Vulnerable Myocardial Interstitium in Patients With Isolated Left Ventricular Hypertrophy and Sudden Cardiac Death: A Postmortem Histological Evaluation

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Abstract

Background

Concentric left ventricular hypertrophy (LVH) is independently associated with increased risk of sudden cardiac death (SCD). Some animal models of LVH display specific alterations of the myocardial interstitium that could increase myocardial vulnerability to ventricular arrhythmias, but these merit evaluation in humans with LVH and SCD.

Methods and Results

Twelve consecutive patients with isolated LVH and SCD (LVH+SCD) in the absence of hypertrophic cardiomyopathy, coronary disease, or other cardiac structural abnormality were ascertained in the Oregon Sudden Unexpected Death Study. Detailed postmortem comparisons were conducted with 18 controls who had isolated LVH and unnatural deaths (Control Group A) and 6 controls who had structurally normal hearts and unnatural deaths (Control Group B). Postmortem left ventricular myocardial sections were obtained for measurement of collagen volume fraction, characterization of gap junctions, and quantification of collagen subtypes. Heart weight normalized to body weight was higher in LVH+SCD cases (6.9±1.2 g/kg) than in Control Group A (5.3±1.4 g/kg) and Control Group B (4.2±0.3 g/kg); P=0.001. Collagen volume fraction was also higher in LVH+SCD cases (3.1±0.4) than in Control Group A (2.3±0.4) and Control Group B (1.6±0.3); P=0.0002. The relative amount of collagen III was significantly higher in LVH+SCD cases (33.0±4.4%) than in Control Group A (20.9±4.3%) and Control Group B (13.4±3.5%); P=0.0001. There was an overall increase in the number of connexin 43–labeled gap junctions with increasing myocyte size. No subject was found to have high-risk hypertrophic cardiomyopathy mutations.

Conclusions

In addition to the expected increase in myocardial mass and overall collagen content, SCD with isolated LVH was associated with relative abundance of type III collagen, a novel finding that warrants further mechanistic evaluation. ( J Am Heart Assoc. 2012;1:e001511 doi: 10.1161/JAHA.111.001511.)

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Most cited references 33

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Molecular mechanisms of myocardial remodeling.

B Swynghedauw (1998)

"Remodeling" implies changes that result in rearrangement of normally existing structures. This review focuses only on permanent modifications in relation to clinical dysfunction in cardiac remodeling (CR) secondary to myocardial infarction (MI) and/or arterial hypertension and includes a special section on the senescent heart, since CR is mainly a disease of the elderly. From a biological point of view, CR is determined by 1 ) the general process of adaptation which allows both the myocyte and the collagen network to adapt to new working conditions; 2) ventricular fibrosis, i.e., increased collagen concentration, which is multifactorial and caused by senescence, ischemia, various hormones, and/or inflammatory processes; 3) cell death, a parameter linked to fibrosis, which is usually due to necrosis and apoptosis and occurs in nearly all models of CR. The process of adaptation is associated with various changes in genetic expression, including a general activation that causes hypertrophy, isogenic shifts which result in the appearance of a slow isomyosin, and a new Na+-K+-ATPase with a low affinity for sodium, reactivation of genes encoding for atrial natriuretic factor and the renin-angiotensin system, and a diminished concentration of sarcoplasmic reticulum Ca2+-ATPase, beta-adrenergic receptors, and the potassium channel responsible for transient outward current. From a clinical point of view, fibrosis is for the moment a major marker for cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, and the propensity for reentry arrhythmias. In addition, systolic dysfunction is facilitated by slowing of the calcium transient and the downregulation of the entire adrenergic system. Modifications of intracellular calcium movements are the main determinants of the triggered activity and automaticity that cause arrhythmias and alterations in relaxation.

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Fibroblasts and myofibroblasts: their source, function and role in disease.

Robin McAnulty (2006)

Fibroblasts are found in most tissues of the body. They exhibit several phenotypes including non-contractile fibroblasts, contractile myofibroblasts, and intermediate phenotypes including the protomyofibroblast. Fibroblasts are metabolically active cells which play critical roles regulating extracellular matrices, interstitial fluid volume and pressure, and wound healing. Fibroblast numbers can be maintained or expanded by proliferation of resident populations but in addition, recent evidence indicates they can also be derived through epithelial-mesenchymal transition or from circulating and tissue-derived mesenchymal stem cells. Many diseases are associated with dysregulation of the injury repair response and fibroblast function, leading to increased or decreased deposition of extracellular matrix proteins, altered tissue architecture, impaired function and in some cases significant morbidity and mortality. There are currently no specific therapies that target fibroblast-associated pathology but increasing knowledge of pathological mechanisms has led to development of new agents providing hope for improved treatment of these diseases.

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Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

H. Watkins, A. Matsumori, Christine S. Moravec … (1995)

Familial hypertrophic cardiomyopathy can be caused by mutations in the genes for beta cardiac myosin heavy chain, alpha-tropomyosin, or cardiac troponin T. It is not known how often the disease is caused by mutations in the tropomyosin and troponin genes, and the associated clinical phenotypes have not been carefully studied. Linkage between polymorphisms of the alpha-tropomyosin gene or the cardiac troponin T gene and hypertrophic cardiomyopathy was assessed in 27 families. In addition, 100 probands were screened for mutations in the alpha-tropomyosin gene, and 26 were screened for mutations in the cardiac troponin T gene. Life expectancy, the incidence of sudden death, and the extent of left ventricular hypertrophy were compared in patients with different mutations. Genetic analyses identified only one alpha-tropomyosin mutation, identical to one previously described. Five novel mutations in cardiac troponin were identified, as well as a further example of a previously described mutation. The clinical phenotype of four troponin T mutations in seven unrelated families was similar and was characterized by a poor prognosis (life expectancy, approximately 35 years) and a high incidence of sudden death. The mean (+/- SD) maximal thickness of the left ventricular wall in subjects with cardiac troponin T mutations (16.7 +/- 5.5 mm) was significantly less than that in subjects with beta cardiac myosin heavy-chain mutations (23.7 +/- 7.7 mm, P < 0.001). Mutations in alpha-tropomyosin are a rare cause of familial hypertrophic cardiomyopathy, accounting for approximately 3 percent of cases. Mutations in cardiac troponin T account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy in this referral-center population. These mutations are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: June 2012

Publication date (Electronic): 22 June 2012

Volume: 1

Issue: 3

Electronic Location Identifier: e001511

Affiliations

Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (B.K.T., B.T.J., K.R., C.T., A.U.-E., S.S.C.)

Department of Pathology, Oregon Health and Science University, Portland, OR (K.G.)

Department of Emergency Medicine, Oregon Health and Science University, Portland, OR (J.J.)

Cleveland Clinic Foundation, Cleveland OH (B.K.T.)

Vancouver Clinic, Vancouver, WA (B.T.J)

Author notes

Correspondence to: Sumeet S. Chugh MD, The Heart Institute, 5702 South Tower, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail sumeet.chugh@ 123456cshs.org

Article

Publisher ID: jah332

DOI: 10.1161/JAHA.112.001511

PMC ID: 3487319

PubMed ID: 23130141

SO-VID: 7394cb57-59af-4b5e-b23b-309ba5285295

License:

This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Vulnerable Myocardial Interstitium in Patients With Isolated Left Ventricular Hypertrophy and Sudden Cardiac Death: A Postmortem Histological Evaluation

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Abstract

Background

Methods and Results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 33

Molecular mechanisms of myocardial remodeling.

Fibroblasts and myofibroblasts: their source, function and role in disease.

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

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