Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.

Tobacco smoke exposure in either the donor or recipient before transplantation accelerates cardiac allograft rejection, vascular inflammation, and graft loss.

BACKGROUND: Tobacco exposure in cardiac transplant recipients, before and after transplantation, may increase the risk of cardiac allograft vasculopathy and allograft loss, but no direct evidence for this phenomenon is forthcoming. In this experimental study, we investigated early consequences of tobacco smoke exposure in cardiac transplant donors and recipients with an emphasis on alloinflammatory mediators of graft outcome. METHODS AND RESULTS: Using heterotopic rat cardiac transplantation, we tested the effects of donor or recipient tobacco smoke exposure in 6 groups of animals (rat heterotopic cardiac transplantation) as follows: tobacco-naïve allogeneic rejecting controls (n=6), tobacco-naïve nonrejecting controls (n=3; killed on day 5 to simulate survival times of tobacco-treated animals), isografts (n=3), both donor and recipient rats exposed to tobacco smoke (n=4), only donor rats exposed to tobacco smoke (n=7), and only recipient rats exposed to tobacco smoke (n=6). Polymerase chain reaction studies of tissue and peripheral (systemic) protein expression were performed to evaluate inflammatory (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and alloimmune (interleukin-1 receptor 2, programmed cell death-1, and stromal cell-derived factor-1) pathways, as was histological analysis of the cardiac allografts. Our experiments reveal that pretransplantation tobacco exposure in donors and/or recipients results in heightened systemic inflammation and increased oxidative stress, reduces posttransplantation cardiac allograft survival by 33% to 57%, and increases intragraft inflammation (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and alloimmune activation (CD3, interleukin-1 receptor 2, programmed cell death-1, and stromal cell-derived factor-1) with consequent myocardial and vascular destruction. CONCLUSIONS: These sentinel findings confirm that tobacco smoke exposure in either donors or recipients leads to accelerated allograft rejection, vascular inflammation, and graft loss. Molecular pathways that intersect as arbiters in this phenomenon include instigation of alloimmune activation associated with tobacco smoke-induced inflammation.

Gene-based bio-signature patterns and cardiac allograft rejection.

Clinicians have long awaited an alternative to invasive endomyocardial biopsy for surveillance of cardiac transplant rejection. Transcriptional signals in peripheral blood mononuclear cells allow for the development of multigene-based panels that can inform on the presence or absence of immunologic quiescence. The informative genes represent several biologic pathways, including T-cell activation (PDCD1), T-cell migration (ITGA4), and mobilization of hematopoietic precursors (WDR40A and microRNA gene family cMIR), and steroid-responsive genes such as IL1R2, the decoy receptor for interleukin 2. The greatest value may include the ability to inform on the potential of future proclivity for rejection, allowing patients to be stratified into low, intermediate, or high risk subsets for future rejection. In these individuals, this knowledge may allow clinicians to use tailored approaches to immunosuppression, thereby avoiding adverse pharmacologic effects in low-risk patients while improving rejection outcomes in those at high risk for future allograft compromise. Despite these advances, clinical entrenchment of gene-based pharmacotherapy in cardiac transplantation will require independent replication and validation of investigational findings.

Cardiomyopathy and the dilemma of geometric mitral regurgitation.

PURPOSE OF REVIEW: Geometric mitral regurgitation is a phenomenon encountered by an otherwise anatomically normal mitral valve in the setting of advanced adverse left ventricular remodeling that alters the alignment characteristics of the mitral valve apparatus leading to functional production of a leaking valve. In this review, we discuss contemporary directions in the knowledge base for managing geometric mitral regurgitation. RECENT FINDINGS: Much progress has been encountered in describing the types of geometric mitral regurgitation (nonischemic and ischemic origins), standardization of echocardiographic techniques to allow for a common language in ascertaining the severity of mitral regurgitation, knowledge on dynamic mitral regurgitation during exercise, effectiveness of therapy and appropriate use and timing of surgical repair. SUMMARY: Geometric mitral regurgitation develops in tandem with progressive ischemic or nonischemic cardiomyopathy and can improve with antiremodeling pharmacological and device-based therapy. Surgical therapy can be accomplished at experienced centers with low morbidity and mortality, and may improve symptoms and enhance pump function. Whether such therapy saves lives remains uncertain. New percutaneous approaches to tackle geometric mitral regurgitation are developing, and early data is encouraging but remains experimental.

Gene expression profiles and B-type natriuretic peptide elevation in heart transplantation: more than a hemodynamic marker.

BACKGROUND: B-type natriuretic peptide (BNP) is chronically elevated in heart transplantation and reflects diastolic dysfunction, cardiac allograft vasculopathy, and poor late outcome. This investigation studied peripheral gene expression signatures of elevated BNP concentrations in clinically quiescent heart transplant recipients in an effort to elucidate molecular correlates beyond hemodynamic perturbations. METHODS AND RESULTS: We performed gene microarray analysis in peripheral blood mononuclear cells of 28 heart transplant recipients with clinical quiescence (absence of dyspnea or fatigue; normal left ventricular ejection fraction [EF >55%]; ISHLT biopsy score 0 or 1A; and normal hemodynamics [RAP <7 mm Hg, PCWP < or = 15 mm Hg, and CI > or = 2.5 L/min per m2]). BNP levels were performed using the Triage B-type Natriuretic Peptide test (Biosite Diagnostics Inc, San Diego, Calif) and median BNP concentration was 165 pg/mL. Seventy-eight probes (of 7370) mapped to 54 unique genes were significantly correlated with BNP concentrations (P<0.001). Of these, the strongest correlated genes (P<0.0001) were in the domains of gelsolin (actin cytoskeleton), matrix metallopeptidases (collagen degradation), platelet function, and immune activity (human leukocyte antigen system, heat shock protein, mast cell, and B-cell lineage). CONCLUSIONS: In the clinically quiescent heart transplant recipient, an elevated BNP concentration is associated with molecular patterns that point to ongoing active cardiac structural remodeling, vascular injury, inflammation, and alloimmune processes. Thus, these findings allude to the notion that BNP elevation is not merely a hemodynamic marker but should be considered reflective of integrated processes that determine the balance between active cardiac allograft injury and repair.

Sexual activity and chronic heart failure.

Little has been published about sexual function in chronic heart failure (CHF) and knowledge among clinicians in this regard is sparse. To review data regarding sexual function and dysfunction in patients with CHF, 2 of the authors (S.A.M. and P.A.U.) independently conducted a literature search using the MEDLINE database. English-language articles and cited bibliographies published between January 1996 and November 2006 were reviewed. Search terms included heart failure or CHF or ventricular dysfunction or heart disease in conjunction with sexual activity, erectile dysfunction, impotence, or sex. Articles were selected for inclusion if they had a primary focus on CHF and sexual function or dysfunction. Critical reviews of the literature, observational studies using self-reported patient surveys, and prospective, blinded, randomized, placebo-controlled trials were included. Articles were not excluded on the basis of patient sample size but were excluded if the article concerned a broad aspect of cardiovascular disease rather than CHF. When properly screened and treated, most patients with CHF can safely engage in sexual activity and be treated for erectile dysfunction with sildenafil, provided that they do not have active ischemia and do not require treatment with nitrates. Clinicians should know the physiological requirements of sexual activity and the impact CHF has on sexual performance. Fear of a cardiac event during intercourse can interfere with patients' ability to perform and enjoy sex, and so it is important that the physician be able to counsel patients with CHF about sexual activity.

Genomic biomarkers and heart transplantation.

Clinicians have entered into a new paradigm for managing heart transplant patients with use of multimarker gene expression profiling. Early after transplantation, when corticosteroid modification is the main concern, gene expression testing might assist in optimizing the balance of immunosuppression, defraying the occurrence of rejection, and avoiding crisis intervention. Late after transplantation, the reliance on endomyocardial biopsy could be lessened. These advances, if continually validated in practice, could usher in an era of decreased immunosuppression complications, lesser need for invasive surveillance, and more clinical confidence in immunosuppressive strategies.

Multicenter Evaluation of Octreotide as Secondary Prophylaxis in Patients With Left Ventricular Assist Devices and Gastrointestinal Bleeding.

BACKGROUND: Gastrointestinal (GI) bleeding is one of the most common complications after continuous-flow left ventricular assist device implantation. More than one third of patients with incident bleed go on to develop recurrent GI bleeding. Octreotide, a somatostatin analog, is proposed to reduce the risk of recurrent GI bleeding in this population. METHODS AND RESULTS: This multicenter, retrospective analysis evaluated 51 continuous-flow left ventricular assist device patients who received secondary prophylaxis with octreotide after their index GI bleed from 2009 to 2015. All patients had a hospitalization for GI bleed and received octreotide after discharge. Patient demographics, medical and medication history, and clinical characteristics of patients who rebled after receiving octreotide were compared with non-rebleeders. These data were also compared with matched historical control patients previously enrolled in the HMII (HeartMate II) clinical trials, none of whom received octreotide, to provide a context for the bleeding rates. Twelve patients (24%) who received secondary octreotide prophylaxis developed another GI bleed, whereas 39 (76%) did not. There were similar intergroup demographics; however, significantly more bleeders had a previous GI bleeding history before left ventricular assist device placement (33% versus 5%; P=0.02) and greater frequency of angiodysplasia confirmed during endoscopy (58% versus 23%; P=0.03). Fewer patients in this study experienced a recurrent GI bleed compared with a matched historical control group that did not receive octreotide (24% versus 43%; P=0.04). CONCLUSIONS: Patients with continuous-flow left ventricular assist device receiving secondary prophylaxis with octreotide had a significantly lower GI bleed recurrence compared with historical controls not treated with octreotide. Additional prospective studies are needed to confirm these data.

Heart failure therapy at a crossroad: are there limits to the neurohormonal model?

The advent of neurohormonal blockade in heart failure (HF) has been an overwhelming success, but current evidence points to a ceiling effect as newer neurohormonal targets are exploited in an incremental manner. This has lead us to question whether the neurohormonal model of HF can be sustained by simply stacking multiple neurohormonal or cytokine blockers together as treatment. A unifying theme in some of these disparate trials relates to either a lack of efficacy or, more importantly, adversity resulting in regression of already achieved benefits. It is our contention that the available evidence has uncovered the remarkable complexity of interaction within the context of the neurohormonal construct. As we stand at a crossroad in HF and begin to fervently pursue non-neurohormonal therapeutic targets, we must also direct attention at navigating the multifaceted labyrinth of the neurohormonal model that has led to the current imbroglio.

The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study.

OBJECTIVES: We evaluated the association of mode of brain death with cardiac allograft vasculopathy. BACKGROUND: Explosive brain death (EBD) is accompanied by a sudden increase in intracranial pressure, with recruitment of pro-inflammatory cytokines, as well as adhesion cell and co-stimulatory molecules. Whether these early events influence the later development of cardiac allograft vasculopathy following heart transplantation remains unknown. METHODS: An inception cohort of 61 consecutive heart transplant recipients between 1993 and 1995 who underwent intravascular ultrasound examination of the coronary arteries were evaluated. Based on the mode of donor brain death, this cohort was divided into either an EBD group (n = 27) or non-EBD (n = 34), and the development of intimal thickness and cardiac events (sudden cardiac death, myocardial infarction, and need for coronary revascularization via percutaneous techniques or surgical bypass) was assessed. RESULTS: Despite similar posttransplant survival and distribution of nonimmunological and immunological variables, heart transplant recipients with EBD demonstrated greater intimal thickening (0.59 +/- 0.1 vs. 0.32 +/- 0.2 mm; p = 0.02) and higher cardiac events (37% vs. 12%; p = 0.01) when compared to those with non-EBD donors. Hearts from donors with EBD had lower survival (63 +/- 19 vs. 72 +/- 17 months) than with non-EBD donors (p = 0.04). CONCLUSIONS: Explosive brain death is a significant determinant for the late development of cardiac allograft vasculopathy and influences long-term allograft survival. Thus, strategies focusing on limitation of vascular allograft injury in the pre-engraftment phase of cardiac transplantation are warranted.

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.

Obesity and suppressed B-type natriuretic peptide levels in heart failure.

OBJECTIVES: This investigation evaluated the relationship between obesity and B-type natriuretic peptide (BNP) in heart failure. BACKGROUND: Obesity is a major risk factor for the development of heart failure, but the precise mechanisms remain uncertain. Physiologically, natriuretic peptides and lipolysis are closely linked. METHODS: A total of 318 patients with heart failure were evaluated between June 2001 and June 2002. Levels of BNP were compared in obese (body mass index [BMI] > or =30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with respect to New York Heart Association functional class and lean body weight-adjusted peak aerobic oxygen consumption. In a subset of 36 patients, plasma levels of tumor necrosis factor-alpha, interleukin-6, and soluble intercellular adhesion molecule-1 were measured. RESULTS: The population's BMI was 29.4 +/- 6.6 kg/m(2); 24% were lean (BMI <25 kg/m(2)), 31% overweight (BMI > or =25 to 29.9 kg/m(2)), and 45% obese (BMI > or =30 kg/m(2)). Obese patients were younger, more often African American, and more likely to have a history of antecedent hypertension, but less likely to have coronary artery disease and with only a trend toward diabetes mellitus. Levels of BNP were significantly lower in obese than in nonobese subjects (205 +/- 22 and 335 +/- 39 pg/ml, respectively; p = 0.0007), despite a similar severity of heart failure and cytokine levels. Multivariate regression analysis identified BMI as an independent negative correlate of BNP level. There were no differences in emergency department visits, heart failure hospitalization, or death between the obese and nonobese patients at 12-month follow-up. CONCLUSIONS: Our investigation indicates that a state of reduced natriuretic peptide level exists in the obese individual with heart failure.

Relationship among epicardial coronary disease, tissue myocardial perfusion, and survival in heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy continues to represent the major limitation to long-term cardiac allograft survival. Routine angiography and intravascular ultrasound fall short in their ability to detect microcirculatory aberrations. Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grades (TMPG) have been used as a measure of microvascular circulation in patients treated for acute myocardial infarction. We studied the correlation of epicardial coronary anatomy with microvascular flow as determined by TMPG and correlated it with patient outcome. METHODS: We enrolled 66 consecutive cardiac transplant recipients (49 men; mean age 52 +/- 13 years; range 15-70 years) undergoing surveillance coronary angiogram during a 9-month period. All angiograms were interpreted for epicardial coronary anatomy by an independent investigator. Another investigator, blinded for clinical data and angiogram interpretation, interpreted TMPGs. TMPG 0 was defined as no apparent tissue-level perfusion; TMPG 1 indicated presence of myocardial blush but no clearance from the microvasculature; TMPG 2 blush cleared slowly; and TMPG 3 indicated that blush began to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). Cardiac deaths served as the primary outcome variable. RESULTS: Fifty-eight of 66 patients had an abnormal TMPG. Mean TMPG in all these patients was 4.2 +/- 3 (normal is 9). Forty-four patients (Group A) with no angiographic coronary narrowing had TMPG 4.81 +/- 3.1, and 22 patients (Group B) with epicardial coronary narrowing 40% of lumen diameter had TMPG 3.0 +/- 2.5 (p = 0.007). There was no difference in TMPG related to the coronary territory involved. At a mean follow-up of 30 +/- 2.5 months, 6 (13.6%) of 44 patients in Group A had died, and 7 (31.8%) of 22 in Group B had died (p < 0.03). CONCLUSIONS: Microcirculatory aberrations as assessed by tissue TMPG is abnormal across all coronary territories in cardiac transplant recipients and associated with poor survival, suggesting a generalized microvascular involvement even in the presence of a normal angiogram. Patients with focal epicardial coronary narrowing have significantly greater decline in tissue perfusion, independent of the coronary territory involved, and exhibit poor survival compared with patients without epicardial coronary disease.

Ethnic disparity in clinical outcome after heart transplantation is abrogated using tacrolimus and mycophenolate mofetil-based immunosuppression.

BACKGROUND: Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients. METHODS: Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened). RESULTS: Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients. CONCLUSIONS: Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

Usefulness of B-type natriuretic peptide levels in predicting hemodynamic perturbations after heart transplantation despite preserved left ventricular systolic function.

The aim of this prospective study was to evaluate the association of peripheral B-type natriuretic peptide (BNP) levels with clinical symptoms and central hemodynamic and echocardiographic measures in cardiac transplantation. BNP reflects ventricular wall stress and correlates with severity of heart failure. No previous investigation has comprehensively assessed the rapid bedside BNP assay for predicting hemodynamic measures of cardiac allograft function in heart transplantation. We evaluated BNP levels using a rapid point-of-care assay in 87 stable cardiac transplant recipients who had 237 consecutive measurements along with endomyocardial biopsy, right-sided cardiac catheterization, and echocardiography. Using median tendencies, 2 groups were identified: the low BNP group (n = 116, BNP <150 pg/ml) and the high BNP group (n = 121, BNP >/=150 pg/ml). The high BNP group had increased right atrial pressures, higher pulmonary artery systolic pressures, pulmonary capillary wedge pressures, and lower cardiac index. Besides hemodynamic variables, the presence of right ventricular dysfunction (p = 0.05) and significant tricuspid regurgitation (p = 0.003) were associated with higher BNP levels. Independent predictors of BNP levels on multivariate analysis included elevated pulmonary capillary wedge pressure, lower cardiac index, and symptoms of dyspnea and fatigue. This initial investigation establishes the accuracy of a point-of-care BNP assay in predicting cardiopulmonary hemodynamic aberrations despite preserved left ventricular systolic function in heart transplant recipients. Rapid bedside BNP analysis may provide a noninvasive surrogate method for the comprehensive assessment of cardiac allograft function and hemodynamics in heart transplantation.

Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure.

This study sought to evaluate the utility of sildenafil in assessing pulmonary artery reactivity in left-sided cardiac failure and secondary pulmonary hypertension (PH). Fourteen consecutive patients with heart failure were studied, with oral doses of either sildenafil 25 mg (n = 8) or 50 mg (n = 6) every 8 hours for 20% decreases in pulmonary artery pressures. There was also a 20% reduction of the pulmonary vascular resistance/systemic vascular resistance ratio, indicating relative pulmonary artery selectivity. Compared with sildenafil 25 mg, sildenafil 50 mg demonstrated greater reductions of pulmonary pressures. Oral sildenafil is safe and effective for the evaluation of PH reactivity in heart failure.

Usefulness of an elevated B-type natriuretic peptide to predict allograft failure, cardiac allograft vasculopathy, and survival after heart transplantation.

B-type natriuretic peptide (BNP) has emerged as an important marker of ventricular wall stress and is predictive of hemodynamic abnormalities in heart transplantation despite "preserved" systolic function. We evaluated the capacity of BNP to predict deaths due to allograft failure in 62 patients long after heart transplantation (mean 5 +/- 2.5 years). Based on the median tendency of measurement of BNP in the absence of rejection during stable surveillance, 2 distinct patient groups were identified as having low BNP (n = 39, < 250 pg/ml; median BNP 70 pg/ml) and high BNP (n = 23, > or =250 pg/ml; median BNP 592 pg/ml). No differences between the 2 BNP groups were noted with regard to age, gender, race, time after transplantation, diabetes mellitus, hypertension, and hyperlipidemia with measurement of BNP. Multivariable analysis showed that decreased left ventricular ejection fraction, angiographic coronary artery disease, and increased serum creatinine were independent predictors of elevated BNP. Cardiac deaths were significantly greater in those with high BNP levels (35%) than in those with low BNP (2.5%, p = 0.01). Absence of significant angiographic coronary artery disease coupled with a BNP of < 250 pg/ml was associated with the lowest event rate (0%), whereas patients with coronary artery disease and BNP > or =250 pg/ml exhibited a 50% cardiac death rate (p <0.01 for trend). Cox's model confirmed that increased BNP and decreased left ventricular ejection fraction are independent predictors of poor survival. Survival analysis associated lower BNP levels with an excellent long-term survival rate (95%) and higher BNP levels with a markedly decreased survival rate (60%, p = 0.002). Higher BNP levels in patients long after heart transplantation are associated with allograft dysfunction and cardiac allograft vasculopathy and are strongly and independently predictive of cardiovascular death.

Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity-quality paradox.

BACKGROUND: Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators' attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a "prognostically relevant" threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free. METHODS: We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass. RESULTS: Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 +/- 0.27 mm, vs Group 2, 0.94 +/- 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up. CONCLUSIONS: These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.

High-impact articles related to the pharmacotherapeutic management of systolic heart failure.

This compilation is part of a series of five articles identifying important literature in cardiovascular pharmacotherapy. This list focuses on pharmacotherapeutic management of acute decompensated and chronic heart failure. Most of the cited works present the results of landmark clinical studies that have shaped the management of patients with left ventricular systolic dysfunction. Limited primary literature is available for some topics; thus, pertinent review articles also are listed. In addition, consensus documents formed by expert panels in the United States and Europe are reviewed. This compilation may serve as a teaching tool, reference resource, or update of the literature for pharmacy clinicians, physicians, and students.

Emergence of Laplace therapeutics: declaring an end to end-stage heart failure.

A large number of chronic heart failure patients escape from the benefits of neurohormonal blockade only to transit into a discouragingly miserable state of what the physician often refers to as end-stage heart failure. Conceptually, the designation of end-stage as a description of a clinical scenario implies pessimism concerning recourse to a therapeutic avenue. A variety of surgical therapeutic techniques that take advantage of the law of Laplace, designed to effectively restore the cardiac shape from a spherical, mechanically inefficient pump to a more elliptical, structurally sound organ are now being employed. Additionally, the field of mechanical device implantation is surging ahead at a rapid pace. The weight of evidence regarding mechanical unloading using assist devices suggests that hemodynamic restoration is accompanied by regression of cellular hypertrophy, normalization of the neuroendocrine axis, improved expression of contractile proteins, enhanced cellular respiratory control, and decreases in markers of apoptosis and cellular stress. Thus, these lines of data point toward discarding the notion of end-stage heart failure. We are at a new crossroad in our quest to tackle chronic heart failure. It is our contention that the use of antiremodeling strategies, including device approaches, will soon signal the end of end-stage heart failure.