Nutritional Intervention in Heart Transplant Recipients – Dietary Recommendations (Treatment Strategies in Cardiac Transplantation) Part 2

Dyslipidemia

Dyslipidemia is common after cardiac transplantation. Multiple factors in transplant recipients promote dyslipemia: inappropriate diet in combination with reduced physical activity, immunosuppression with cyclosporine and steroids, anti-hypertensive agents and concomitant conditions, such as diabetes, obesity, age and male gender. Total and low-density lipoprotein (LDL) cholesterol are prominent risk factors for major progression of CAV disease (Pethig et al., 2000).

To accommodate the lipid profile the following is recommended: a cholesterol intake below 300 mg per day, to limit total dietary fat to less than 30% of total calories, to limit saturated fats to less than 10% of total calories, to increase mono- and polyunsaturated fat (the latter about 7% of total calories) (Casado, 2005).

In recent years the benefit of certain food components has been referenced. Phytosterol, plant stanol and sterol esters, reduce serum cholesterol by inhibition of cholesterol absorption. Substitution of part of the daily fat intake with stanol ester margarine has been shown to reduce serum cholesterol by 10.2% and LDL cholesterol by 14% after one year (Miettinen et al., 1995).

Margarine containing stanol/sterol esters is a safe, simple and efficient way to reduce total LDL cholesterol in patients after cardiac transplantation. The tolerance of the margarine containing stanol or sterol esters is good. It is possible to reduce the dose of statins while maintaining LDL cholesterol at <115 mg/ dl (Vorlat et al., 2003). The concomitant use of statins and stanol esters has shown additional lipid-lowering effects (Blair et al., 2000).


Phytosterol therapy produces an average 10-11% reduction in LDL cholesterol concentration, but it is unknown whether this effect persists beyond two years. Phytosterol products are well tolerated and have few drug interactions, but their long-term safety has not been established. Current evidence is sufficient to recommend phytosterol for lowering LDL cholesterol in adults (Malinowski & Gehret, 2010).

On the other hand, m-3 fatty acids have been studied in cardiac transplant recipients treated with cyclosporine and have been found to have beneficial effects on hypertension (Andreassen et al., 1997; Holm et al., 2001) and coronary endothelial function (Fleischhauer et al., 1993). They may also be added to statin therapy in cardiac transplant recipients with persistent hypertriglyceridemia. An m-3 fish oil preparation consisting of 80% m-3 polyunsaturated fatty acids (44% eicosapentaenoic acid and 36% dehydroacetic acid) when used with simvastatin has been shown to reduce triglyceride levels by an additional 20-30% (Durrington et al., 2001). When triglyceride levels are >200 mg/ dl after LDL-lowering therapy, a trial of an m-3 concentrate or fish oil (which usually contains approximately 35% ffl-3 polyunsaturated fatty acids) is reasonable because of the potential benefits and favourable safety profile (Bilchick et al., 2004).


Beneficial effects of certain nutrients

There are investigations that demonstrate that single nutrients, such as arginine, m-3 fatty acids and pyruvate, and the fasted and post absorptive state can dramatically alter the short and long-term function of transplanted organs (Helton, 2001).

Nutrition also may be used to help treat symptoms of end-stage organ failure. For example, an increased intake of calories and protein should help deter fat and muscle loss. Fluid retention can be treated with dietary sodium restriction. Branched-chain amino acid-enhanced formulas may be helpful for patients with intractable hepatic encephalopathy. Adequate intake of iron, folic acid and B vitamins can prevent or treat anaemia. Medium-chain triglyceride supplementation may be useful when steatorrhea and long-chain fat malabsorption are present (Hasse, 2001).

Calcium and vitamin D

Calcium and vitamin D are necessary when patients have osteoporosis or renal osteodystrophy (Hasse, 2001). Magnesium depletion (hypomagnesemia has been documented in cardiac transplant recipients) which may be the results of diuretic therapy, has been implicated as a risk factor for osteoporosis.

After transplantation, there is further acceleration in bone loss. Factors associated with congestive heart failure that may contribute to bone loss include cardiac cachexia, reduced exercise or immobilisation, smoking, alcohol abuse, low calcium intake, heparine administration and loop diuretics (Pisani & Mullen, 2002). Vitamin D deficiency is significantly more common in the patients with more severe heart failure (Rodino & Shane, 1998).

Optimal treatment of osteoporosis requires adequate calcium and vitamin D intake. The Institute of Medicine recommends calcium intakes of 1000 to 1500 mg/ d (depending on age and menopausal status) for adults (NIH, 2001) and vitamin D (400-1000 IU, or as necessary to maintain serum 25-hydroxyvitamin D levels above 30 mg/ ml= 75 nmol/L) (Costanzo et al., 2010). Of note, bone loss occurs despite supplementation with vitamin D and calcium (Shane et al., 1997). The use of calcium and vitamin D supplements, although recommended, is inadequate for the prevention of bone loss and complications such as vertebral fractures (Pisani & Mullen, 2002).

Folic acid

The aminoacid homocysteine has recently been identified as a risk factor for native coronary artery disease (Welch et al., 1997) and even mild to moderate hyperhomocysteinemia is associated with premature vascular disease (Kark et al., 1999). Growing evidence suggests that elevated total plasma homocysteine levels (tHCY) are associated with CAV following heart transplantation (Kutschka et al., 2001).

The homeostasis of homocysteine is altered in solid organ transplant recipients and may be partially caused by cyclosporine. The cyclosporine may be associated with secondary hyperhomocysteinemia by inducing renal insufficiency.

Homocysteine is formed by the transmethylation of methionine. Its catabolim is either through a folate-cobalamin dependent remethylation pathway catalyzed by methionine synthase, or by transsulfuration by cystationine-synthasa, a vitamin B6-dependent enzyme (Chan, 2001).

Beside parameters like age (Kark et al., 1999), sex (Selhub et al., 1999), genetic determination (Deloughery et al., 1996) and renal function (Moustapha et al., 1998) are influenced by dietary intake of vitamins B6, B12 and folic acid (Selhub et al., 1999; Verhoef et al., 1996). Hyperhomocysteinemia as well as deficiencies in folate and vitamin B6 are common in HT recipients, especially in older individuals and patients with renal insufficiency (Kutschka et al., 2001).

Folic acid supplementation (5 mg per day) provides a simple and effective measure to lower elevated tHCY concentrations without side effects (Kutschka et al., 2001, Chan, 2001).

L-Arginine

Endothelial dysfunction is associated with the decreased exercise capacity observed in HT recipients. L-Arginine supplementation (LAS) increases nitric oxide (NO) and decreases endothelin-1 plasma concentrations, thereby improving endothelial function and exercise capacity in heart failure or HT patients (Doutreleau et al., 2004; Rector et al., 1996).

The NO/endothelin ratio significantly increases after chronic LAS, suggesting that the beneficial effects of L-Arginine (amino acid precursor of NO production) on the exercise capacity of patients after an HT might, at least partly, be related to an improvement in skeletal muscle vasodilatation and oxygen delivery, and extraction during exercise as suggested by the significant increase in the oxygen pulse after LAS. This pilot study provides support that oral LAS may be a useful adjuvant therapy to improve the quality of life and exercise tolerance in HT recipients (Doutreleau et al., 2010). The L-Arginine-NO pathway has been recognized to play critical roles during infection, inflammation, organ injury and transplant rejection (Helton, 2001).

These dietary interventions, when used in combination with other therapies, may improve the quality of life of patients (Hasse, 2001).

Side effects of cyclosporine

Cyclosporine has significant effects on the metabolism and disposition of several biomolecules. Hyperglycemia, hypercholesterolemia and electrolyte disturbances are a few of its common side effects. Hyperkalemia (cyclosporine has a direct effect on the renin-angiotensin-aldosterone system which further worsens potassium homeostasis [Bantle et al., 1985]) and hypomagnesemia are the two most frequently observed electrolyte disorders caused by this calcineurin inhibitor.

Patients taking cyclosporine should be educated on their dietary potassium intake (the hypertension is another common side effect of cyclosporine). Most patients will subsequently require oral supplementation of magnesium to maintain a normo-magnesic state and the chronic hypomagnesemia may affect parathyroid function and rennin activity (Ichihara et al., 1993; Mori et al., 1992; Navarro et al., 1999). The altered parathyroid hormone activity can have a secondary effect on calcium and vitamin D disposition, and may indirectly contribute to post transplant osteoporosis (Grenet et al., 2000; Thiebaud et al., 1996).

Mediterranean diet

It has been suggested that the healthy effects of the Mediterranean diet observed in epidemiologic studies are exerted partly through plausible mechanisms: improved lipid profiles (Bemelmans et al., 2002; Zambon et al., 2000) and reductions in blood pressure (Perona et al., 2004) , insulin resistance and systemic markers of inflammation (Chrysohoou et al., 2004; Esposito et al., 2004). These beneficial effects on surrogate markers of cardiovascular risk add biological plausibility to the epidemiologic evidence that supports the suggested protective effects of the Mediterranean diet (Estruch et al., 2006). Moreover, the Mediterranean diet could protect against the development of coronary heart disease, not only because of its beneficial role regarding cardiovascular risk factors, but also due to a possible effect on body weight and obesity (Kastorini et al., 2010).

Drug-nutrient interaction

HT recipients are polymedicated patients; they use multiple medications to manage graft rejection, opportunistic infections and other associated complications. This patient population has a very high risk of drug-nutrient interactions (Chan, 2006). In some cases, the interactions are not identified until serious adverse events have occurred.

The consequences of unrecognized and unmanaged drug-nutrient interactions in the transplant recipient can be very serious and these adverse outcomes represent important contributing factors to post transplant morbidity and mortality (Chan, 2001).

Drug-nutrient interactions can significantly affect the availability and potency of immunosuppressive therapy. Alterations in food intake, inadequate digestion and these interactions can lead to changes in the pharmacokinetics of immunosuppressive drugs leading to either toxicity or organ rejection as a result of inadequate blood drug levels (Helton, 2001).

Drugs have the potential to interact with nutrients, which could lead to the reduced therapeutic efficacy of the drug, nutritional risk or increased adverse effects of the drug.

Food-drug interactions are defined as alterations of pharmacokinetics or pharmacodynamics of a drug or nutritional element, or a compromise in nutritional status as a result of the addition of a drug. Nutrient-drug interactions can result in two clinical effects: either a decreased bioavailability of a drug, which predisposes to treatment failure, or an increased bioavailability, which increases the risk of adverse events and may even precipitate toxicities (Genser, 2008).

On the other hand, medications can lead to altered food choices. Many drugs are reported to directly affect the sense of taste and smell, and some drugs themselves have an unpleasant taste that might interfere with food intake (Brownie, 2006).

The evidence that water-soluble vitamin E interacts with orally administered cyclosporine is quite convincing. This interaction has only been observed with water-soluble formulation of vitamin E. Further investigations using different dosage forms of vitamin E are necessary. Grapefruit juice-drug interactions represent some of the most significant examples of drug-nutrient interactions. When a single dose of cyclosporine was taken with 200 mL of grapefruit juice, its absorption was increased. The reported increase in bioavailability of cyclosporine ranged from 17% to 63% (Chan, 2001).

Other drugs with increased absorption when taken with grapefruit juice are atorvastatin and sertralin (Chan, 2006).

Conclusion

It is necessary to make more efforts in studying the metabolic syndrome in transplant patients and how this syndrome can affect the transplanted graft.

There are still many doubts about the interactions between different drugs used, nutrients and other substances in the diet. Moreover, further studies are needed to provide information on the potential benefit that some types of diet (such as the Mediterranean), antioxidants or other molecules present in the diet can contribute to the benefit of patients. Moreover, not only is it important to know that various substances can be beneficial, it is also important to know the amount we can use.

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