.8%) patients had definite, 1 had borderline, and 7 had (0.04%) possible ARVC. With the 1994 criterion, 81 patients satisfied CMR criterion, of which 36 (44%) had major and 45 (56%) had minor criteria. Upon reclassification with the revised criterion, 61 of the 81 patients were not assigned any criteria, even though many patients had significant risk factors. The negative predictive values (NPV) for both CMR criteria were 100% but the positive predictive values (PPV) for combined CMR major or minor criteria improved from 23% to 55%.

Conclusions: Revision of the criterion has enhanced the diagnostic capabilities of CMR but has resulted in a large cohort of patients not classified. In these patients, there is presently no official consensus on imaging or clinical strategy for surveillance of the evolution of pathology over time.
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http://dx.doi.org/10.1016/j.ijcard.2013.11.092DOI Listing
February 2014

No association of G-protein-coupled receptor kinase 5 or β-adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort.

Eur J Heart Fail 2013 Jul;15(7):730-3

North Shore Heart Research Centre, University of Sydney, Australia.

Aims: Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the β1-adrenergic receptor (β1AR) and β2AR.

Methods And Results: We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor α (ERα) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean ± SD = 66.3 ± 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci.

Conclusion: In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERα, β1AR, β2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome.
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http://dx.doi.org/10.1093/eurjhf/hft040DOI Listing
July 2013

Respiratory distress and perinatal lethality in Nedd4-2-deficient mice.

Nat Commun 2011 ;2:287

Department of Haematology, Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia.

The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2(-/-) animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2(-/-) animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival.
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http://dx.doi.org/10.1038/ncomms1284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104547PMC
August 2011

Comparison of left atrial phasic function in hypertrophic cardiomyopathy versus systemic hypertension using strain rate imaging.

Am J Cardiol 2011 Jan 2;107(2):290-6. Epub 2010 Dec 2.

Westmead Hospital, University of Sydney, Australia.

The aim of this study was to determine if left atrial (LA) phasic function evaluated by Doppler tissue imaging-derived strain and strain rate would be differentially decreased in patients with hypertrophic cardiomyopathy (HC) compared to patients with hypertension and to normal controls. Thirty-seven patients with HC were compared to 44 patients with systemic hypertension (SH) and 65 normal controls using transthoracic echocardiography. Maximal and minimal LA volume and LA volume just before active atrial contraction (pre-P LA volume) were measured, and phasic LA volumes were calculated. Global and segmental systolic strain rate, early diastolic strain rate, and late diastolic strain rate (A-Sr) and strain were measured from Doppler tissue imaging. Left ventricular mass was increased in the HC and SH groups compared to normal controls, but diastolic dysfunction was greater in the HC group. LA volumes were increased in patients with HC compared to those with SH and to normal controls, with corresponding reductions in A-Sr and atrial strain in the HC group. In contrast, only early diastolic strain rate was decreased in the SH group compared to controls. A-Sr remained reduced in patients with HC compared to the SH group, even after adjusting for left ventricular mass. When left ventricular mass, parameters of diastolic function (peak E and E' velocity), and the effect of patient group (SH vs HC) were examined in a stepwise regression model, patient group (SH vs HC) was the only independent determinant of A-Sr. In conclusion, HC results in LA enlargement with reduced LA phasic function that is reflected in reductions in A-Sr and atrial strain. Atrial enlargement is a likely consequence of the greater diastolic dysfunction in the HC group.
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http://dx.doi.org/10.1016/j.amjcard.2010.08.071DOI Listing
January 2011

Left atrial phasic volumes are modulated by the type rather than the extent of left ventricular hypertrophy.

J Am Soc Echocardiogr 2010 May 11;23(5):538-44. Epub 2010 Mar 11.

Westmead Hospital, University of Sydney, Sydney, Australia.

Background: The aim of this study was to evaluate whether maximal left atrial (LA) volume and phasic atrial function would be further altered in patients with hypertrophic cardiomyopathy (HCM) compared with patients with systemic hypertension (HT) with similar left ventricular (LV) mass. LA enlargement on echocardiography has been documented in HCM and moderate or severe HT, both conditions causing LV hypertrophy.

Methods: Thirty-five patients with HCM were compared with patients with HT matched for LV mass and normal controls matched for age and gender. Maximal, minimal, and pre-"p" LA biplane and real-time 3-dimensional volumes and LA phasic function were evaluated. Atrial function was estimated by LA ejection force, atrial fraction, and A' velocity.

Results: Maximal, minimal, and pre-"p" LA volumes were significantly increased in the HCM group compared with the HT group and controls. Additionally, LA phasic volumes demonstrated that conduit volume and total, passive, and active emptying fractions were decreased in the HCM group. Despite similar LV mass, the HCM group had a higher incidence of abnormal diastolic filling (60% vs 34%, P = .001).

Conclusions: Patients with HCM appeared to have larger LA volumes, poorer LA function, and greater severity of diastolic dysfunction compared with those with HT having comparable LV mass. LA changes may be due to coexistent atrial myopathy associated with other pathophysiologic aspects of HCM, including outflow obstruction, mitral regurgitation, and myocardial fibrosis in HCM.
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http://dx.doi.org/10.1016/j.echo.2010.01.022DOI Listing
May 2010

A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice.

Hum Mol Genet 2005 Mar 20;14(5):667-77. Epub 2005 Jan 20.

Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

We have identified waved 3 (wa3), a novel recessive mutation that causes abnormalities of the heart and skin. The cardiac defect results in a severe and rapidly progressive dilated cardiomyopathy. We identified the gene mutated in these mice, which we call NFkB interacting protein1 (Nkip1), using positional cloning. Nkip1 is expressed in skin, heart and vascular endothelium and shares homology with a small family of proteins that play a role in the regulation of transcription factors. A C-terminal fragment of this protein was previously identified as the RelA associated inhibitor (RAI). We show that the full-length protein is larger than previously described, and we confirm that it interacts with NFkB in vivo. Expression analysis of genes known to be regulated by NFkB revealed that Intercellular adhesion molecule 1 (Icam1) expression is consistently elevated in mutant mice. This result suggests that wa3 mutant mice represent a potentially important model for the analysis of the role of inflammatory processes in heart disease.
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http://dx.doi.org/10.1093/hmg/ddi063DOI Listing
March 2005