The challenge of rejection and cardiac allograft vasculopathy.

Since the first human heart transplantation was performed in 1967, the field of heart transplantation has advanced to the point where survival and acceptable quality of life are commonplace. Despite remarkable progress in the clinical management of rejection, rejection continues to limit survival and quality of life in the heart transplant population. This review will discuss the biologic processes involved in hyperacute rejection, acute rejection, and humoral (vascular) rejection. The development of endomyocardial biopsy techniques represented a significant advancement in the diagnosis of cardiac rejection, and endomyocardial biopsy remains the 'gold standard' in the diagnosis of cellular rejection. To date, no noninvasive parameters will diagnose rejection with adequate sensitivity and specificity. Biopsy frequency and immunosuppressive therapies may be tailored to the risk of rejection. Immunosuppression for cardiac transplantation can be divided into three major phases: 1) perioperative immunosuppression; 2) maintenance immunosuppression, and; 3) treatment of rejection. The strategy for treating transplant rejection should be influenced by several variables: 1) Histologic grade of rejection; 2) Evidence of hemodynamic compromise by ejection fraction or right heart catheterization; 3) Severity of previous rejection episodes and types of immunosuppressives used; and 4) Risk factors for rejection, including time after transplantation. Future rejection therapy will involve more sophisticated attempts to alter host responses toward the donor organ in a more specific and selective way. Despite considerable advances in the care of the heart transplant recipient, long-term survival is limited by cardiac allograft vasculopathy. The final section of this chapter will review the pathology, immunopathology, nonimmunologic risk factors, diagnosis, prevention and treatment of allograft vasculopathy.

Difficult cases in heart failure: Importance of patient selection in the use of intermittent inotrope infusions for advanced heart failure.

Intermittent infusions of inotropes have been used with increasing frequency for patients with advanced heart failure (HF). The use of intermittent inotrope infusions remains controversial for several reasons. However, the effect, either positive or negative, of intermittent inotropes in refractory unstable HF patients is not well studied. While prior experience with chronic oral inotropes in stable, advanced HF raises substantial concerns, it may not be directly applicable to a critical evaluation of intermittent inotrope infusions in unstable patients. Further study demonstrating the safety and efficacy of this approach in these patients is imperative. The uncertainties surrounding this therapy, mandate the selection of appropriate candidates be made with substantial care. We report three patients with advanced HF despite conventional therapy, in whom intermittent inotropes were considered. These cases illustrate that this therapy can be avoided in many patients by acceleration of conventional medications, patient education, and aggressive follow up intermittent. However, outpatient inotrope infusions may be helpful in highly selected patients with refractory, unstable HF.

Time course of cytokine release and complement activation after implantation of the HeartMate left ventricular assist device.

Pro-inflammatory mediators, including interleukin-6 (IL-6), IL-8, and complement C3a, are released after cardiac surgery as part of the inflammatory response related to blood-biomaterial interaction in the cardiopulmonary bypass circuit. Post operative time course data for these mediators are not fully defined in patients receiving left ventricular assist device (LVAD) support. The authors performed enzyme linked immunosorbent assays for concentrations of IL-6, IL-8, and C3a in plasma in six HeartMate LVAD recipients at the following times: pre operatively; 4, 8, 16, 24, 36, and 48 hr post operatively; daily through the first week; and weekly thereafter for 6 weeks. All patients survived without major complications during the study. Pre operative concentrations of IL-6 and C3a in plasma were significantly increased compared with age matched controls. Post operatively, the concentrations of IL-6 and IL-8 in plasma took longer to return to baseline values after insertion of the LVAD than the trends reported in the literature after routine cardiopulmonary bypass alone. Concentrations of IL-6 and complement C3a continued to decrease to lower than baseline post operatively, reaching statistical significance after 6 weeks of LVAD support. The authors conclude that the presence of the HeartMate LVAD delays the return of pro-inflammatory mediator concentrations back to baseline values compared with routine cardiopulmonary bypass alone, but the device does not appear to be an ongoing source of cytokine release or complement activation.

Function of the transplanted heart: unique physiology and therapeutic implications.

Orthotopic heart transplantation has become an established treatment for selected patients with refractory heart failure. Long-term survival rates are superior to those resulting from other forms of therapy for that patient population. In addition, an improved quality of life has been reported by many patients. However, despite these encouraging results, the transplanted heart does not provide the recipient with normal cardiac function. Cardiac physiology after heart transplantation is unique. Resting hemodynamics differ significantly, acutely and chronically, from those seen in healthy subjects. In addition, neural mechanisms undergo changes as a result of surgical denervation. Afferent control mechanisms and efferent responses both are altered, leading to important clinical abnormalities. Examples include altered cardiovascular responses to exercise, altered cardiac electrophysiology, and altered responses to cardiac pharmacologic agents. An improved understanding of the changes in cardiac physiology, which occur after heart transplant, may allow the care of these patients to be optimized.