Myocardial fibrosis as a risk stratifier for sudden arrhythmic death

Keywords::

• afterpotential
• late gadolinium
• myocardial fibrosis
• re-entry
• serum markers of fibrosis enhancement
• sudden cardiac death
• ventricular arrhythmia

Sudden cardiac death (SCD), which prematurely claims the lives of more than 300,000 Americans and 7 million people worldwide each year [1], primarily occurs in individuals who have an underlying structural cardiac disease. Regardless of the type of the underlying cardiac condition (heart failure, dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], myocardial infarction [MI] and aging), SCD is almost always caused by ventricular tachycardia (VT), which then rapidly degenerates into ventricular fibrillation (VF) [2,3]. The implantable cardioverter defibrillator (ICD), while effective in aborting arrhythmic death, has its drawbacks including its high cost and the delivery of inappropriate shocks that are not without hazard. According to the current criteria for risk stratification, only 30% of the patients who receive an ICD will have an appropriate shock in their lifetime and only approximately 20% of patients with SCD each year meet the current clinical criteria for ICD implantation [4]. Understanding the pathophysiological mechanisms that lead to SCD becomes of considerable importance in the correct identification of patients who are at risk of developing SCD and who would benefit the most from ICD implantation.

Almost all of the cardiac conditions associated with SCD, including MI, heart failure, DCM or HCM, valvular diseases and aging [5], share a common pathological feature, namely increased cardiac fibrosis [6–9] characterized by increased interstitial collagen deposition and proliferation and transformation of fibroblasts to myofibroblasts. In addition, increased cardiac fibrosis positively correlates with increased left ventricular end-diastolic pressure and decreased left ventricular ejection fraction [9], which is generally considered a reliable marker of increased risk of SCD. The presence of uniform association between increased cardiac fibrosis and increased incidence of SCD on one hand and the growing experimental evidence on the other suggest an important causal role for cardiac fibrosis in the initiation of VT/VF in clinical settings.

Mechanisms by which myocardial fibrosis promotes ventricular arrhythmia

Alterations in cardiac conduction and conduction block, resulting in re-entrant wavefront of excitation, are the classically accepted arrhythmic consequences of increased cardiac fibrosis. Increased interstitial deposits of collagen filaments act as insulating barriers, promoting conduction slowing and conduction block [3,10].

Recent experimental findings in isolated whole-heart studies indicate that fibrosis may also importantly modulate the formation and propagation of cardiac afterpotentials that lead to triggered activity causing VT/VF [11,12]. While various stressful stimuli (oxidative, metabolic and angiotensin) readily promote early afterdepolarizations (EADs) and triggered activity in isolated ventricular myocytes, these same stimuli fail to promote EADs in well-coupled, nonfibrotic cardiac tissue owing to source-to-sink mismatches. That is, a small current sufficient to reverse repolarization and cause an EAD in an isolated cardiac myocyte fails to do the same in a well-coupled tissue owing to diffusive current dilution into adjacent repolarizing myocytes (unless they are also simultaneously primed for an EAD). As a result EADs will be suppressed. Consistent with the predicted suppressive effects of well-coupled tissue on EADs, we found that oxidative and metabolic stress that lead to VF in fibrotic aged hearts fail to induce any ventricular arrhythmias in nonfibrotic (well-coupled) normal adult hearts [11–13]. Our detailed quantitative histological analyses showed that a critical level of fibrosis is required to promote EAD-mediated VT/VF, as densely fibrotic sites (>90%) prevent EAD propagation and mildly fibrotic sites (<10%) do not allow EAD initiation [11].

In addition, increased fibroblast density in myocardial fibrosis may promote heterocellular coupling between cardiomyocytes and myofibroblasts causing ectopic pacemaker activity, as shown in recent studies of co-cultures of cardiac myocytes and myofibroblasts [14]. The myocyte–fibroblast coupling is also likely to reduce the repolarization reserve, an effect noted in our experimental and cardiac simulation studies that showed an increased propensity for EADs and triggered activity in fibrotic atria [15] and fibrotic ventricles [11,12]. While heterocellular coupling promotes arrhythmias, these tissue culture studies still await confirmation in in situ hearts.

Serum markers & cardiac MRI to quantify fibrosis

The observation that angiotensin-II-mediated hypertrophy and fibrosis were eliminated in mice deficient in TGF-β1 provided direct evidence of the involvement of TGF-β1 in angiotensin-II-mediated cardiac hypertrophy and fibrosis [16]. Moreover, the level of cardiac TGF-β1 and cardiac fibrosis have also been shown to be increased in patients with cardiac conditions including MI, DCM, HCM and valvular diseases [9,17,18]. Sanderson and colleagues demonstrated that in patients with DCM, the serum level of TGF-β1 is twice as high as that in control subjects with no heart disease [19]. The C-terminal peptides of procollagen type I and type III are other serum markers that correlate with the synthesis of collagen and increased fibrosis [20–22].

Cardiac fibrosis is a dynamic rather than a fixed static process. For instance, angiotensin II and aldosterone-blocking agents are capable of reversing cardiac fibrosis [23,24]. Increased collagen deposition in the heart is usually immediately followed by the increased degradation of collagen. Matrix metalloproteinases are a family of zinc-containing enzymes that degrade many extracellular matrix proteins, including collagen fibers. Increased levels of matrix metalloproteinases have been shown to be associated with increased cardiac fibrosis after MI [25]. The carboxyl-terminal telopeptide of collagen is another marker of collagen degradation that correlates with increased cardiac fibrosis.

Recently, it has been shown that late gadolinium enhancement (LGE) detected by cardiac MRI correlates with the size and location of myocardial fibrosis with a reasonable degree of accuracy [26]. LGE was also found to predict adverse outcomes including VT/VF in patients, with cardiovascular disorders [27,28]. Given the close association between the level of cardiac fibrosis and VT/VF in these patients, we may then postulate that cardiac fibrosis could indeed play a major independent role in the genesis of VT/VF and SCD. Consistent with this argument is the recent study that showed patients who met current criteria for ICD implantation for primary prevention of SCD but with no myocardial fibrosis assessed by the LGE technique on cardiac MRI did not manifest VT/VF [29]. These new findings suggest that myocardial fibrosis detected by LGE on cardiac MRI can be implemented into the risk stratification method for SCD.

Conclusion & future directions

Current SCD risk stratification criteria do not utilize cardiac fibrosis as an independent risk factor for SCD. Many experimental and clinical studies strongly suggest that fibrosis has a central role in the genesis of arrhythmia and have identified a correlation between the amount of cardiac fibrosis and the risk of SCD. There are several plausible mechanisms by which a critical level of cardiac fibrosis can facilitate the promotion of VT/VF and the current imaging modalities, such as cardiac MRI, allow quantitative assessment of myocardial fibrosis in patients at risk of developing VT/VF. We recognize that onetime assessment of cardiac fibrosis may not be sufficient to estimate the life time risk of SCD because not only is fibrosis a naturally dynamic process, but also many patients with the diagnosis of cardiomyopathy are treated with drugs such as angiotensin-II-blocking agents that may reverse the fibrosis [23,24]. Furthermore, serial imaging with cardiac MRI may not be cost-effective and practical. For example, those patients who receive ICD may not be able to have MRI in their lifetime. The serial measurements of key serum markers of fibrosis such as TGF-β1 [7] may be an effective complement to cardiac MRI to predict and/or estimate evolving cardiac fibrosis. It would be reasonable to expect that the combination of LGE detected by cardiac MRI and the serial measurement of the serum markers of fibrosis such as TGF-β1 could significantly improve the predictive accuracy of patients at risk of SCD.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.