Idiopathic left ventricular hypertrophy (LVH) / Idiopathic Fibrosis (ILVF) is a fairly novel entity that is increasingly reported following post-mortem examination in cases of sudden cardiac death (SCD)9,10. Studies from our group and others reveal that in selective cohorts idiopathic LVH/ILVF may be reported in up to 30% of sudden cardiac deaths. Professor Sheppard, one of our senior investigators, was among the first cardiac pathologists to describe idiopathic LVH/ILVF and distinguish it from hypertrophic cardiomyopathy (HCM) with specific pathologic criteria.
How is idiopathic LVH/ILVF diagnosed?
Idiopathic LVH/ILVF is characterized by:
1) Unexplained LVH/ILVF (heart weight > 500 g in males and > 400 g in females or increased heart weight as a function of body weight according to established nomograms.
2) Absence of the pathognomonic histological feature of HCM, notably myocardial disarray.
3) Absence of a past medical history of arterial hypertension or valvular conditions, as these conditions increase the afterload and are possible causes of LVH.
The significance of idiopathic LVH and its causal relationship with SCD is unclear. Postulated theories include that it is 1) part of the spectrum of HCM; 2) a trigger for fatal arrhythmias in individuals with an underlying arrhythmogenic syndrome, because LVH exacerbates electric instability; 3) a pathological variant of apparently physiological LVH in individuals who are genetically predisposed; 4) an innocent by-stander.
Idiopathic LVH is an autoptic definition in decedents of sudden death and it is not a cardiac condition meeting well defined and independent diagnostic criteria in living individuals.
Is idiopathic LVH part of the HCM spectrum?
One of the main unanswered questions is whether idiopathic LVH may represent a spectrum of HCM, a well-defined clinical entity, which is characterized by unexplained LVH and a genetic/familial background.
Recently, we showed that idiopathic LVH is a relatively common finding at the post-mortem, especially in athletes and obese individuals who died suddenly. Although idiopathic LVH and HCM share many common features, significant clinical and histopathological differences suggest a distinct pathogenesis.
A comprehensive family screening for relatives of decedents of SCD with a post-mortem diagnosis of idiopathic LVH revealed that none of the first-degree relatives showed phenotypic features of HCM, suggesting that idiopathic LVH and HCM are distinct clinical entities. Cardiac ion channelopathies such as Brugada syndrome were the most frequent diagnosis in first-degree relatives of decedents of SCD. This finding has important clinical implications, as cardiac screening in this context should not be limited to an ECG and echocardiogram, but should be comprehensive, in order to rule out primary arrhythmia syndromes.
What research needs to be done next?
These findings matched with the results of molecular autopsy in decedents of sudden death. Although molecular autopsy has been used previously following SADS deaths, targeting mainly channelopathy genes, studies on its role in the context of SCD and idiopathic LVH are lacking. We showed that while long QT syndrome pathogenic variants are the most commonly found in cases of SCD with a post-mortem consistent with idiopathic LVH, classic sarcomeric mutations were not identified, corroborating the thesis that idiopathic LVH and HCM are distinct entities.
Future research should focus on unravelling the mechanisms leading to LVH in decedents of SCD and in understanding whether idiopathic LVH represents a distinct clinical entity with increased propensity for potentially fatal arrhythmias.
REFERENCES:
1) Finocchiaro G, Papadakis M, Robertus JL, Dhutia H, Steriotis AK, Tome M, Mellor G, Merghani A, Malhotra A, Behr E, Sharma S, Sheppard MN. Reply: How Often Does Athlete Sudden Cardiac Death Occur Outside the Context of Exertion? J Am Coll Cardiol. 2016;68(19):2126.
2) Finocchiaro G, Dhutia H, D’Silva A, Malhotra A, Steriotis A, Millar L, Prakash K, Narain R, Papadakis M, Sharma R, Sharma S. Effect of Gender and Sporting Discipline on Left Ventricular Adaptation to Exercise. JACC Cardiovasc Imaging. 2016 10(9):965-972.
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7) Finocchiaro G, Papadakis M, Dhutia H, Cole D, Behr ER, Tome M, Sharma S, Sheppard MN. Obesity and sudden cardiac death in the young: Clinical and pathological insights from a large national registry. Eur J Prev Cardiol. 2018. doi: 10.1177/2047487317751291.
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9) Finocchiaro G, Papadakis M, Robertus JL, Dhutia H, Steriotis AK, Tome M, Mellor G, Merghani A, Malhotra A, Behr E, Sharma S, Sheppard MN. Etiology of Sudden Death in Sports: Insights From a United Kingdom Regional Registry. J Am Coll Cardiol. 2016 67(18):2108-15.
