Regrowing the Heart

Motivation: With the recent AHA conference, a flurry of new findings has been released.  Although there have been many negative findings, there was one recent trial in particular that caught my attention.  Wouldn't it be nice if we could somehow regrow heart cells in patients with heart failure? People have tried it in the past and failed.  But, there was a recent report of success!

Paper:   Bolli, R. et. al. "Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial" Lancet (2011) epub.

Methods: The full trial consisted of an early safety analysis and then a randomized portion.  Given low recruitment so far, the reported results combine the results of the whole experience.  The trial included patients of (1) less than 75 who were (2) undergoing CABG with (3) LVEF <= 40% and (4) history of previous MI.  Initial screening occurred at time of CABG during which the right atrial appendage was harvested and cardiac stem cells bearing cell surface marker c-kit were isolated.  At a mean of 113 days after CABG, the cardiac stem cells were infused into the infarcted territory using a balloon catheter.

Results:
Subjects: In total, 16 patients received stem cells while there were seven patients in the control group.  The two groups were overall similar in terms of age, gender, and comorbidities though the number of patients in each group is obviously very small.

Treatment Effect: At four month follow-up, the left ventricular ejection fraction (LVEF) increased from mean of 30.3% to 38.5% (p = 0.001).  By contrast, in the controls, the LVEF remained unchanged from mean of 30.1% to 30.2%.  The authors had injected the stem cells into the infarcted territory of previous MI.  In the infused territory, the regional wall motion score improved significantly (1.97 to 1.78, p = 0.007), with lower scores indicating less wall motion defect.  The regional wall motion score did not change in the control group.

Cardiac MRI: Seven patients treated with cardiac stem cells underwent cardiac MRI to assess mean infarct weight.  In the seven patients, the mean infarct weight decreased by 7.8 g (standard error, 1.7 g) at four months.  A reduction in infarct size was also noted.

Functional Data:  In the stem cell treated patient, the NYHA functional class decreased from mean of 2.19 to 1.63 four months after infusion.  The NYHA class of control patients stayed identical. 

Adverse effects: No serious adverse effects occurred more frequently in the treatment group including MI, arrhythmia, new tumor, or stroke.

Discussion: The trial is pretty exciting because it shows that a one-time procedure of stem cell infusion can generate long-lasting benefits including ejection fraction increase and functional benefit in terms NYHA heart failure severity.  This trial, however, must be taken in the context of a proof-of-concept safety analysis trial.  The number of patients in each group is pretty small.  Also, the entire trial was not randomized, and there may have been non-obvious differences in the two cohorts.  Despite media hype about this trial, both of these are strong limitations in extending stem cell infusions to routine practice just now.  Nonetheless, this trial provides hope that rather than just thinking about slowing down the pace of heart failure progression, we may actually in the future think about reversing heart failure.  Perhaps, in the future, standard therapy for STEMI will be PCI with stem cell infusion.  There is much more to come from this field!

Parkinson's Disease Prevention

Motivation: Lately, I have been meeting too many people with Parkinson's Disease - one of those random streaks of fate.  Controllable at first, the disease is pretty disabling as it progresses.  I was wondering about causes of this "idiopathic" disease and whether there are protective factors like say eating a salmon each day.  During this search, I came across some rumors that calcium channel blockers may be protective against Parkinson's Disease.  And, the data?

Paper: Ritz, B. et. al. "L-Type Calcium Channel Blockers and Parkinson Disease in Denmark." Ann. Neurol. (2010) 67: 600-606.

Methods: A case-control study in Denmark using the Denmark National Health Service registry that covers medical service for all citizens.  Authors identified initial diagnoses of Parkinson's Disease (PD) between 2001-2006.  Cases were identified either by first coded diagnosis of PD or first prescription of PD medication.  Controls were chosen after matching for birth year and sex.  Patients with any type of dementia or cerebrovascular disease before diagnosis of PD were excluded (along with matched controls).  Also excluded were patients with PD who were not prescribed any PD drugs.

Results:
Subjects: In total, the authors identified 1931 cases of PD with 9651 matched controls.  Five years prior to the index date of PD, the general health of cases and matched controls as measured by the Charson index was similar. 

Non-dihydropyridine Calcium Channel Blockers: Authors looked at prescription drug use two years prior to diagnosis of PD to account for the pre-clinical phase and risk factors for developing PD.  For non-dihydropyridine calcium channel blockers (verapamil and diltiazem), no association with PD was found. 

Dihydropyridine CCB: For dihydropyridine calcium channel blockers (such as amlodipine or felodipine), authors separated analysis for amlodipine, which has low central nervous system penetrance, and other members of this class, which have higher CNS availability.  For amlodipine, no protective effects were found.  For other members of dihydropyridine CCB, use was associated with protective effects: odds ratio of 0.70, adjusted confidence interval (0.52-0.94).  Of note, there were 55 patients with PD and 368 controls using medications of this class.

Discussion: The paper shows that use of non-hydropyridine calcium channel blockers (excepting amlodipine) was associated with about 30% decreased risk of PD diagnosis.  While this paper is a case-control study, the results have some biological plausability.  Non-CNS penetrant drugs did not show any effect while CNS penetrant calcium channel blockers had some protective effects.  It is plausible that blocking calcium influx into oxidatively stressed cells may provide some degree of protection.  On the other hand, the association observed may be indirect indicators of some other condition that is protective.  In the study, not much information was provided about details of comorbidities and how comorbidities were different between cases and controls.  This study is suggestive but far from definitive in using calcium channel blockers in the clinic.  As usual, more rigorous study is needed.