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Background: Due to the lack of nephrotoxic activity, proliferation signal inhibitors (PSI) such as everolimus are recommended for immunosuppression after heart transplantation, but the assessment of renal function in patients receiving PSI has led to conflicting results. We examined renal integrity and function using neutrophil gelatinase-associated lipocalin (NGAL) and conventional markers [plasma creatinine, cystatin C, urine albumin, a1-microglobulin (a1M)] in heart transplant patients, who underwent conversion to everolimus due to allograft vasculopathy, graft rejection episodes, or renal function deterioration, and in patients maintained on calcineurin inhibitors (CNI). Methods: This cross-sectional study included 121 consecutive heart transplant recipients: 44 patients received CNI-free immunosuppressive therapy with everolimus and 77 patients received CNI. Renal parameters were determined in plasma and urine samples using standard enzymatic or immunochemical methods. Results: Heart transplant recipients receiving everolimus therapy had significantly lower NGAL concentrations in plasma [median (95% CI): 128 (97–176) ng/mL vs. 252 (224–283) ng/mL, p < 0.001] and urine [median (95% CI): 6.4 (4.5–7.6) ng/g vs. 15.7 (10.2–25.9) ng/g creatinine, p < 0.001]. In contrast, no significant differences were observed between everolimusand CNI-treated groups with regard to creatinine and cystatin C, as well as urine albumin and a1M levels. Significant correlations were noted between plasma NGAL and creatinine (r = 0.42, p < 0.001), cystatin C (r = 0.44, p < 0.001), N-terminal brain natriuretic propeptide (r = 0.31, p < 0.01) and indicators of chronic inflammation [lipoprotein-associated phospholipase A2 (Lp-PLA2), r = 0.31, p < 0.01] and soluble CD40 ligand (sCD40L, r = 0.22, p < 0.05), and between urinary NGAL and a1M (r = 0.21, p < 0.05). Multiple regression analysis indicated that cystatin C and Lp-PLA2 were the best predictors of plasma NGAL. Conclusion: The present study documents reduced plasma and urinary NGAL levels in the absence of differences in conventional renal parameters in patients on CNI-free immunosuppressive therapy with everolimus. These results support favorable effects of everolimus on renal integrity in heart transplant recipients. 2015 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus.After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed.After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P.001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P.001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)].CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.

Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients.In a prospective, single-arm, single-center study, CNI-treated heart transplant patients were converted to everolimus and were followed up for 24 months. The primary endpoints were kidney function and arterial hypertension at 12 and 24 months after conversion.Fifty-eight patients were recruited (mean time posttransplant 5.6±3.7 years), 55 of whom (91.7%) had renal impairment. Mean creatinine clearance increased from 43.6±21.1 mL/min to 49.5±21.2 mL/min at month 24 (P=0.02). Median blood pressure increased from 120/80 mm Hg at baseline to 122.5/80 mm Hg (P=0.008 and 0.006 for systolic and diastolic pressure, respectively). Lipid parameters did not change significantly over the 24-month follow-up. Early resolution of most non-renal CNI-related adverse events was sustained. CNI therapy was re-introduced at a mean of 309 days (range, 31-684 days) in eight patients after month 6 due to adverse events (n=13) or withdrawal of consent (n=2). No significant changes in cardiac function parameters were observed.CNI-free immunosuppression with everolimus is an effective and safe option in selected heart transplant maintenance patients. Most adverse effects under everolimus occurred early after conversion and generally resolved without intervention within a few weeks. Refining selection criteria may reduce the need to re-introduce CNI therapy.

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (α-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFβ2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF. Electronic supplementary material The online version of this article (doi:10.1007/s00109-008-0385-4) contains supplementary material, which is available to authorized users.

Myocardial remodeling determines the degree of left ventricular dysfunction and mortality after transmural chronic myocardial infarction (CMI). Noninvasive characterization and quantitation of myocardial borderzone and collagenous scar are therefore parameters of clinical interest. The aims of this study were (i) to measure accuracy of reconstructive 3-D echocardiography (3DE) in scar and myocardial borderzone size assessment and (ii) to investigate the incremental value of low-dose dobutamine stress. 3DE was performed in 14 immunodeficient rats (rnu-rnu, 180-200 g) with anterior CMI 25 d after coronary ligation. Briefly, consecutive parallel short-axis cineloops were obtained electrocardiogram-gated starting from base to the apex. Morphology (mass, surface) and function (contractility, contractile reserve) of different compartments were assessed and correlated with 3-D histomorphometry. Histology was done using picrosirius red for collagen staining. 3DE left ventricular mass correlated closely with histomorphometry (y = 0.89x + 155, p0.0001, r = 0.80). Hypo- and akinetic myocardial surface correlated well with borderzone myocardium (y = 0.34x + 17, p = 0.009, r = 0.62) and collagenous scar (y = 1.9x + 4.4, p0.0001, r = 0.79), respectively. Extent of abnormal wall motion was closely related to borderzone and scar tissue area (y = 0.82x + 7, p0.0001, r = 0.77). 3DE quantitation of borderzone myocardium, but not collagenous scar, was more closely correlated to histomorphometry during inotropic stimulation. Global contractile reserve is positively associated with the size of myocardial borderzone. Regional contractile reserve of borderzone myocardium is not negatively associated with its collagen content. 3DE allows precise quantitation of myocardial borderzone and identification of transmural scar tissue noninvasively. Assessment of contractile reserve improves characterization and estimation of myocardial borderzone after CMI.

Background Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)–free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus. Methods During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months. Results After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 ± 0.6 vs 1.5 ± 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 ± 21.6 vs 61.8 ± 23.4 ml/[min · 1.73 m 2 ], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia ( n = 2), skin disorders ( n = 2), reactivated hepatitis B ( n = 1), and fever of unknown origin ( n = 3). Conclusion Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

Pulmonary hypertension (PHT), defined as a pulmonary vascular resistance (PVR) greater than 2.5 Wood units [WU] and(or) transpulmonary gradient (TPG) greater than 12 mm Hg, is a risk factor for mortality in cardiac transplantation due to elevated postoperative right heart failure. Orthotopic heart transplantation is possible if PVR could be reversed below 2.5 WU and TPG below 12 mm Hg. We show the Muenster experience from the last 10 years.From April 1996 to December 2005 all cardiac transplant recipients separated into patients with and without PHT were included. All patients with PHT had successful reduction (PVRor = 2.5 WU and TPGor = 12 mm Hg) using prostaglandin I2 or E1. Posttransplant early and late mortality and incidence of right heart failure were studied.Two hundred seventeen patients were included in this study. Of these, 168 had normal pulmonary pressures (non-PHT group), 49 (22.6%) had reversible PHT (rev-PHT group). Mean PVR was 1.6 +/- 1.1 WU vs 2.1 +/- 1.1 WU (p0.01; non-PHT vs rev-PHT) and mean TPG 8.0 +/- 1.9 mm Hg vs 10.6 +/- 4.1 mm Hg (p = not significant [NS]). Thirty-day survival after orthotopic cardiac transplantation was 85% vs 78% (p = 0.150) and 10 year survival 63% vs 61% (p = NS). Right heart failure during the first 30 days after transplantation occurred in 27% in the non-PHT group and in 64% in the rev-PHT group (p = 0.035). However, in patients transplanted after 2001 it did not appear.Cardiac transplant candidates with reversible PHT have still significantly elevated pulmonary pressures compared with patients without PHT. Despite a significantly higher risk of right heart failure, long-term survival after orthotopic cardiac transplantation was not affected.

Background Left ventricular assist devices (LVADs) with continuous flow properties are increasingly used to bridge heart failure patients to cardiac transplantation. Advantages in comparison with the pulsatile LVADs are smaller size, better endurance, and lower thromboembolic events. However, whether these new pumps have similar pre- and posttransplant outcomes is not clear. Methods Fifty patients with a continuous flow device (Micromed DeBakey, Houston, TX or InCor BerlinHeart, Berlin, Germany) were compared with an age-, disease-, and LVAD duration-matched control group (n = 80) supported with a pulsatile device (Novacor, WorldHeart, Oakland, CA or HeartMate, Thoratec Corp, Pleasanton, CA). Results Age (44.3 ± 13.4 vs 46.1 ± 11.1 years), disease (idiopathic dilated cardiomyopathy, 58% vs 65%), and LVAD duration (138 ± 131 vs 128 ± 106 days) were comparable in both groups. Successful bridging to transplantation was similar with continuous flow in comparison with pulsatile device support (52% vs 56%, p = not significant [NS]). Thirty-day mortality after cardiac transplantation in patients with continuous flow LVAD support was 21.7% vs 22.2% with pulsatile LVADs ( p = NS). Reasons for death were similar among the different LVAD groups. Long-term survival was similar in both LVAD groups compared with patients without previous LVAD support. Interestingly, severe rejections were significantly more frequent in patients with a continuous flow LVAD ( p Conclusions The new generation of cardiac assist devices with continuous flow pattern has a similar rate of pre- and posttransplant mortality in comparison with pulsatile LVADs. However, the rate and severity of posttransplant rejection was significantly higher in the group with continuous flow devices. Further studies are warranted to explain the higher rate of severe rejections.

Background A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0–40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. Methods We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. Results The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). Conclusion In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. Trial registration Clinicaltrials.gov identifier NCT00761787 Electronic supplementary material The online version of this article (doi:10.1186/s12872-015-0106-1) contains supplementary material, which is available to authorized users.

Immunosuppression is necessary after transplantation but it is associated with distinct adverse side effects. These negative effects could at least partially be overcome with the mammalian target of Rapamycin (mTOR) inhibitor everolimus. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients (HTx).In this prospective, single-arm, single-center study, maintenance patients after HTx were converted from CNI to everolimus. They were followed for 48 months. Primary endpoints were kidney-function and arterial hypertension.Forty-eight patients were recruited (mean post-transplant time 5.4 ± 3.5 years). Of these, 36 were followed for the entire 4-year period. Median calculated glomerular filtration rate increased from 40.7 (32.4 to 59.1) mL/minute at baseline to 48.9 (29.7 to 67)) mL/minute at month 48 (p = not significant). Median systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol, did not change significantly in a comparison of the values at baseline and at 48 months. Early resolution of most non-renal CNI-related adverse events was sustained. Due to adverse events, CNI therapy had to be reintroduced in 6 patients (12.5%). No significant changes in cardiac function parameters were observed.Calcineurin inhibitor-free immunosuppression with everolimus is an effective and safe option in selected maintenance HTx patients. Most adverse effects under everolimus occurred early after conversion and in most cases resolved without intervention within a few weeks. Refining selection criteria may help both in identifying patients who will profit most from switching and in alleviating the need to reintroduce CNI therapy.

Department of Cardiology and Angiology (F Landeta MD, J Stypmann MD, P Kirchhof MD, J Waltenberger MD), Department of Thoracic and Cardiovascular Surgery (A Hoff meier MD, H Scheld MD), Institute of Clinical Radiology (D Maintz MD), Department of Nuclear Medicine (O Schober MD), and GerhardDomagk Institute of Pathology (T Spieker MD), University Hospital Muenster, Muenster, Germany; and Department of Nuclear Medicine, St Franziskus-Hospital, Muenster, Germany (M Fuchs MD)

For patients with chronic heart failure (CHF), left bundle branch block (LBBB) is associated with impaired systolic function and increased morbidity and mortality, but data on diastolic function are scarce. In this patient population, we attempted to define the impact of LBBB on diastolic function, filling pressures, and brain natriuretic peptide and its circulating N-terminal precursor (NT-proBNP) levels.A total of 94 patients with stable CHF (48 with complete LBBB, 46 without intraventricular conduction delay and normal QRS duration) underwent conventional 2-dimensional/Doppler echocardiography and Doppler tissue analysis of mitral annular velocities. As a measure of left ventricular filling pressures, the ratio of peak early mitral flow velocity to peak early diastolic mitral annular velocity was derived. NT-proBNP measurements were carried out on a bench-top analyzer (Elecsys-2010, Roche Diagnostics, Mannheim, Germany).Patients with or without LBBB did not differ with respect to the cause of CHF or ejection fraction, but in LBBB deceleration time was shorter (163 +/- 66 vs 205 +/- 95 milliseconds, P = .021) and a restrictive mitral filling pattern was more frequent (35% vs 11%, P = .005). In such patients, the ratio of peak early mitral flow velocity to peak early diastolic mitral annular velocity was higher (14.5 +/- 6.2 vs 10.6 +/- 5.2, P.001) and NT-proBNP was elevated (3553 +/- 3725 vs 850 +/- 896 pg/mL, P.01) as compared with patients without LBBB.For patients with CHF and comparable systolic performance, LBBB is associated with more severe diastolic dysfunction, elevated filling pressures, and higher NT-proBNP levels. These findings may contribute to increased morbidity and mortality of such patients.

Background Mitral annular velocities derived from tissue Doppler imaging (TDI) provide information about left ventricular (LV) long-axis function and allow for the assessment of LV filling pressures in selected subsets of patients. It was the aim of this study to assess the usefulness of TDI in patients with moderate to severe aortic valve stenosis (AS). Methods Twenty-three patients with moderate to severe AS (mean aortic valve area 0.8 0.4 cm 2 ), in whom coronary artery disease had been ruled out, and 36 asymptomatic age-matched control subjects underwent assessment of ejection fraction, fractional shortening, and mitral inflow (E, A, E/A ratio). TDI velocities (S’, E’, A’) were derived from the septal mitral annulus. In patients with AS, LV pressure before atrial contraction (LV pre-A pressure), LV end-diastolic pressure, and cardiac index were measured during cardiac catheterization. Results In patients with AS, systolic (S’) and early diastolic mitral annular velocities (E’) were significantly reduced in comparison to control subjects (systolic, 5.5 1.2 vs 8.3 1.3 cm/s; early diastolic, 5.6 1.6 vs 10.2 3.0 cm/s, P .001 for both comparisons), but ejection fraction, fractional shortening, and cardiac index were normal. In patients with AS, LV pre-A pressures (14 4 mm Hg) and end-diastolic pressures were high (19 7 mm Hg). In such patients, the mitral E/E’ ratio was significantly related to LV pre-A pressure (r 0.75, P .001) and to LV end-diastolic pressure (r 0.78, P .001). In patients with AS, an E/E’ ratio 13 identified an LV end-diastolic pressure 15 mm Hg, with a sensitivity of 93% and a specificity of 88%. Conclusions In patients with moderate to severe AS, TDI allows for a reliable, noninvasive estimation of filling pressures. In such patients, systolic long-axis function is impaired even in the presence of normal ejection fraction and cardiac index. Thus, TDI integrates information about systolic and diastolic performance and may be a useful addition in the echocardiographic workup and care of patients with AS. (Am Heart J 2004;148:696‐702.)

Nonpulsatile axial or centrifugal pumps are the latest generation of left ventricular assist devices (LVAD). Whether left ventricular (LV) unloading and outcome in these devices is similar to pulsatile LVADs during long-term support has not been investigated. We compared LV unloading and mortality between different types of LVAD support (pulsatile versus nonpulsatile).In 31 patients undergoing long-term LVAD implantation (nonpulsatile = 10, pulsatile = 21) preoperative and postoperative echocardiographic and hemodynamic assessment with right heart catheterization had been obtained.All patients had similar echocardiographic, hemodynamic, and clinical heart failure characteristics at baseline. The degree of LV pressure unloading was the same in both device types, caused by similar reduction of mean pulmonary pressure (18.6 +/- 5.1 versus 18.3 +/- 7.5 mm Hg) and pulmonary capillary wedge pressure (8.9 +/- 4.4 versus 8.0 +/- 7.0 mm Hg). Left ventricular volume unloading was pronounced with a pulsatile device owing to a statistically significant higher pump output (5.1 +/- 1.0 L/min) in comparison with nonpulsatile LVADs (3.6 +/- 0.9 L/min, p0.001). Echocardiographic-determined end-systolic indicators confirm this augmentation in pulsatile LVADs. Etiology or the time interval of hemodynamic reassessment had no impact in left ventricular pressure unloading, but LV volume unloading decreased between day 60 and 120 in patients with nonpulsatile LVADs. The preoperative and postoperative transplant mortality was comparable in both groups.Left ventricular pressure unloading is similar in patients with nonpulsatile as compared with pulsatile implantable long-term assist devices. Left ventricular volume unloading is pronounced in pulsatile LVADs.

Background Vasoactive peptides are accepted indicators of the degree of heart failure and its progression or improvement following medical therapy. Normalization of cardiac hemodynamics by cardiac transplantation (HTx) may lead to normalization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) plasma levels shortly after the procedure. Methods Long-term follow-up was done for 14 consecutive patients, 12 men and 2 women, 49 years of age (range 24 to 64 years). ANP and BNP were measured by radioimmunoassay (RIA) in central venous plasma samples (before breakfast, at steady state) at the following intervals after HTx: 7 to 30 (1), 31 to 60 (2), 61 to 90 (3), 120 to 180 (4) and 210 to 365 (5) days. Results During follow-up, ANP decreased significantly within 2 months after HTx and continued of this level, whereas BNP decreased continuously without reaching normal values. The mean ratio of ANP:BNP increased from 3.23 to 8.01 during follow-up. Whereas right atrial pressure (RAP), right ventricular pressure (RVP), right ventricular end-diastolic pressure (RVEDP) and pulmonary capillary wedge pressure (PCWP) did not change during follow-up, cardiac output (CO) improved slightly, but significantly from 5.21 liters/min to 5.9 liters/min ( p = 0.035). Conclusions Normalization of left ventricular function after orthotopic HTx does not induce an early diminution of ANP and BNP plasma levels to normal concentrations. Although elevated ANP concentrations showed only minimal changes within 1 year, BNP decreased significantly as early as 2 months after HTx, without reaching normal values during the year of follow-up. Also, the ratio of ANP and BNP increased significantly from 3.23 to 8.01. These results demonstrate the contribution of other factors beyond cardiac function that determine the levels of these peptides.

Objective: To evaluate the adriamycin-induced cardiomyopathy in the dog for research on partial left ventriculectomy (PLV). Methods: An intracoronary catheter was introduced into the left main stem via the first diagonal branch in a retrograde fashion in 6 adult FBI (Foxhound Boehringer Ingelheim) dogs weighing 30 to 35 kg. The catheter was connected to a percutaneous access port that was used for weekly adriamycin administration (10 mg over a 1-hour period for 5 times). Follow-up examinations (transthoracic echocardiography, hemodynamic parameters, cardiopulmonary status, and neurohormones) were done before, 1 week after the last adriamycin administration, and 6 weeks later. After the last measurements, all dogs were euthanized with saturated potassium chloride under general anesthesia and the hearts were excised for histologic examinations. All data were calculated as mean values and standard error of the mean. Differences were calculated by the Wilcoxon signed rank test for paired and unpaired data. p values less than 0.05 were considered significant. Results: Central venous pressure (2.2 ± 0.8 vs 5.2 ± 0.4 mm Hg, p = 0.03), mean pulmonary artery pressure (8.6 ± 1.1 vs 12.4 ± 0.5 mm Hg, p = 0.03), pulmonary wedge pressure (2.6 ± 0.9 vs 7.0 ± 0 mm Hg, p = 0.03), left ventricular endsystolic diameter (2.5 ± 0.2 vs 3.1 ± 0.4 cm, p = 0.03), and enddiastolic (4.5 ± 0.2 vs 4.9 ± 0.2 cm, p = 0.03) diameter increased significantly after adriamycin administration, whereas cardiac output (4.0 ± 0.3 vs 3.3 ± 0.1 liter/min, p = 0.03), stroke volume index (66.0 ± 7.4 vs 54.0 ± 3.9 ml/beat/m 2 , p = 0.03), and ejection fraction (61.1 ± 5.1 vs 37.7 ± 5.7%, p = 0.03) decreased markedly. These changes were accompanied by a significant decline of oxygen delivery (1130 ± 170 vs 790 ± 65 ml/min, p = 0.03), which led to an enhanced oxygen extraction (0.12 ± 0.01 vs 0.24 ± 0.01, p = 0.03). Consequently, venous oxygen saturation (82.7 ± 4.1 vs 71.3 ± 2.5%, p = 0.03) decreased. Troponin I (0.02 ± 0.025 vs 1.7 ± 0.6 ng/ml, p = 0.03) and the anti-diuretic hormone (1.9 ± 0.9 vs 20.0 ± 1.9 pg/ml, p = 0.03) increased significantly after adriamycin administration. Deterioration of cardiac function continued after termination of adriamycin administration, albeit slower than during adriamycin administration. All hearts had severe histologic alterations, which were characteristic of adriamycin-induced toxicity: cytoplasmic vacuolation, myocyte degeneration, and increased fibrosis. Conclusions: The adriamycin-induced cardiomyopathy in the dog is similar to the dilated cardiomyopathy in humans and may be an appropriate model for PLV.