Matters of the Heart

Human embryonic stem cells can be used to create pacemakers or adult mesenchymal stem cells may be used as platforms for delivery of pacemaker genes to cardiac muscle

Dr KM Cherian

Cardiology has witnessed many advances that have changed the way cardiac diseases are treated. Here the top three trends in this field

Biological Pacemakers

The sinoatrial node is the primary biological pacemaker in the heart and a potential template for any biological pacemaker to be fabricated. All channels and transporters necessary to generate the heartbeat in mammals are present in the sinoatrial node myocyte membrane and in other pacemaker tissues of the conducting system and myocardium. Genetically-engineered pacemakers could be a possible alternative to implantable electronic devices for the treatment of slow heart beat or heart block. Molecular approaches to the development of a biological pacemaker are a conceptually attractive alternate treatment modality for heart blocks. The current advanced molecular strategies can convert cardiac muscle into pacemaker cells by stem cell or gene therapy. The genetic treatment can be applied to heart by use of viral constructs or stem cell therapy.

Human embryonic stem cells can be used to create pacemakers or adult mesenchymal stem cells may be used as platforms for delivery of pacemaker genes to cardiac muscle. The advantage of these cells includes their ability to make functional gap junctions and generate spontaneous rhythms.

Human mesenchymal stem cells (hMSCs) as a platform for delivery of genes into heart is a more attractive option because they can be obtained in large numbers, easily expanded in culture, capable of long-term transgene expression and their administration can be autologous or via banked stores.

Nanotechnology

There are certain limitations regarding the above approaches of development of biological pacemaker. Use of viruses to deliver the necessary genes has inherent problems. Regulating the level of expression to achieve optimal pacemaker rate is critical. Biological pacemaker needs an optimal cell mass and optimal cell-cell coupling for long term normal function. Conjugating non-viral polymer vector-gene complexes to magnetic nanobeads induced local gene expression in the heart via magnetic field stimulation may be a sound possibility. This technique could open a new prospect of gene therapy in the cardiovascular system.

Heart Transplantation

The incidence of heart failure and the number of patients with end stage heart disorders is increasing over the years. Despite significant advances with polypharmacy of heart failure, many patients progress to unsatisfactory stages with rather profound haemodynamic distress. Thus, the morbidity and mortality remain high. Since the first heart transplantation performed in 1967, more than 75,000 heart transplantations have been performed all over the world. However, over the last 13 years, the total number of transplants done in India remains at 50.

Recent Advances

The results of heart transplantation has improved tremendously because of introduction of cyclosporin as the immunosuppressive agent, better myocardial protection techniques, introduction of newer immunosuppressive agents like everolimus, use of biatrial technique and prophylaclic tricuspid valve repair.

Introduction of cyclosporin has reduced the rejection episodes significantly. Comparison of results between pre and post cyclosporin era has revealed significant improvement in survival and reduction of rejection episodes. Post transplant coronary artery disease remains the main cause of graft loss and death beyond the first years after transplantation. Use of intravascular ultrasound for detection of CAD, control of hyperlipidemia and use of everolimus has led to the reduction of post-transplant coronary artery disease. With better myocardial protection techniques available now, the cold ischemic time can be extended up to four hours and facilitates the use of hearts from marginal donors. Experimental studies in pig have shown that recovery of donor hearts from non-heart beating donors are comparable with recovery of organs harvested from heart beating donors with new preservation technique. Advanced age has traditionally been considered a contraindication for heart transplantation because of the reported effect of increased age on long-term survival.

The criteria regarding the recipient upper age have been expanded and recent studies in selected patients of 70 years age and older have shown that heart transplantation can be performed, as successfully as in younger patients with similar morbidity, mortality. Use of bicaval anastomotic technique instead of biatrial technique and prophylactic tricuspid valve repair has led to reduction of right ventricular failure in the peri-operative period. These advances have helped to improve the one-year survival rate to 90 per cent and five years survival rate up to 80 per cent in these patients.

In the West, the current cardiac transplant population differs from earlier population in that more number of critically-ill patients including those who have developed pulmonary hypertension; those with ventricular arrest device and pulmonary hypertension are undergoing transplantation. These previously identified risk factors did not adversely affect short or long-term survival of heart transplants in the current era. Heart transplant remains as the gold standard in the management of these patients with end stage heart disorder and incremental progress continues.

The total clinical experience in this country is very limited especially in view of reluctance for donating the organs. The expenses involved in it are not high as would imagine. As the number of years pass after the transplantation, the expenses for immuno-suppression comes down. In our experience, after five years of transplant, the expenses are in the region of Rs 400-500 per month. The longest survival in our series has been 11 years after heart transplant leading a normal life. The heart and lung transplant patient's longest survival has been two years.

For technology to develop, it is important to pay attention in great detail to basic sciences. It is necessary to have a combination of clinical medicine, regenerative medicine and basic sciences.

With inputs Dr Soma Guhathakurta and Dr Madhu N Sankar
The writer is MD Frontier Lifeline & Dr KM Cherian Heart Foundation Chennai
E-mail: drkmc@frontierlifeline.com