HEART TRANSPLANTATION. A GOOD OPTION FOR PATIENTS WITH END STAGE HEART FAILURE

The number of patients with heart failure is growing, as a consequence in the improvement in management of several cardiovascular diseases and the change in longevity of the population, as well as improved survival of heart failure patients. The incidence is estimated to be around 1%. Despite the advances in early diagnosis and treatment of cardiovascular diseases, including drugs and devices, the mortality in end stage heart failure is very high. Since the first human heart transplant performed in South Africa by Christian Barnard in 1967, the science of human transplantation has been changing. In the two last decades the heart transplant has evolved of a purely experimental procedure until becoming an effective therapeutic option for many patients with end stage cardiomyopathies. Improvement in treatment of patients with heart failure, better donor management, changes in surgical technique, better organ preservation, advances in the field of immunosuppression, initially with the introduction of cyclosporine as the main immunosuppressive agent and actually with other drugs like tacrolimus, everolimus, and mycophenolate and induction therapy significantly improved survival. In the last report of the Registry of the International Society for Heart and Lung Transplantation the transplant half-life, the time at which 50% of those transplanted remain alive, for the entire cohort is currently 10 years, with a half life of 13 years for those surviving the first year.
It is calculated between 10 to 40 procedures by millions of inhabitants per year to cover completely the indication of heart transplantation in a population. Heart failure is the main cause of death in 40.000 patients and contributes to this one in other 250,000 cases every year in the United States; nevertheless of the population of patients who potentially would benefit from a heart transplant, about 25,000, only 2.500 patients are undergoing of this procedure, around of 10%. This situation is explained for multiple reasons, in developed countries the most important is the limitation in the availability of donors, but in underdeveloped countries, like ours, there are a very limited waiting list and many donor’s heart are not utilized. In some cases patients with heart failure never know the benefit of this type of procedures, limiting his probability of survival.
Other interesting finding in the last report is the changing in characteristics of the most recent cohort. The primary indication for adult heart transplantation was non-coronary cardiomyopathy, the percentage of recipients aged 60 years has increased whereas the percentage of recipients 40 to 49 years of age has continued decline, 41% percent were receiving inotropic support and 29% were on mechanical support, only 44% percent of patients were hospitalized before the transplant and the percentage of patients with a panel reactive antibody (PRA) > 10% has increased from 5% to 12.4%.

Current Indications
Patients should only be considered for transplantation when they are on optimal therapy. The optimal non-pharmacological and pharmacological therapy include follow-up in a heart failure clinic, considering several therapies such as cardiac resynchronization therapy, implantable cardioverter defibrillator, coronary revascularization therapy, alternative surgical options and others. The decision to accept a patient for heart transplantation is made after a strict clinical evaluation by a cardiologist with broad experience in this topic, and of course by a transplantation team. The general experience is that the patients with clear indications are never referred, the majority of patients referred for transplantation are never listed and that those who are listed are rarely listed immediately after referral. It is important to evaluate the prognosis in an individual patient, although it is extremely difficult because of the variability of the clinical course of heart failure.

Criteria for Cardiac Transplantation

Accepted

High risk by Heart Failure Survival Score (HFSS)
Very low peak VO2 after reaching anaerobic threshold

NYHA class III-IV refractory to maximum therapy

Severe myocardial ischemia non-susceptible of revascularization therapy

Severe ventricular arrhythmia refractory to medical, surgical and ICD treatment

Probable

HFSS intermediate risk
Low peak VO2 and severe functional limitation

Instability of fluid status and renal function despite of adherence, daily weight, restriction of liquids and salt and flexible diuretics.

Recurrent unstable ischemia non-susceptible of revascularization therapy

Inadequate

HFSS low risk
Peak VO2 > 14 ml/kg/min without another indication
Low Left Ventricular ejection fraction

History of NYHA class III/IV

History of ventricular arrhythmias

Peak oxygen consumptionPatients with peak VO2 ≥ 14 ml/kg/min have 94% survival at one year follow-up. Patients with peak VO2 of 10-14 ml/kg will be insisted on medical treatment and reevaluate according to its evolution.Patients with peak VO2 less than 10 ml/Kg/min or less than 50% of predicted for age and gender during anaerobic exercise (respiratory quotient, RQ more than 1.05) are considered a clear indication of the procedure. In addition to peak VO2, it is important to consider others variables like VE/VCO2 slope during exercise more than 35, the VE/VCO2 slope/ pVO2 ratio more than 2.51 and peak systolic arterial pressure less than 120 mmHg.

Algorithm for Heart Transplantation.

Heart Failure Survival Score
The Heart Failure Survival Score (HFSS) predict risk in heart failure patients. Additionally, patients with a predicted high risk of dying by HFSS are the only group that has a survival benefit of transplantation.

Heart Failure Survival Score

High Risk ≤ 7.19, medium risk 7.2-8.09 and low risk ≥ 8.10. Event free survival rates at 1 year for the low, medium and high risk HFSS strata are 93 ± 2%, 72 ± 5% and 43 ± 7%, respectively.

See video of a Heart Transplant Procedure.

References

1. JACC 2004;43;787-793
2. Circulation 1997;95:2660-2667
3. Heart 2002;87;177-184
4. Netherlands Heart Journal 2008;16 Number 3
5. J Heart Lung Transplant 2006; 25:1003–23.
6. J Heart Lung Transplant 2008; 27:943–56.
7. JACC 2008; 52:587–98

WHAT IS IMPORTANT IN BONE MARROW DERIVED STEM CELL TRANSPLANTATION

Coronary artery disease is one of the leading causes of mortality in western world. One of the most important factors in the progression of left ventricular dilatation, the process of ventricular remodelling, is the loss of cardiomyocytes after an acute myocardial infarction. After the injury, the endogenous repair mechanisms are inadequate and the injured tissue is replaced by a fibrous scar, promoting more dilatation, infarct expansion, hypertrophy and loss of ventricular function until the patient develop progressive heart failure and death. Although the old concept that the adult cardiomyocytes is terminally differentiated has been challenged by the recent evidence that myocytes have the potential capability to initiate cell cycle after myocardial infarction, the ratio of myocytes undergoing proliferation and differentiation is only 0.015-0.08%. Recently, bone marrow derived stem cell transplantation has become a realistic option of treatment to replace damaged cardiomyocytes. The bone marrow cells are a heterogeneous group of undifferentiated cells that have the capacity to self-renew, proliferate, as well as the ability to generated many differentiate cells. Since the original work published by Orlic and colleagues in PNAS in 2001, many different human trials has been published. After twelve months of the original work, Bodo Strawer et al published the first clinical experience with bone marrow derived cell transplantation in patients with acute myocardial infarction. After that, several clinical trials and metaanalysis are now reported with data from more than 800 patients demonstrating the safety, feasibility and beneficial effects of this kind of therapy.

But, why many investigators say: “Curb your enthusiasm?” like one article published in Circulation as an editorial? There are many unresolved questions about stem cell transplantation, for example: what type of cells is better to regenerate cardiomyocytes? What is the better way to implant these cells? What kind of patients benefits to this type of treatment? What disease we should treat? Acute or chronic ischemic heart disease? At what point of the disease we should treat our patients?
At this time, we do not have all answers, however is possible to explain some negative results in clinical trials. The first concern was about the results of the BOOST trial. This study originally published in Lancet in 2004 showed a change in left ventricular ejection fraction (LVEF) by 6.7 percent after 6 months of follow-up in the bone marrow cell (BMC) group, however in the long term follow-up at 18 months the difference between groups was no longer significant, 3.1% percent improvement in LVEF in the control group vs 5.9% in the BMC group. Is possible to expect a trend toward improvement in LVEF in the control group? And is possible to demonstrate any differences between two groups at 18 months in a trial planned for a 6 months follow-up? The sample size was calculated to achieve a power of at least 80% to detect a difference in global LVEF change of 5 percent points between study groups, with a two sided significance level of p<0.05,> and common standard deviation of 6.5 percentage points for the global LVEF change from baseline to 6 months follow-up. We should remember that many drugs approved to use in the setting of acute myocardial infarction produce only modest improvement in LVEF.
What happened with the Janssens trial? The answer was in the baseline characteristics of patients in this trial. The mean LVEF was 55-56% and the bone marrow cell transplantation was performing in the first 24 hours of index event. The recent REPAIR AMI trial showed that the differences between groups are statiscally significant when the procedure is performing after 5 days of infarction and in patients with ejection fraction less than 50 %.
REPAIR AMI Results

The last trial with negative results was the ASTAMI trial, published in the New England Journal of Medicine in 2006. In the same issue of the journal was published the REPAIR AMI trial and TOPCARE CHD. The trials used different protocols for cell isolation and storage. Cell isolation protocols have a major impact in functional capacity of stem cells. It affects significantly the recovery of cell numbers, hematopoietic and mesenchymal colony forming cells, and the functional activity.

Cell Isolation Protocol
ASTAMI

REPAIR AMI

Finally, in the field of stem cell transplantation for myocardial regeneration, we are agreeing with the phrase of Winston Churchill: “Now is not the end, it is not even the beginning of the end, but it is perhaps, the end of the beginning”.


References

1. Circulation. 2006; 113:1287-1294.
2. European Heart Journal 2007 28, 766–772.
3. Lancet 2004; 364: 141–48.
4. www.thelancet.com Published online January 5, 2006 DOI:10.1016/S0140-6736(05)67861-0
5. N Engl J Med 2006; 355:1199-209.
6. N Engl J Med 2006;355:1210-21
7. European Heart Journal (2006) 27, 2775–2783
8. N Engl J Med 2006; 355:1222-32.
9. J Am Coll Cardiol 2007;50:1761–7)

Trasplante Celular

STEM CELLS TRANSPLANTATION FOR MYOCARDIAL REGENERATION http://www.scielo.org.co

Heart failure is a heterogeneous clinical syndrome that is developed subsequent to an " index event", the one which produces damage of the cardiac tissue, for the lost of cardiomyocytes or by the alteration of the capacity of the myocardium to generate an efficient force for the ventricular contraction. The initial injury can be of sudden appearance as in the acute coronary syndrome or gradual as in the chronic coronary heart disease. Independent of the factor that generate the syndrome, is produced a series of hemodynamic alterations and neurohormonals responses with complex molecular changes, that lead to the progression of the ventricular dysfunction and to a greater loss of contractile cells.
The therapeutic strategies developed to interrupt this vicious circle of ventricular remodeling, only change the conditions of the myocardial work, with the consequent improvement in the quality of life and in mortality. However, this therapeutic approach does not produce myocardial regeneration, what permits the progression of the disease until terminal heart failure and death.
Experimental and clinical studies have shown that the implantation of bone marrow stem cells produce angiogenesis and improves cardiac function in patients with acute and chronic ischaemic heart disease. This therapy produces meaningful improvement in symptoms, exercise capacity, in the functional state, in the size of the myocardial perfusion defect by nuclear medicine, in the ejection fraction and decrease of the end-systolic volume of the left ventricle, without complications related with the procedure.
Conclusion: The bone marrow stem cells transplantation is an effective and safe therapy to promote neovascularization and improve perfusion and myocardial contractility in patients with acute and chronic ischaemic heart disease and no other option for standard revascularization therapies.