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!

From Heart Failure to Renal Failure - The Myth

Motivation: Ever since the week on heart failure in second year of medical school, I have been thinking about congestive heart failure (CHF) as consisting of "backup" symptoms like dyspnea and edema or "forward flow" symptoms like somnolence and fatigue.  One of the CHF exacerbation symptoms that I usually categorize under forward flow  is renal failure.  The presumed explanation for renal failure is relative renal hypoperfusion from decreased cardiac output in acute CHF exacerbation.  Recently, I learnt about some trials that challenged this view.  Here is one of the trials:

Paper: Nohria, A., et. al. Cardiorenal Interactions: Insights From the ESCAPE Trial. J. Am. Coll. Cardiol.(2008) 51: 1268-74.  http://content.onlinejacc.org/cgi/content/full/51/13/1268

Methods: The ESCAPE trial was a randomized trial comparing pulmonary artery catheter versus clinical volume assessment based treatment for acute heart failure exacerbation.  Included patients had LVEF<30% with SBP<125 mmHg with signs and symptoms of acute heart failure.  Patients with baseline creatinine >3.5 mg/dL  were excluded.  The current paper was an ad hoc analysis of baseline hemodynamic parameters from pulmonary artery catheter measurements and serum creatinine.

Results:
Subjects: In general, the mean age of the patient group was 56 with serum creatinine of 1.5.  Most of the patients were getting an ACE-I/ARB and beta-blocker.

Hemodyamic Correlation: There was no correlation between baseline serum creatinine or estimated GFR and cardiac index, systemic vascular resistance, or wedge pressure!  There was a weak but significant correlation between baseline serum creatinine and right atrial pressure (r = 0.165, p = 0.03).  Similar correlation was found between baseline estimated GFR and right atrial pressure (r = -0.195, p = 0.01), meaning higher right atrial pressures were correlated with decreased GFR.

Discussion: This paper clearly calls into question the assumption that renal dysfunction from acute heart failure is directly linked to renal hypoperfusion.  Renal failure seen in acute heart failure is being increasingly called the "cardiorenal syndrome" in recognition of the more complex pathophysiology.  Rather than renal arterial hypoperfusion, this trial along with other evidence suggests that elevated venous pressures may directly compromise renal function.  One of the problems in extrapolating from trials like this is the complexity of interacting factors.  The patients in this trial were sick and being treated with multiple agents like beta-blockers and ACE-I/ARB that also affect the renal vasculature.  But, these pharmacologic confounders would be expected to affect vascular tone, and no correlation was found between  systemic vascular resistance and renal dysfunction either.  Besides the effects of elevated venous pressure, other possible explanations for renal dysfunction include undefined direct toxic effects of therapeutic agents.  Also, many processes that worsen CHF, like HTN and diabetes, also have pathologic effects on the kidneys.  In the coming years, we will likely learn more about the complex pathophysiology of cardiorenal syndrome!  

Beta-Blockers in Acute Heart Failure

Motivation: When a patient is admitted with acute heart failure and laboring to breathe, I often debate whether or not to continue the home metoprolol.  In chronic heart failure, I understand the bit about beta-blockade having protective effects.  But, acutely, beta-blockers decrease heart inotropy resulting in decreased cardiac output and elevated left ventricular filling pressures - effects that are not helpful in acute heart failure.  Like so many things in cardiology, it turns out that there has been a randomized trial with a nice acronym (B-CONVINCED) that examines this issue.

Paper:  "B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failue hospitalizED for a decompensation episode." Jondeau, G. et. al. European Heart Journal (2009) 30: 2186-2192.

Methods: Randomized, controlled, open-labelled trial conducted in 36 centres in France.  Eligible patients were older than 18 on chronic beta-blocker therapy hospitalized for acute heart failure (including pulmonary edema) with left ventricular ejection fraction less than 40%.  Patients were excluded if found to have STEMI, bradycardia, or second-third degree heart block.  Patients who were initially judged to need dobutamine therapy were also excluded.  Intervention was continuation of home-dose beta-blocker therapy or discontinuation of beta-blocker for at least 3 days.  Primary endpoint was the general health and dyspnea at 3 days of hospitalization. 

Results:
Subjects: Analysis was performed in 147 patients (69 on BB therapy and 78 without BB).  There were no significant differences between groups including age, etiology (ischemic vs non-ischemic), ejection fraction, prevalence of atrial fibrillation, or home CHF treatment regimen.  The most common cause for acute exacerbation was non-adherence to therapy.  The beta-blockers most commonly used were bisoprolol (beta-1 blocker) 70%, carvedilol 11%, and atenolol 10%.  In the group on beta-blocker therapy, beta-blockers were stopped in four patients (three needed dobutamine and one had bronchospasm).

Hospital Courses: There were no significant differences in clinical features of heart failure (dyspnea, pulmonary rales, lower extremity edema, JVD, hepatomegaly) on the first 8 days of hospitalization (including day 3) between the two groups.  Patients without BB had higher heart rates :)  There were no differences in blood pressure during the course of hospitalization in the two groups.  No differences were observed in BNP levels either.  One death occurred in the BB group while two deaths occurred in the BB stopped group (difference not significant).

Long-term Follow-up: At 3 months, death rate and re-hospitalization rate were similar in both groups.  After 3 months, patients who were continued on beta-blockers were more likely to be receiving beta-blockers (90%) than those who had beta-blockers stopped (76%, p=0.04). 

Discussion: This paper shows that even during acute heart failure exacerbations, beta-blockers can be safely continued without adversely affecting rate of recovery.  On the other side of the fence, one can also say that this paper shows beta-blockers can be discontinued during hospitalization without affecting rate of recovery.  Between these two varying viewpoints, I would favor continuing beta-blockers since beta-blockers decrease myocardial ischemia and have proven anti-arrhythmic effect.  Also, as shown in the paper, once beta-blockers are discontinued upon hospitalization, the risk of beta-blockers not being restarted upon discharge increases.

While the paper demonstrates non-inferiority of continuing beta-blockers during acute heart failure, this trial has some important limitations.  First, the study was underpowered to detect potential benefit of beta-blockers in preventing arrhythmias during heart failure.  That part of the benefit of beta-blockers in acute heart failure remains speculative.  Also, in the study, the beta-blocker dosage was not standardized.  It is unclear if beta-blocker titrated to, for example, heart rate is beneficial in one dosage but detrimental at higher doses.