Understanding Heart Transplantation

Heart transplantation is one of the most successful advances in modern medicine. A fascinating aspect is that heart transplantation is the product of research, surgical technique, and medical forethought that have come together to allow its occurrence as a regular procedure saving countless lives.

The Basics of Heart Transplantation

Heart transplantation is the replacement of a failing heart with a healthy heart from a suitable donor. It is an operation usually reserved for people with a poor condition of their heart which hasn’t improved with medications or other therapies.

The number of people in need of heart transplantation far exceeds the number of available donor organs. Because of that, there is a waitlist for receiving a donor heart, and a multidisciplinary team of healthcare providers put a patient on this waiting list only after determining that a transplant would be the best course of action. Patients should undergo a rigorous assessment and be cleared for transplantation as those in poor overall health might not be able to survive the operation and post-operative period.

Reasons for Heart Transplantation

Heart disease is the leading cause of death worldwide and heart transplantation might be needed for various reasons. The most common reason is severe heart failure, a condition in which the heart fails to pump blood effectively through the body. If severe heart failure is diagnosed and other therapies are exhausted, then the patient might be put on a transplant waiting list in the hopes of receiving a heart transplantation before  the underlying condition leads to death. Other reasons are heart problems people are born with (congenital heart disease), or dangerous recurrent abnormal heart rhythms (arrhythmias) not controlled by other treatments.

Outcomes and Risks of Heart Transplantation

Survival and functional status after heart transplantation are generally excellent. Patients are usually able to return to work, regardless of their profession. The 1-year survival is almost 90%, and the mean survival for donor heart recipients is 13 years.

As with any type of surgery, however, there are certain risks which include the following:

• Bleeding
• Infection
• Breathing problems
• Kidney failure
• Rejection of the donor heart
• Death

Patients are closely and regularly monitored following heart transplantation as there is the risk that the recipient’s body rejects the donor heart. The immune system is set up to see any foreign object as a threat and attack it and this also the case with a donor organ which comes from another person. Anti-rejection medications have revolutionized the field of heart transplantation and currently available prescription medications provide a good chance that the donor organ will be accepted. There are side effects to these medications, however, including the following:

• Infections that might occasionally be severe
• Cancer
• Kidney failure

Non-compliance with the recommended medication and monitoring plan will increase the chance that the donor heart is rejected. As such, patients undergoing heart transplantation should closely follow their doctors’ orders.

How a Heart Transplant is Performed

The first step to heart transplantation is the identification of a suitable donor heart. After that, the donor organ is procured and transported to the recipient’s hospital where the heart transplant will take place. The surgery is an open-heart procedure that takes several hours.

First, medications that put the patient to sleep (anesthesia) are given. Then the chest wall is cleaned and possibly shaved, and the surgeon makes an incision in the chest.

The chest bone is cut and separated, and the rib cage is opened so that the surgeon can operate on the heart. Tubes are put into the chest vessels to pump oxygen-rich blood through the body (heart-lung bypass machine) while the transplant is being performed. The diseased heart is removed and the donor’s heart is sewed into place. Then, the surgeon will attach the major blood vessels to the donor heart and ensure there is no leakage.

The donor heart often starts beating once blood flow is restored. Sometimes the donor heart is given an electrical shock make it beat properly. Then, the team will watch the donor heart closely to ensure that it is working properly. Finally, the surgeon will rejoin the chest bone with small wires and sew the skin back together. Tubes will be inserted in the chest to drain blood and fluids and a sterile bandage will remain in place until the wound is fully healed. Medications are given to help with pain control, and a ventilator is used to help with breathing. Fluids and medications are given via intravenous tubes.

The patient usually stays for a few days in the intensive care unit (ICU) and is then moved to a regular hospital room. Most times, patients remain in the hospital for a week or two, but the time spent in the ICU and in the hospital in general can vary.

Conclusion

Heart transplantation is a successful treatment option for patients suffering severe heart disease. It has been made possible after years of experimentation in the lab and bedside, and has become a standard, first line therapy option saving the lives of countless people. What is certain, is that more innovations and advances lie ahead to make this therapy even more successful and applicable to more and more patients. Heart transplants will continue to get better and more successful with further advances in cardiovascular research.

Next Frontier – CVRTI Research

CVRTI Investigators are not just performing heart transplants[TH1]  and taking care of patients[TH2]  before and after they receive their transplant, but are advancing science[TH3]  to also recover failing hearts[TH4] , understand the science of what makes hearts fail (Chaudhuri, Drakos, Dosdall, Franklin, Hoareau, Hong, Palatinus, Ranjan, Shaw)[TH5] , and developing novel gene therapies to treat patients with heart failure (Dosdall, Hoareau, Hong, Palatinus, Shaw)[TH6] .  Each heart transplant is a medical miracle yet CVRTI Investigators are advancing the field towards an ultimate goal of patients never needing a replacement heart to survive.

Resources:

Alraies MC, Eckman P. Adult heart transplant: indications and outcomes. J Thorac Dis. 2014 Aug;6(8):1120-8. doi: 10.3978/j.issn.2072-1439.2014.06.44. PMID: 25132979

Ace Inhibitors vs Beta Blockers vs Angiotensin Receptor Blockers: Their Role in Heart Failure Therapy

Heart disease is extremely common in the USA. Over 600,000 people die from heart disease in the United States each year, accounting for 1 in 4 causes of death. Heart disease can progress into heart failure, from which it is difficult for patients to recover normal heart function.

Fortunately, thanks to advances in research, there are more treatment options and the number of available pharmacological therapies for treating heart failure, particularly for heart failure with reduced ejection fraction (HFrEF), have grown.

Efficacy of Multiple Drug Therapies for Heart Failure with Reduced Ejection Fraction

The use of new therapies as well as multiple drug therapies together has improved the overall prognosis of HFrEF.

Heart failure patients used to be treated with vasodilators and then clinical trials established that ACE inhibitors and angiotensin receptor blockers (ARBs) are crucial aspects for cardiac recovery of patients suffering from HFrEF. These medicines have been shown to reduce morbidity from heart failure and should be administered as the first line of therapy in heart failure patients.

Adding Beta Blockers and MRAs to Ace Inhibitor and ARB Treatment Plans

In addition, these studies found that in patients who are being treated with ACE inhibitors and ARBs, adding beta-blockers and mineralocorticoid receptor antagonists (MRAs) to the treatment regimen provides additional benefits.

In recent developments, a study found that the use of angiotensin receptor neprilysin inhibitor in patients was shown to be superior in some circumstances to the traditional pharmaceutical ACE inhibitor usually used, called enalapril.

The Importance of ACE Inhibitors

ACE inhibitors work by chemically reducing peripheral resistance and reducing the load on the failing myocardium by inhibiting the conversion of angiotensin I to angiotensin II. Preventing this conversion inhibits vasoconstriction and allows the relaxation of the vasculature.

The CONSENSUS trial, which compared enalapril ACE inhibitor with placebo, showed that enalapril reduced patients’ overall mortality risk by 27%. Enalapril also slowed or stopped the progression of heart failure with reduced ejection fraction in these patients.

Patients Who Need to Exercise Caution When Using ACE Inhibitor Treatments

ACE inhibitors are generally well tolerated by patients. However, patients with conditions such as pre-existing hypotension, baseline hyperkalemia, those receiving concomitant potassium supplements or potassium-sparing diuretics, or previous angioedema from ACE inhibitor use, should use caution when taking these medications. In some cases, another pharmaceutical therapy should be chosen for patients that match this profile.

The Importance of Angiotensin Receptor Blockers

Similar to ACE inhibitors, ARBs inhibit the action of angiotensin II in patients with heart failure with reduced ejection fraction. However, instead of preventing the conversion from angiotensin I to angiotensin II, like ACE inhibitors do, ARBs work by blocking angiotensin II from binding to its receptor.

Blocking the action of angiotensin decreases vasoconstriction and relaxes vasculature. However, ARBs do not cause inhibition of kininase as ACE inhibitors do. For this reason, ARBs can be a suitable pharmaceutical therapy for patients who are intolerant of ACE inhibitors.

Comparing ARBs and ACE Inhibitors in Heart Disease Therapy

It’s been shown that ARBs have the same result as ACE inhibitors in heart disease therapy; they both reduce morbidity. In the 2003 Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM Alternative) study, ARBs showed great potential in cardiovascular outcomes compared with placebo groups. The study focused on cardiovascular death or hospital admission in patients with symptomatic heart failure with an ejection failure of 40% or less who were intolerant of ACE inhibitors. The outcome shows that 33% of patients who took the ARB therapy had passed away due to cardiovascular causes, compared to 40% in the placebo group.

The Importance of Beta Blockers in Heart Failure

The beneficial effects of beta-blockers in patients who have heart failure with reduced ejection fraction have been long studied. Since 1975, studies have shown that beta-blockers have decreased mortality in these patients.

So far, bisoprolol, carvedilol, and sustained-release metoprolol succinate are the beta-blockers that have been widely studied in large clinical trials. These three medicines all reduce mortality rates in patients with HFrEF. For this reason, beta-blockers are integrated as a first line of defense in many heart disease treatments.

These medicines all work in the same way: they block the β1 receptor located in the heart.  By stopping β1 receptors, these beta-blockers prevent ventricular remodeling, thus enhancing a patient’s likelihood of recovery from heart disease.  At first, beta blockers can decrease heart function, so need to be initiated carefully with low dosage that is increased slowly over time.

Final Thoughts on Heart Failure Therapies

In addition to ACE inhibitors, ARBs, and beta-blockers, there are many other pharmaceutical heart failure therapy options for patients today. These other therapies include aldosterone receptor antagonists, diuretics for fluid retention control, vasodilators, and digoxin.

Beta-blockers and ACE inhibitors have been found to greatly decrease the risk of morbidity in a wide array of patient demographics. However, the best results come from personalized therapy plans where medications are chosen for the specific patient and their unique needs.

Heart Failure Research at the Cardiovascular Research and Training Institute

The Investigators in the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) are pioneering the development of new drug therapies for heart failure. Over the past decade, we have been exploring molecular mechanisms underlying genetic dysregulation, proteomics alteration, insufficient energy supply, and metabolicabnormalities of the heart  when it fails. By studying the fundamental biology of healthy and failing heart muscle cells, our Investigators are identifying critical molecules that can be targeted for the functional rescue of failing hearts. With many years of extensive research at the bench, researchers in the CVRTI now found two proteins (GJA1-20k  and cBIN1 ) that can be used to treat injured hearts in both acute and chronic settings. GJA1-20k is a stress response protein which helps maintain normal heart rhythms and energy supply. During acute injury, GJA1-20k can maintain myocyte survival, thus limiting heart damage.  cBIN1, on the other hand, is a protein organizing the excitation-contraction machinery in heart muscle cells to maintain normal pump function of the heart. A multidisciplinary team has been formed within the CVRTI to use gene transfer methods to deliver exogenous GJA1-20k or cBIN1 to failing hearts. The therapeutic effect  of GJA1-20k and cBIN1 gene therapy  is currently under advanced preclinical studies and toxicity and safety studies are underway in anticipation of clinical trials. 

Effects of Epigenetics in Cardiovascular Disease & Research

In biology, epigenetics is the study of heritable changes that do not involve alterations in the DNA sequence. The Greek prefix ‘epi’ means over, outside of, or around. Thus, its definition is the feature of the genetic code that exists or develops in addition to traditional genetic inheritance.

Epigenetics is, in essence, the study of how things like lifestyle choices and the environment can cause changes that affect the way your genes work, including what diseases you become predisposed to. Most epigenetic changes are reversible; however, their effects can worsen or cause diseases that are not.

Epigenetics has emerged as a powerful tool to aid in the therapeutic treatment of cardiovascular disease by looking closely at the epigenetics of cardiovascular patients and customizing treatment plans based on someone’s unique epigenetic factors.

Studies That Link Epigenetics and Cardiovascular Disease

Epigenetics was initially studied in patients with cardiovascular disease to better understand their prominent role in inflammation and vascular involvement. These studies in cardiovascular patients showed a significant number of certain epigenetic modifications affecting the development and progression of cardiovascular disease.

In the case of cardiovascular hypertrophy, epigenetics studies found that cardiac hypertrophy is linked with histone acetylation, implicating both histone acetyltransferases (HATs) and histone deacetylases (HDACs).

Cardiac Arrhythmias

Epigenetics has also been studied in afflictions like cardiac arrhythmias. Atrial fibrillation is one of the most common heart arrhythmias, particularly in older patients, and can be deadly. In a study done on its role in atrial fibrillation, transgenic mice were programmed to develop cardiac hypertrophy, and then treated with an epigenetic approach, “Liu and colleagues showed that an injection of a specific HDAC inhibitor reverses atrial fibrosis and diminishes atrial fibrillation vulnerability following an electrical stimulation.” (1)

Among miRNAs that have been widely studied in experimental environments, miR-1 was found to be essential in normal electrophysiological conduction. When miR-1 was deleted in rodents, the rate of sudden death was much higher. This points to the idea that the miR-1 subtype of miRNAs is essential to healthy cardiac rhythms and lowering levels of miR-1 could signal an oncoming arrhythmia. Epigenetic interventions can more effectively return the heart back to a normal state when combined with traditional methods.

Atherosclerosis

In atherosclerosis (hardening of the arteries or artery disease), epigenetic studies reveal some key factors to recognize developing atherosclerosis, sometimes before the patient even feels symptoms. DNA methylation, miRNAs, and epigenetic mechanisms have all been described in atherosclerosis. Two studies were done that show coexisting DNA methylation alongside atherosclerotic lesions in rodents. Interestingly, it was observed that DNA methylation could often be detected in animals far before the anatomical presentation of the disease itself. In short – DNA methylation testing could stand as a powerful screening tool to determine the early stages of atherosclerosis.

Diabetes and Cardiovascular Disease

In studying the relationship between diabetes and cardiovascular disease, epigenetics can be used to demonstrate the effect of untreated or poorly treated diabetes on worsening heart disease. In a study conducted and published by Louisa Villeneuve and colleagues, they found connections between diabetes and the inflammatory epigenetic reactions that can be caused by high glucose.

This study found that the occurrence of inflammatory genes in vascular cells that were exposed to high glucose for extended periods was increased. (2) Conversely, they found that histone H3 (specifically, H3K9me3), which is known to guard the body against the biochemical effects of diabetic inflammation, were decreased in environments in which they had to succumb to high glucose. The finding shows that uncontrolled glucose levels (usually caused by uncontrolled or poorly treated diabetes) can simultaneously cause inflammatory reactions while hindering the effectiveness of key histones like H3K9me3.

In all studies that have been completed, one thing was clear. Epigenetic changes are a clear indicator that can tell us important information about a patient’s ongoing cardiovascular disease or likelihood of developing impending cardiovascular disease.

Conclusion on Epigenetics and Cardiovascular Research

Epigenetics are genetic changes that happen in reaction to external factors. These external factors are usually caused by environmental or lifestyle exposures. Epigenetic changes can be important ‘warning signs that a disease is worsening or about to occur. Furthermore, by studying epigenetics in relation to heart disease, we can get a better idea of what prevention and intervention tactics should be taken.

Epigenetic factors and expressions are somewhat unique and can vary from patient to patient, but overall, there are quantifiable patterns of what role epigenetics plays in cardiovascular disease. Studying these micro-changes can make a big difference in preserving the quality of life in patients with cardiovascular disease and aid in early detection of patients with epigenetic risk factors for the disease.

Cardiovascular Research and Training Institute

Researchers at the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) are focused on understanding the epigenetic factors that alter transcription and thereby cardiac physiology during the development of arrhythmias, cardiac hypertrophy, and heart failure. Specifically, research at CVRTI has centered on understanding the role of lysine methyltransferases in modifying histones within the nucleosome, characteriz ing specific histone modifications that are differentially regulated during disease, and identifying the role of transcription factors  in pathological remodeling and reverse remodeling . These studies have utilized zebrafish , mouse models and human induced pluripotent stem cells  as transgenic models of disease to further our understanding of these key processes. By incorporating cutting-edge technology with novel animal models of disease, the epigenetics research at CVRTI is making significant contributions not only to basic science, by elucidating the fundamental basis of gene expression and transcriptional regulation in the cardiomyocyte, but also to the clinical realm by identifying key regulators of cardiac pathophysiology that may also protect the heart from ischemic injury or heart failure.