We observed significant and specific alterations in the nature of myocardial interstitial remodeling in LVH+SCD that were not identified in LVH controls or normal controls. In addition to greater normalized heart weight adjusted to body weight, there was an increase in the amount of myocardial fibrosis, quantified as a 1.3-fold increase CVF in individuals with LVH+SCD compared to individuals with isolated LVH and noncardiac death. Specifically, this increase in the amount of collagen was associated with an altered distribution in collagen type I and type III, with a significant increase in the relative abundance of collagen type III. There was an overall increase in the number of connexin 43–labeled gap junctions with increasing myocyte size; however, the density of gap junction plaques per intercalated disc did not change with this increase.
A likely strength of this study relates to the design: postmortem access to hearts of subjects who had isolated LVH and SCD and the ability to compare these with hearts from subjects with isolated LVH or normal hearts who had unnatural deaths. Prior autopsy series have demonstrated a prevalence of isolated LVH of ≈18% in subjects who sustain SCD.25
An increase in the incidence of ventricular arrhythmias with LVH has long been documented,31,32
and LVH is recognized as an independent risk factor for SCD.1,2
There also appears to be a continuous and graded increase in the occurrence of ventricular arrhythmias with increasing LV mass,11,33
suggesting an association between the extent of hypertrophy and the risk of arrhythmia. Consistent with these earlier studies, we found that individuals with LVH who sustained SCD manifested a greater degree of hypertrophy, defined by heart weight : body weight ratios, compared to a control group of individuals with LVH and non-SCD.
From the mechanistic standpoint, it has been hypothesized that the increase in the ECM creates an anatomic uncoupling of adjacent myocytes such that zigzag and slow electrical propagation may occur, thereby creating potential sites for reentry.18
Although increased collagen is expected to be observed in LVH,34,35
we detected a significant increase in the amount of collagen in individuals with LVH+SCD compared to the LVH controls and normal control groups, which supports the concept that LVH+SCD subjects were more vulnerable to ventricular arrhythmogenesis due to fibrosis-mediated reentry. More importantly, earlier studies were not designed to make these specific comparisons, which have yielded what could be a novel form of remodeling unique to patients with SCD and isolated LVH. Our observation that there is a preferential increase in type III collagen in the myocardium of individuals with LVH who experience SCD suggests that changes in the composition of the ECM may affect the conduction properties of the myocardium and may create conditions conducive for ventricular arrhythmias. Myocardial collagen consists primarily of type I and type III collagen, and in animal models LVH has been shown to be associated with an early increase in the amount of type I collagen with a resultant alteration in the type I : type III collagen ratio.23,36
Previous studies have demonstrated elevated serum markers of both type I and type III collagen in human hypertensive heart disease,34,37–39
but there had been a lack of studies identifying the relative tissue distribution of these collagen subtypes in ventricular hypertrophy in humans, especially in the context of SCD. Type III collagen is thought to be the primary isoform that increases within the endomysial weave that surrounds individual myocytes during the development of ventricular hypertrophy,22
and an increase in the density of this endomysial weave has been documented by scanning electron microscopy.34
Increasing the lateral cell-to-cell contact may result in alterations in the anisotropic properties of the myocardium and may create the conditions favorable for reentry.40
Resident fibroblasts normally found in the myocardium are relatively quiescent, but under conditions of myocardial injury or stress they transdifferentiate into myofibroblast cells that are responsible for the enhanced synthesis of ECM proteins, including collagen I, collagen III, and fibronectin.41–43
In pathological states such as LVH, there is a dysregulation of myofibroblast removal, and the continued presence of myofibroblasts is thought to result in the sustained synthesis of the ECM proteins and myocardial fibrosis.44
It is possible that the abnormal collagen remodeling occurs because of proliferation or abnormal function of myofibroblasts in the LVH interstitium. The high secretory capacity of myofibroblasts may disrupt the normal balance between ECM synthesis and degradation, resulting in a rate of collagen deposition that far outweighs the rate of collagen degradation.45
Gap junction organization is an important determinant of normal myocardial conduction, in that it allows low-resistance conduction in a longitudinal orientation. It has been shown that alterations in gap junction distribution can affect the anisotropic properties of the myocardium. Previous studies in humans with decompensated LVH have shown a decrease in the relative density of connexin 43 gap junctions at the intercalated disc.39
Our studies demonstrate that the density of connexin 43 gap junctions at the intercalated disc in individuals with LVH+SCD and in individuals with LVH + unnatural death (Control Group A) is similar. We observed, however, that there was an increase in the number of connexin 43–labeled gap junctions with an increase in the myocyte cross section. These gap junctions could potentially mediate conduction in the transverse orientation. By maintaining the expected number of gap junctions at the intercalated disc, the longitudinal conduction properties in myocardium of individuals with LVH would remain preserved, whereas the transverse conduction properties of the hypertrophied myocytes might be significantly altered.
This is a retrospective study performed in a small number of patients who sustained SCD or died of noncardiac causes and who underwent autopsy. Because we have relied on tissue from autopsy for histological characterization of myocardium, the individuals in this study comprise a highly selected group. Given these constraints, cases and controls were not matched for age, sex, or risk factors. The restricted sample size, especially in Control Group B, may have limited our ability to discern a statistically significant difference in normalized heart weight f Control Group A (LVH and death from noncardiac causes). Echocardiographic data was not available from all individuals included in this study, and therefore it is likely that not all individuals studied exhibited concentric LVH. Given these limitations, the observations presented in this study would need to be validated in a larger patient cohort and might need to be tested in other populations.
We observed significant and specific alterations in the LV myocardial interstitium of individuals with isolated LVH and SCD, which may contribute to myocardial vulnerability for ventricular arrhythmias and warrant further mechanistic evaluation.