CardioExchange Archive

CardioExchange welcomes Carolyn Ho to discuss her study in the New England Journal of Medicine, which looked at myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy (HCM). Her team found that levels of serum C-terminal propeptide of type I procollagen (PICP) were higher in mutation carriers without LVH and in patients with HCM than in controls. The authors conclude that “incorporating genetic testing to identify at-risk mutation carriers, defining features of early disease, and developing therapies to mitigate fibrosis will foster vital new opportunities to change the natural history of hypertrophic cardiomyopathy.”

Do these data imply a role for anti-fibrotic drugs, such as aldosterone antagonists, in patients with HCM?  If so, would you advocate treating patients prior to, or after the development of, overt hypertrophy?

It is intriguing to consider that anti-fibrotic agents may be able to modify disease, but such an approach should initially be investigated by randomized clinical trials.  We’ve begun to address this process by administering losartan to mouse models that carry human HCM mutations and preliminary results are promising; however, further investigation is needed before starting treatment in patients.  Notably in animal studies, early treatment in mice that carry sarcomere mutations but have not yet developed cardiac hypertrophy seemed far more beneficial than later treatment started after mice developed overt HCM.  Thus, defining the optimal time to initiate treatment will be very important in human patients.  Another related consideration is that angiotensin receptor blockers or aldosterone antagonists may not be well tolerated by HCM patients with obstructive physiology.  Therefore, treating genetically at-risk patients before the development of hypertrophy may be the most effective strategy.

To directly define the role of anti-fibrotic drugs in human HCM, we have initiated a multi-center effort to identify key early phenotypes and surrogate endpoints of treatment effect.  This information will serve as a springboard to launching translational clinical trials of disease modification and prevention in pre-hypertrophic sarcomere mutation carriers.

In your patient population, was there any correlation between PICP levels and history of arrhythmias/symptomatic heart failure? If so, do you think PICP levels (or similar biomarkers) could be used in the future to determine prognosis or guide the need for a prophylactic ICD in HCM patients?

PICP levels were significantly higher in the small number of patients with end-stage HCM/symptomatic heart failure as compared to the rest of patients with overt HCM.  This preliminary finding may suggest a use for PICP levels in predicting patients at risk for developing heart failure.  However, further confirmation and long-term follow up are needed to fully understand the potential applications of PICP levels in clinical practice.  PICP values were not significantly higher in the small subset of patients with VT and/or appropriate ICD discharges.

How does this research relate to patient care? How do you think research in HCM genetics will be applied to patient care?

Our findings demonstrate that the integration of genetics into clinical medicine has the power to transform the care of patients with HCM. Using this approach, LVH is seen to be a late manifestation of sarcomere mutations.  In contrast, we have now found that collagen synthesis, as reflected by serum levels of PICP, is increased early in the development of HCM, before a clinical diagnosis can be made by imaging studies.  These findings provide provocative new information about the biology of HCM.  Fibrosis appears to be an early and perhaps fundamental consequence of sarcomere mutations.  As discussed earlier, this suggests that early anti-fibrotic therapy may be able to change the natural history of disease.

By defining an at-risk population and identifying critical mechanistic triggers to target for therapy, new therapeutic paradigms are possible based on genetic discoveries and diagnosis. Early interventions can now be designed to target a preclinical population with the goal of preventing the development of disease, rather than simply managing its consequences.