Cardiac allograft vasculopathy prevention

# Overview

# Prevention
As the pathogenesis of CAV consists of both immunological and non-immunological insults, it has been suggested that preventative strategies should consist of control of risk factors for CAV and optimal immunosuppressive therapy. However, the best preventative strategy to delay development of CAV is yet to be determined.

## Optimization of Immunosuppressive Therapy
The rapamycin derivatives, sirolimus and everolimus, have been proven to have significant benefit in the prevention of CAV in addition to statins. Other options for immunosuppressive therapy include :
- Corticosteroids
- Mycophenolate mofetil

### Everolimus and Sirolimus
- Act by inhibiting mTOR (mammalian target), thereby having anti-proliferative effects in response to allo-antigens.
- Everolimus is currently not FDA approved for clinical use in the United States.
- Associated with significantly reduced incidence of graft rejection.
- Serial IVUS studies to evaluate intimal proliferation demonstrated smaller increase in maximal intimal thickness and intimal index in patients taking everolimus . Similar results were found in trials that studied sirolimus .
- Side effect profile:
Everolimus: increase in serum creatinine levels, hyperlipidemia, anemia, thrombocytopenia, peripheral edema, hypertension. However, opportunistic viral infections less often seen.
Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.
- Everolimus: increase in serum creatinine levels, hyperlipidemia, anemia, thrombocytopenia, peripheral edema, hypertension. However, opportunistic viral infections less often seen.
- Sirolimus: Similar to everolimus, however recent reports of impaired wound healing have been reported in renal transplant patients.

### Mycophenolate mofetil
- Studies have shown trend towards a lower maximal intimal thickness on IVUS, lower incidence of retransplantation and death with mycophenolate when compared to azathioprine .
- Side effect profile: chest pain, hypertension/hypotension, tachycardia, peripheral edema, headache, fever, rash, abdominal pain, nausea, diarrhea/constipation, leukopenia, anemia, thrombocytopenia, liver function test abnormalities, abnormal creatinine and BUN, increased risk for infections

### Calcineurin inhibitors
- The use of calcineurin inhibitors i.e cyclosporin and tacrolimus have not been shown to lower the risk of developing CAV.
- This suggests that other immunological pathways may exists that play a role in the pathogenesis of CAV. Moreover, side effects from use of these drugs leads to a high incidence of not only chronic renal disease but also hypertension and hyperlipidemia which in turn may accelerate the process of CAV.

## Non-Immunosuppressive therapy
Non-immunosuppressive therapy includes:
- Lipid lowering therapy with statins
- Anti-hypertensive medications to optimize blood pressure
- Optimal glucose control in diabetic patients
- Anti-cytomegalovirus therapy
- Antioxidants

### Statins
- Obesity, elevated levels of cyclosporine, use of steroids and insulin resistance all contribute to the development of hyperlipidemia in cardiac transplant patients. Use of statins have proven to reduce mortality in multiple randomized controlled trials.
- Immunomodulatory effects of statins include:
Inhibition of smooth muscle proliferation
By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
By inhibiting expression of genes for growth factors essential for proliferation of smooth muscles
Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against atherogenesis.
Prevents attachment of monocytes to endothelium, which is the first step in atherogenesis 
In the presence of immunosuppressants like cyclosporin A, statins reduce natural killer cell activity, T cell proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A .
- Inhibition of smooth muscle proliferation
By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
By inhibiting expression of genes for growth factors essential for proliferation of smooth muscles
- By inhibiting lipid production, statins halt the intra-cellular signal transduction and consequently protein synthesis
- By inhibiting expression of genes for growth factors essential for proliferation of smooth muscles
- Direct influence on gene expression of endothelin-1, leading to improved endothelial function thereby protecting against atherogenesis.
- Prevents attachment of monocytes to endothelium, which is the first step in atherogenesis 
- In the presence of immunosuppressants like cyclosporin A, statins reduce natural killer cell activity, T cell proliferation and activity in vitro. Moreover, statin induced LDL receptor activation leads to increase in intracellularly available LDL-bound cyclosporin A .
- Long term effects of simvastatin: The effects of simvastatin over a period of 8 years was studied in a randomized controlled trial by Wenke and colleagues  in which the study group received simvastatin on the fourth post-operative day, whereas the control group was managed with dietary therapy alone.
At the end of 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
- At the end of 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P< 0.006 by log rank, HR 0.24,95% CI, 0.08-0.71). The incidence of angiographically proven CAV was also found to be lower in the simvastatin group compared to the control group.
- Long term effects of pravastatin: Another randomized controlled trial by Kobashigawa and colleagues studied the effects of pravastatin at one year  and at the end of ten years .
After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.
- After 1 year of follow up, the patients in pravastatin group had reduced incidence of severe episodes of transplant rejections causing hemodynamic instability as well as CAV determined by angiography and autopsy. This group also had better survival compared to the non-pravastatin group.
- These significant differences also persisted in a 10 year follow up of the same study cohort which, similar to the above mentioned study, demonstrated survival benefits and reduced incidence of CAV by angiography in an intention to treat analysis.

### Calcium Channel Blockers and ACE inhibitors
- Mechanisms by which calcium channel blockers (CCB's) and ACE inhibitors are thought to prevent CAV are as follows :
Preservation of endothelial function
Reduced oxidative stress
Suppression of smooth muscle cell migration and proliferation
Additionally nifedipine has been shown to cause vasodilatation in coronary arteries with endothelial dysfunction and inhibition of endothelin production .
- Preservation of endothelial function
- Reduced oxidative stress
- Suppression of smooth muscle cell migration and proliferation
- Additionally nifedipine has been shown to cause vasodilatation in coronary arteries with endothelial dysfunction and inhibition of endothelin production .
- In a study by Schroeder and colleagues involving 57 cardiac transplant patients randomized to either receive diltiazem or placebo, showed that the coronary artery diameter decreased at a slower rate in patients receiving diltiazem compared to placebo at 1 year follow-up. However the overall survival at the end of 2 years remained unchanged.
- Synergistic effect of CCBs and ACE inhibitors: This was suggested by Erinc et al. when their study involving 82 heart transplant patients showed that combined use of CCB's and ACE inhibitors was associated with improvement in IVUS indices of CAV. These patients were randomized to receive either calcium channel blockers or ACE inhibitors or both or placebo and followed for one year.
- However, longer term trials are required to prove the effects of CCBs and ACE inhibitors on survival and mortality.

### Anti-cytomegalovirus Therapy
- Cytomegalovirus (CMV), the most common infection encountered in cardiac transplant patients, may be subclinical and causes acceleration of CAV development by the following mechanisms:
Dysregulation of nitric oxide pathway,
Cytokine activation and
Affects mononuclear adhesion and smooth muscle migration, causing endothelial dysfunction
- Dysregulation of nitric oxide pathway,
- Cytokine activation and
- Affects mononuclear adhesion and smooth muscle migration, causing endothelial dysfunction
- Simialr to CMV, adenovirus, parvovirus and Chlamydiae pneumoniae is thought to trigger development of CAV .
- Gancicylcovir appears to slow the progression of CAV. Also early control of subclinical CMV infections may limit rejection and prevent CAV .

### Antioxidants
- Mechanism of antioxidants in prevention of CAV involved:
Augmenting endothelial nitric oxide (NO) activity
Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
- Augmenting endothelial nitric oxide (NO) activity
- Inhibiting the deleterious effects of free oxygen radicals on nitric oxide synthesis thereby preventing endothelial dysfunction and development of CAV
- Vitamin C & E, L-arginine and tetrahydrobiopterin supplementation can theoretically be beneficial, however long term trials to establish the effects of these agents in improving survival are lacking .