Myung H. Park

Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival

OBJECTIVES We sought to evaluate the relative effects of low doses of pravastatin (20 mg/day) and simvastatin (10 mg/day) on indices of cardiac allograft rejection. We further examined the relative efficacy and safety of these two drugs on lipid-lowering in heart transplantation. BACKGROUND The immunomodulatory effects of hydroxy methyl glutaryl-coenzyme A reductase inhibitors have been increasingly recognized. Previous studies have demonstrated an ameliorative influence of pravastatin on hemodynamically compromising rejection after heart transplantation. A recent observational trial suggested that simvastatin 20 mg/day was associated with trends to lower survival and more adverse effects than pravastatin 40 mg/day. METHODS In a 12-month prospective, open-label study, 50 heart transplant recipients received either open-label pravastatin 20 mg daily (n = 24) or simvastatin 10 mg daily (n = 26) within four weeks of transplantation. Indices of allograft rejection including treated rejection, rejection with hemodynamic compromise, noncellular rejection, and mean one-year biopsy score were compared between the two cohorts, as well as with a statin-naive control population (n = 37). Lipid levels, safety, and post-transplant outcomes were also assessed as secondary end points. RESULTS We found no significant differences in any allograft rejection parameter between the two groups. However, total low-density lipoprotein (LDL), but not high-density lipoprotein cholesterol or triglycerides, were lower in the simvastatin arm (-23% vs. -11%, p = 0.02). No cases of rhabdomyolysis or myositis occurred in either group. Survival at one year was similar in both treatment groups (91% for patients on pravastatin and 92% for patients on simvastatin). Both groups had better survival compared with the statin-naive control group (80%, p = 0.04). CONCLUSIONS Simvastatin (10 mg/day) and pravastatin (20 mg/day) are associated with similar beneficial effects on cardiac allograft rejection and one-year survival. At these doses, simvastatin decreases LDL cholesterol more so than pravastatin with no increase in adverse effects in heart transplantation.

Anything but a biopsy: noninvasive monitoring for cardiac allograft rejection

Endomyocardial biopsy has stood the test of time as a surveillance technique; however, the expense, resources required, invasive nature, and low but definite risks have motivated investigators to pursue less invasive techniques. The search for noninvasive surveillance techniques for cardiac rejection have centered on measurements of cardiac function, intragraft electrical events, peripheral proteomic markers of graft micronecrosis, immune activation, and nonimmune accompaniments of rejection. Although several investigations allude to a reasonable negative predictive value of such monitoring, the specificity of these techniques remains poor. Until well-constructed studies not only define the predictive values of noninvasive techniques but also appropriately evaluate the clinical safety of any such approach, invasive endomyocardial biopsy will remain the gold standard.

Allosensitization in heart transplantation: implications and management strategies.

The detection of anti-human leukocyte antigen (HLA) donor-specific antibodies has been associated with a variety of clinical syndromes that determine short-term and long-term outcomes of cardiac transplant recipients, including an increased incidence of early and more severe allograft rejection and cardiac allograft vasculopathy. Recent surveys indicate marked heterogeneity in clinical protocols for detection and management of sensitization in heart transplantation. The commonly performed complement-dependent cytotoxicity assay is insensitive compared with newer methods such as flow cytometry for antibody screening. The imperative exists to create strategies that can decrease the level of sensitization and increase the likelihood for a negative crossmatch. In this effort, several strategies have been suggested, including administration of intravenous immunoglobulin, apheresis, and combination therapies using potent immunosuppression, particularly with cyclophosphamide. The future of managing allosensitization may be in induction of a chimeric state to allow graft tolerance.

Usefulness of the combined index of systolic and diastolic myocardial performance to identify cardiac allograft rejection

Systolic and diastolic myocardial performance characteristics are altered during allograft rejection. Noninvasive diagnostic markers of allograft rejection have thus far not been found to be clinically useful and have not replaced routine endomyocardial biopsy as a method to detect rejection. We examined the clinical utility of the Index of Myocardial Performance (IMP), or the Tei index, a combined index of systolic and diastolic performance (derived as a composite ratio of isovolumetric contraction time and isovolumetric relaxation time to the ejection time), in evaluating and following cardiac allograft rejection. Twenty heart transplant recipients with moderate cellular rejection (International Society for Heart and Lung Transplantation [ISHLT] grade 3A) underwent echocardiographic assessment to derive the IMP at baseline (rejection free), during treatment of rejection, and after recovery from rejection (group I). A parallel group of 20 nonrejecters (ISHLT grade 1A) were also similarly examined to serve as controls (group II). In group I patients, there was a mean increase of IMP by 98% (p <0.0001) during the rejection episode compared with baseline. After treatment, IMP decreased to its baseline value. In the control group there was no significant change in IMP over time. An IMP increase of >/=20% from baseline had 90% sensitivity and 90% specificity in detecting high-grade cardiac allograft rejection. The change in IMP in patients with grade 3A cellular rejection was independent of both the ejection fraction at baseline and change in ejection fraction during the rejection episode. These results indicate that changes in IMP, a sensitive marker of early diastolic and systolic performance, accurately evaluate the development of, and recovery from, cardiac allograft rejection. IMP can provide a clinically useful noninvasive indicator to assess the impact of therapy for amelioration of allograft rejection.

Intravenous thyroid hormone supplementation in heart failure with cardiogenic shock

BACKGROUND Thyroid hormone level abnormalities commonly exist in severe heart failure and may be of prognostic value. The therapeutic potential of using thyroid hormone for cardiogenic shock resulting from progressive heart failure has not been previously delineated. We sought to evaluate the role of an intravenous infusion of thyroxine as an adjunct to conventional inotropic agents and intra-aortic balloon counterpulsation in patients with severe heart failure with cardiogenic shock. METHODS AND RESULTS We studied 10 consecutive patients with severe systolic heart failure that progressed to a cardiogenic shock state unresponsive to conventional pharmacological inotropic measures. Intravenous thyroxine (20 micrograms/h) was used as an adjunctive salvage measure after the failure of conventional pharmacological and mechanical support by intra-aortic balloon pump. The invasive hemodynamic profile (right atrial pressure, pulmonary capillary wedge pressure, cardiac index, mean arterial pressure), overall clinical status, core temperature, renal function, and tachyarrhythmias were compared before and sequentially at 6, 24, and 36 hours after the initiation of thyroxine administration. Long-term outcome was also defined. All patients had statistically significant improvements in cardiac index, pulmonary capillary wedge pressure, and mean arterial pressure at 24 and 36 hours post-initiation of thyroxine. No sustained tachyarrhythmias were seen during the thyroxine infusion. In 9 of 10 patients who underwent left ventricular assist device placement and/or heart transplantation, the use of thyroxine served as an effective adjunctive measure to allow transitioning to definitive surgical therapy. The 6-month and 1-year cohort survival rates, achieved by the transition to surgical therapy, were 90% and 80%, respectively. CONCLUSION The beneficial hemodynamic properties of intravenous thyroid hormone can be effectively used in otherwise terminal situations of cardiogenic shock, and in such situations, the use of thyroid hormone can serve as a pharmacological adjunct to a definite surgical intervention. Further studies in larger numbers of patients might be warranted to confirm these findings.

Right heart failure: toward a common language.

In this perspective, the International Right Heart Foundation Working Group moves a step forward to develop a common language to describe the development and defects that exemplify the common syndrome of right heart failure. We first propose fundamental definitions of the distinctive components of the right heart circulation and provide consensus on a universal definition of right heart failure. These definitions will form the foundation for describing a uniform nomenclature for right heart circulatory failure with a view to foster collaborative research initiatives and conjoint education in an effort to provide insight into echanisms of disease unique to the right heart.

High-density lipoprotein cholesterol levels and prognosis in advanced heart failure.

BACKGROUND High-density lipoproteins (HDLs) influence the generation of prostacyclin via cyclooxygenase stimulation. Prostaglandins represent an important compensatory pathway in advanced heart failure (HF). Whether HDL levels discriminate prognosis in HF remains unknown. METHODS We prospectively evaluated the prognostic relationship of HDL levels in severe HF by examining 132 consecutive patients listed for heart transplantation (52 +/- 11 years of age, 80% men, 79% white, mean follow-up 18 months). Using population mean HDL levels (HDL <33 mg/dl [n = 47] vs > or =33 mg/dl [n = 85]), patients were grouped and followed for the primary composite end-points of HF hospitalizations or death, stratified by underlying etiology (non-ischemic, n = 52; ischemic, n = 80). RESULTS Patients with HDL <33 mg/dl had lower serum sodium (135 vs 137 mEq/liter, p = 0.008), higher total bilirubin (1.3 vs 0.7 mg/dl, p < 0.001) and higher uric acid (7.6 vs 6.7 mg/dl, p = 0.048) levels, but similar serum creatinine compared with the > or =33 mg/dl HDL group. Survival analysis, using a Cox proportional hazards model, revealed reduced HDL (<33 mg/dl) as the most significant independent predictor of HF hospitalizations or death, independent of underlying etiology. Low-cholesterol and low-density lipoprotein (LDL)-cholesterol alone were not found to be independently predictive of outcome. CONCLUSIONS Lower HDL levels correlate with adverse prognosis independent of etiology and predict clinical worsening or death in advanced HF. Further study is warranted as to whether these findings represent a clinical marker or suggest a potential therapeutic target.

Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

Recrudescent Tobacco Exposure Following Heart Transplantation: Clinical Profiles and Relationship with Athero-Thrombosis Risk Markers

To identify tobacco recidivism among 86 heart transplant recipients who were smokers but demonstrated compliance with a smoking cessation program pre‐transplant, we used a questionnaire and randomly tested urine for nicotine and its by‐products. In 36 patients, we also evaluated circulating levels of HS‐CRP, homocysteine and MPV. Twenty‐eight (32.5%) of 86 patients met our definition for tobacco exposure. In this cohort, 28 (32.5%) of 86 patients met our definition for tobacco exposure. Of these 28, 12 patients self‐reported tobacco use and demonstrated biochemical verification; 14 patients demonstrated only biochemical evidence of significant tobacco exposure; 2 patients self‐reported tobacco use but did not demonstrate biochemical positivity. Smoking cessation within 6 months of transplantation (r = 0.52) and time post‐transplantation (r = 0.43) were independent predictors for recidivism of tobacco use, p < 0.01. No differences in HS‐CRP, homocysteine and MPV levels were noted among the groups. Our investigation demonstrates a high rate of tobacco recidivism among heart transplant recipients, yet few admit to it. The adverse effects of tobacco do not appear to be directly modulated by an effect on athero‐thrombotic risk markers.

Advances in diagnosis and treatment in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review.