Harry Graber

The Ohio State University, Columbus, OH, United States

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Publications (7)76.03 Total impact

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    ABSTRACT: A close collaboration between the physicians-scientists of the Division of Cardiology, The Ohio State University and the basic scientists of the Department of Genetics, Harvard Medical School was essential to define the multiple phenotypic expressions and the genetic abnormalities in the heritable conduction and myocardial disease in a family from central Ohio (Family OSU). The Family OSU presents evidence of sequential hierarchical progression through multiple cardiac phenotypes (sinus bradycardia, atrioventricular conduction defects requiring pacemaker, supraventricular arrhythmias including atrial fibrillation, heart failure, and sudden cardiac death) on a decade-to-decade basis. In this setting, each phenotype may be mistakenly considered as a specific diagnosis by physicians working without a pedigree or long-term follow-up. Genetic analysis, however, confirms lamin A/C mutation. The role of the physician-scientist and the basic scientist for the study of heritable disorders is equally important but different. Only the physician-scientist, however, who is in constant contact with the patient understands the complexity of the disease. The physician-scientist with an interest in a particular disease can guide the basic scientist to define molecular mechanisms of that disease and by extension learn important lessons for other diseases.
    No preview · Article · Jun 2011 · Cardiology
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    ABSTRACT: Aims: Family members with a heritable cardiac conduction system and myocardial disease (chromosome 1p1-1q1) manifest: sinus bradycardia, PR interval prolongation, atrial/ventricular arrhythmias, advanced atrioventricular block, congestive heart failure or sudden cardiac death. A ten family members subset with atrial myopathy/atrial fibrillation was evaluated while in sinus rhythm, prior to the development of atrial fibrillation. Multidimensional analysis of atrial function in sinus rhythm provided atrial myopathy diagnostic criteria and evaluated left atrial electromechanical function in atrial myopathy/atrial fibrillation family members over time. Methods and Results: A nine-generation pedigree (n=636) was constructed over a 40-year period; of the 325 family members studied, 106 were affected. Multidimensional analyses of electrical, mechanical and electromechanical left atrial function in ten atrial myopathy/atrial fibrillation family members demonstrated: decreased P wave voltage and increased duration, increased left atrial maximal volume, peak acceleration time, pre-ejection period and ejection time. Follow-up (7-10 years) echocardiographic studies in five atrial myopathy/atrial fibrillation family members showed increased left atrial maximal volume, left atrial and left ventricular diameters. Autopsy confirmed atrial myopathy in one atrial myopathy/atrial fibrillation family member with severe biatrial dilatation, atrial cytoplasmic vacuolization, myocyte hypertrophy and interstitial fibrosis. Conclusions: Multidimension left atrial analyses detected atrial myopathy prior to the development of atrial fibrillation, providing an electrophysiological substrate for the subsequent development of heritable atrial fibrillation. Heritable atrial myopathy and heritable atrial fibrillation emerge as phenotypes within the continuum of heritable cardiac conduction system and myocardial disease.
    No preview · Article · Nov 2000 · European Heart Journal Supplements
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    ABSTRACT: The purpose of this study was to identify the clinical characteristics of family members at risk of sudden death. The significance of sudden death in heritable cardiac disorders with delayed expression is incompletely understood. Additional insights come from a four-decade experience of seven generations of a family of German origin with autosomal dominant (chromosome 1p1-1q1) cardiac conduction and myocardial disease. A total of 38 family members (20 males; 18 females) were identified with sudden death. Twenty-eight family members (mean age 48+/-8 years) from earlier generations had no pacemaker at the time of sudden death. In this group, 15 subjects were asymptomatic prior to sudden death. Ten family members with sudden death, from later generations, had chronically implanted pacemakers for high grade atrioventricular block. This group was older (mean age 57+/-2 years), with decreased functional status (New York Heart Association class II to IV), enlarged left atria, dilated left ventricles with reduced systolic function and documented ventricular fibrillation in three members. Twenty-eight family members with sudden death were descendants of sib lineages 2 or 6; 21 family members with sudden death were offspring of a parent who also suffered sudden death. Sudden death is an important late outcome in heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease. Pacemaker therapy is important for the treatment of symptomatic bradycardia, but it does not prevent sudden death. Family members who are beyond the third decade of life with reduced functional capacity, left ventricular dysfunction, pacemakers and who are the offspring of a parent with sudden death appear to be at greatest risk
    Preview · Article · Dec 1998 · Journal of the American College of Cardiology

  • No preview · Article · Oct 1994 · The American Journal of Cardiology
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    ABSTRACT: Longitudinal evaluation of a seven generation kindred with an inherited conduction system defect and dilated cardiomyopathy demonstrated autosomal dominant transmission of a progressive disorder that both perturbs atrioventricular conduction and depresses cardiac contractility. To elucidate the molecular genetic basis for this disorder, a genome-wide linkage analysis was performed. Polymorphic loci near the centromere of chromosome 1 demonstrated linkage to the disease locus (maximum multipoint lod score = 13.2 in the interval between D1S305 and D1S176). Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy.
    No preview · Article · Sep 1994 · Nature Genetics
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    ABSTRACT: The presence of beta-receptor autoantibodies and their relationship to restriction fragment length polymorphisms of the human leukocyte antigen (HLA) class II genes were studied in 42 affected and unaffected members of a family with a heritable disorder of the conduction system and cardiac muscle. Antibodies were detected in 34% of all members (59% of affected and 22% of unaffected; p < 0.01). Significant differences between affected and unaffected individuals and between anti-beta-receptor antibody positive and negative individuals were noted in the prevalence of polymorphisms obtained with Taq I for the HLA-DR beta and HLA-DQ alpha genes. In affected individuals, there was a strong positive correlation between these polymorphisms and the presence of anti-beta-receptor antibodies. These results suggest that autoimmune mechanisms under the control of the class II genes play an important role in the pathogenesis of familial cardiomyopathy.
    No preview · Article · Feb 1994 · American Heart Journal
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    ABSTRACT: Cardiac autoantibodies have been detected in a significant proportion of patients with dilated cardiomyopathy, but their relation to the pathogenesis of the disease remains unknown. This issue was examined in 41 members of an Ohio family with a heritable disorder of the cardiac conduction system and the myocardium. In 41.5% of all members studied, serum anti-beta-receptor antibodies were identified by a combination of techniques: ligand binding inhibition assay, enzyme-linked immunoassay of a beta 1-receptor peptide, and adenylate cyclase inhibition. The prevalence of autoantibodies was significantly higher (p < 0.01) in the affected (64.7%) than in the unaffected (25.0%) members. A 10.0 kb restriction fragment length polymorphism of the C beta region of the T-cell receptor gene was also overrepresented in affected males (60% versus 30% unaffected males, p < 0.01). In males, the presence of anti-beta-receptor antibodies was linked to the 10.0 kb C beta polymorphism. In affected males, a BlgII C alpha 2.14 kb polymorphism was also more frequent (62% versus 32% in unaffected, p < 0.01) and was linked to the presence of anti-beta-receptor antibodies. The distribution of haplotypes defined by V beta 8, C alpha, and C beta probes was significantly different between affected and unaffected (p < 0.04) and between antibody-positive and antibody-negative individuals. Since the major function of the T-cell receptor is the recognition of processed autoantigens, these results provide additional support for the role of autoimmunity in dilated cardiomyopathy.
    No preview · Article · Nov 1992 · American Heart Journal

Publication Stats

236 Citations
76.03 Total Impact Points


  • 1998-2011
    • The Ohio State University
      • • Division of Cardiovascular Medicine
      • • Division of Cardiology
      Columbus, OH, United States
  • 1994
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States