Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene

doi:10.1016/j.yjmcc.2003.10.003

Journal of Molecular and Cellular Cardiology

Volume 36, Issue 1, January 2004, Pages 91-99

https://doi.org/10.1016/j.yjmcc.2003.10.003 Get rights and content

Abstract

We investigated inducibility of life-threatening arrhythmias with programmed ventricular stimulation (PVS) in relation to clinical markers of sudden cardiac death (SCD) in subjects with hypertrophic cardiomyopathy (HCM) attributable to the Asp175Asn mutation in the α-tropomyosin gene (TPM1-Asp175Asn). PVS was performed with up to three extrastimuli and distribution of markers of SCD was evaluated in 21 adult subjects with the TPM1-Asp175Asn. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in seven of 21 subjects (33%). Inducible subjects had more severe left ventricular hypertrophy (LVH) and an increased number of markers of SCD (family history of SCD, syncope or presyncope, fall in systolic blood pressure (BP) during exercise, documented non-sustained VT (NSVT), and marked LVH) compared to non-inducible subjects (IVS 2.4 ± 0.3 cm vs. 1.6 ± 0.5 cm, P < 0.001; and two to three vs. one to two markers of SCD, P = 0.007, respectively). In conclusion, in HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene, life-threatening arrhythmias were induced in one third of the patients. Inducibility was associated with the maximum left ventricular (LV) thickness and the number of markers of SCD, suggesting that in HCM patients with an identical causative mutation, susceptibility to ventricular arrhythmias is related to the cardiomyopathic phenotype.

Introduction

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease caused by mutations in sarcomeric genes. In the young, including athletes, HCM is the most common cause for sudden cardiac death (SCD) [1]. The overall annual mortality rate, however, ranges from 1% in unselected patients with HCM, to at least 5% in high-risk patients [1], which has necessitated risk stratification in HCM. Prior cardiac arrest or sustained ventricular tachycardia (VT) is a strong risk factor for SCD [1]. Clinical risk factors, including family history of SCD, syncope and presyncope, bursts of non-sustained VT (NSVT) on Holter electrocardiographical (ECG) recording, hypotensive blood pressure (BP) response to exercise and extreme left ventricular hypertrophy (LVH) also increase the risk for SCD [1], but the positive predictive value of each of these markers of SCD is low, unless two or more of them occur simultaneously [2].

Some HCM-causing mutations, especially those in the β-myosin heavy chain and troponin T genes, are associated with a high risk for SCD, but the risk is variable in individual patients, even in affected members of the same family sharing one disease-causing mutation [1]. There are, however, no previous studies on risk factors for SCD in genotype-confirmed HCM subjects. Therefore, it is not known if clinical markers of SCD are related to genotype or phenotypic expression of cardiomyopathy. Furthermore, inducibility of life-threatening arrhythmias during programmed ventricular stimulation (PVS), which has been shown to be present particularly in HCM patients with serious clinical manifestations [3], [4], and predict SCD in HCM [5], has not been studied in genotype-confirmed HCM patients.

Defects in the α-tropomyosin (TPM1) gene have been shown to cause HCM in a minority (<5%) of HCM patients in Europe and US [6], but a single hot-spot mutation Asp175Asn in this gene (TPM1-Asp175Asn) is very common in eastern Finland, accounting for 11% of all cases of HCM [7]. This mutation has been considered benign previously, but a few HCM-related SCDs have been reported in HCM patients with this mutation [8], suggesting intermediary risk. In the present study, we investigated clinical markers of SCD and inducibility of life-threatening arrhythmias with PVS in 21 patients with HCM attributable to the TPM1-Asp175Asn mutation.

Section snippets

Methods

The study protocol was approved by the Kuopio University Hospital Ethics Committee and all subjects gave written informed consent.

Genetic findings in the TMP1 gene

Of the 36 aforementioned unrelated patients with HCM in the Kuopio area, four had the TPM1-Asp175Asn, accounting for 11% of all HCM cases [7].

Families with the Asp175Asn mutation in the TPM1 gene

All available relatives of the index patients with the TPM1-Asp175Asn were examined, and 23 relatives were found to have the TPM1-Asp175Asn mutation (Families A–D, Fig. 1 ). In addition, one family from western Finland with the identical TPM1 mutation in four family members was included in the study (Family E, Fig. 1). Thus, altogether 31 patients with

Discussion

In the present study, life-threatening arrhythmias were induced with PVS in one third of the HCM patients with the Asp175Asn mutation in the TPM1 gene. The inducibility of life-threatening ventricular arrhythmias was associated with the maximum thickness of LV on echocardiography and clustering of clinical markers of SCD, suggesting that the arrhythmia vulnerability in HCM patients with identical genotype is related to cardiomyopathic phenotype.

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Cited by (21)

Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis
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Citation Excerpt :
Sudden death in FHC is associated with ischemia and the initiation of sustained ventricular arrhythmias but the mechanisms of the progression to cardiac arrest are unclear. Localized regions of ischemia and scarring in hypertrophic left ventricle predispose the tissue to electrical instability and re-entry consistent with microvascular dysfunction [40,41]. On the level of the myofilaments, there is evidence indicating arrhythmogenic Ca2+ waves arise at sites of functional non-uniformity in rat cardiac trabeculae, caused by local mechanical or ischemic damage [42].
Familial hypertrophic cardiomyopathy (FHC) is a leading cause of sudden cardiac death among young athletes but the functional effects of the myofilament mutations during FHC-associated ischemia and acidosis, due in part to increased extravascular compressive forces and microvascular dysfunction, are not well characterized. We tested the hypothesis that the FHC-linked tropomyosin (Tm) mutation Tm-E180G alters the contractile response to acidosis via increased myofilament Ca²⁺ sensitivity. Intact papillary muscles from transgenic (TG) mice expressing Tm-E180G and exposed to acidic conditions (pH 6.9) exhibited a significantly smaller decrease in normalized isometric tension compared to non-transgenic (NTG) preparations. Times to peak tension and to 90% of twitch force relaxation in TG papillary muscles were significantly prolonged. Intact single ventricular TG myocytes demonstrated significantly less inhibition of unloaded shortening during moderate acidosis (pH 7.1) than NTG myocytes. The peak Ca²⁺ transients were not different for TG or NTG at any pH tested. The time constant of re-lengthening was slower in TG myocytes, but not the rate of Ca²⁺ decline. TG detergent-extracted fibers demonstrated increased Ca²⁺ sensitivity of force and maximal tension compared to NTG at both normal and acidic pH (pH 6.5). Tm phosphorylation was not different between TG and NTG muscles at either pH. Our data indicate that acidic pH diminished developed force in hearts of TG mice less than in NTG due to their inherently increased myofilament Ca²⁺ sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction.
Drug induced shortening of the QT/QTc interval: An emerging safety issue warranting further modelling and evaluation in drug research and development?
2009, Journal of Pharmacological and Toxicological Methods
A session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh.
The session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing “for” and “against” QT/QTc shortening being a safety issue and a panel discussion with the audience.
Compared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future.
Currently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.
The canine model with chronic, complete atrio-ventricular block
2008, Pharmacology and Therapeutics
Proarrhythmic susceptibility to drug-induced Torsades de Pointes is restricted to individuals with a predisposed phenotype characterized by a reduced repolarization reserve. Additional factors are often involved in a further impairment of repolarization, possibly culminating with dangerous ventricular polymorphic tachyarrhythmias. Drugs that block repolarizing currents represent such an additional hit.
The dog model with chronic, complete atrio-ventricular block has been used frequently for proarrhythmic drug screening. The ventricular remodeling seen after ablation of the AV node enhances the susceptibility for repolarization-dependent arrhythmias. In this review, we 1) describe the cellular and molecular basis of ventricular remodeling, 2) validate the CAVB dog as a drug screening model and 3) introduce a new surrogate predictive proarrhythmic parameter: beat-to-beat variability of repolarization.
Myocardial perfusion, oxidative metabolism, and free fatty acid uptake in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene: A positron emission tomography study
2007, Journal of Nuclear Cardiology
Citation Excerpt :
However, only 31 subjects with this specific Asp175Asn substitution in the α-tropomyosin gene have been identified in Eastern Finland.3 Most of these identified subjects had already undergone very comprehensive noninvasive and invasive studies previously17-19,37 and were not willing to participate in this voluntary study. As the results of our study were consistent and statistically significant, it is likely that they represent true findings.
The relationship between myocardial metabolic changes and the severity of left ventricular (LV) hypertrophy in patients with hypertrophic cardiomyopathy (HCM) is largely unknown. We characterized metabolic abnormalities in patients with a genetically identical cause for HCM but with variable LV hypertrophy.
Eight patients with HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene underwent myocardial perfusion, oxidative, and free fatty acid (FFA) metabolism measurements via positron emission tomography and oxygen 15–labeled water, carbon 11 acetate, and fluorine 14(R,S)-[18F] Fluoro-6-thia-heptadecanoic acid (18 FTHA). LV mass, work, and efficiency were assessed by echocardiography. Thirty-six healthy volunteers served as control subjects. Compared with control subjects, HCM patients had increased myocardial oxidative metabolism and FFA uptake (P < .05). However, in patients, LV mass was inversely related to global myocardial perfusion, oxidative metabolism, and FFA uptake (all P < .03), and regional wall thickness was inversely related to regional perfusion (P < .01), oxidative metabolism (P < .001), and FFA uptake (P < .01). Therefore patients with mild (LV mass less than median of 177 g) but not advanced LV hypertrophy were characterized by increased perfusion, oxidative metabolism, and LV efficiency as compared with control subjects (P < .05).
In HCM attributable to the Asp175Asn mutation in the α-tropomyosin gene, myocardial oxidative metabolism and FFA metabolism are increased and inversely related to LV hypertrophy at both the whole heart and regional level. Increased metabolism and efficiency characterize patients with mild myocardial hypertrophy. These hypermetabolic alterations regress with advanced hypertrophy.
Ryanodine receptors and ventricular arrhythmias: Emerging trends in mutations, mechanisms and therapies
2007, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
Genetic mutations underlying malignant arrhythmias have recently been identified in cardiac Ca2+ channels including the L-type Ca2+ channel (LTCC, also termed the dihydropyridine receptor (DHPR), or more recently, Cav1.2) [8,9], and ryanodine receptors (RyR2), large multi-functional Ca2+ release channels that are crucial for cardiac development and excitation–contraction (EC) coupling (for reviews see [10–15]). However, unlike defects in Na+ and K+ ion handling, cellular Ca2+ dysfunction does not arise exclusively from Ca2+ channel abnormalities, but also from mutation-linked defects in intra-organellar Ca2+ storage (calsequestrin (CSQ), a major Ca2+ binding protein of the sarcoplasmic reticulum (SR) [16–18]), Ca2+ sequestration (phospholamban (PLB), a regulator of the SR Ca2+ ATPase (SERCA) [19,20]) and the altered ‘shaping’ of cytoplasmic Ca2+ signals by cytoplasmic Ca2+ binding proteins involved in EC coupling (tropomyosin and troponin [21–23]). Furthermore, alterations in cytoskeletal architecture that disrupt the spatial organisation of Ca2+ signalling networks may be highly arrhythmogenic in the absence of any genetic defects in Ca2+ handling proteins per se [24].
It has been six years since the first reported link between mutations in the cardiac ryanodine receptor Ca²⁺ release channel (RyR2) and catecholaminergic polymorphic ventricular tachycardia (CPVT), a malignant stress-induced arrhythmia. In this time, rapid advances have been made in identifying new mutations, and in understanding how these mutations disrupt normal channel function to cause VT that frequently degenerates into ventricular fibrillation (VF) and sudden death. Functional characterisation of these RyR2 Ca²⁺ channelopathies suggests that mutations alter the ability of RyR2 to sense its intracellular environment, and that channel modulation via covalent modification, Ca²⁺- and Mg²⁺-dependent regulation and structural feedback mechanisms are catastrophically disturbed. This review reconciles the current status of RyR2 mutation-linked etiopathology, the significance of mutational clustering within the RyR2 polypeptide and the mechanisms underlying channel dysfunction. We will also review new data that explores the link between abnormal Ca²⁺ release and the resultant cardiac electrical instability in VT and VF, and how these recent developments impact on novel anti-arrhythmic therapies. Finally, we evaluate the concept that mechanistic differences between CPVT and other arrhythmogenic disorders may preclude a common therapeutic strategy to normalise RyR2 function in cardiac disease.
MetaVA: Curriculum Meta-learning and Pre-fine-tuning of Deep Neural Networks for Detecting Ventricular Arrhythmias based on ECGs
2022, arXiv

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Original ArticleInducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene

Abstract

Introduction

Section snippets

Methods

Genetic findings in the TMP1 gene

Families with the Asp175Asn mutation in the TPM1 gene

Discussion

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Hypertrophic cardiomyopathy

JAMA

Sudden death in hypertrophic cardiomyopathy: identification of high risk patients

J Am Coll Cardiol

Electrophysiologic abnormalities in patients with hypertrophic cardiomyopathy

Circulation

Prognostic determinants in hypertrophic cardiomyopathy

Circulation

The management of hypertrophic cardiomyopathy

New Engl J Med

Experience from clinical genetics in hypertrophic cariomyopathy: proposal for new diagnostic criteria in adult members of affected families

Heart

enetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes

Original Article
Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the α-tropomyosin gene