Divergent mitochondrial biogenesis responses in human cardiomyopathy.

BACKGROUND: Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. METHODS AND RESULTS: To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). CONCLUSIONS: In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α-dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.

Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts.

BACKGROUND: Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors. METHODS AND RESULTS: Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors. CONCLUSIONS: BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury.

Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion.

BACKGROUND: Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. METHODS AND RESULTS: Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. CONCLUSIONS: During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

Studying semblances of a true killer: experimental model of human ventricular fibrillation.

It is unknown whether ventricular fibrillation (VF) studied in experimental models represents in vivo human VF. First, we examined closed chest in vivo VF induced at defibrillation threshold testing (DFT) in four patients with ischemic cardiomyopathy pretransplantation. We examined VF in these same four hearts in an ex vivo human Langendorff posttransplantation. VF from DFT was compared with VF from the electrodes from a similar region in the right ventricular endocardium in the Langendorff using two parameters: the scale distribution width (extracted from continuous wavelet transform) and VF mean cycle length (CL). In a second substudy group where multielectrode phase mapping could be performed, we examined early VF intraoperatively (in vivo open chest condition) in three patients with left ventricular cardiomyopathy. We investigated early VF in the hearts of three patients in an ex vivo Langendorff and compared findings with intraoperative VF using two metrics: dominant frequency (DF) assessed by the Welch periodogram and the number of phase singularities (lasting >480 ms). Wavelet analysis (P = 0.9) and VF CL were similar between the Langendorff and the DFT groups (225 ± 13, 218 ± 24 ms; P = 0.9), indicating that wave characteristics and activation rate of VF was comparable between the two models. Intraoperative DF was slower but comparable with the Langendorff DF over the endocardium (4.6 ± 0.1, 5.0 ± 0.4 Hz; P = 0.9) and the epicardium (4.5 ± 0.2, 5.2 ± 0.4 Hz; P = 0.9). Endocardial phase singularity number (9.6 ± 5, 12.1 ± 1; P = 0.6) was lesser in number but comparable between in vivo and ex vivo VF. VF dynamics in the limited experimental human studies approximates human in vivo VF.

Reporter-based isolation of induced pluripotent stem cell- and embryonic stem cell-derived cardiac progenitors reveals limited gene expression variance.

RATIONALE: Induced pluripotent stem (iPS) cells can differentiate into multiple cell types, including cardiomyocytes and have tremendous potential for drug discovery and regenerative therapies. However, it is unknown how much variability exists between differentiated lineages from independent iPS cell lines and, specifically, how similar iPS cell-derived cardiomyocytes (iPS-CMs) are to embryonic stem (ES) cell-derived cardiomyocytes (ES-CMs). OBJECTIVE: We investigated how much variability exists between differentiated lineages from independent iPS cell lines and how similar iPS-CMs are to ES-CMs. METHODS AND RESULTS: We generated mouse iPS cells in which expression of NKX2-5, an early cardiac transcription factor, was marked by transgenic green fluorescent protein (GFP). Isolation of iPS- and ES-derived NKX2-5-GFP(+) cardiac progenitor pools, marked by identical reporters, revealed unexpectedly high similarity in genome-wide mRNA expression levels. Furthermore, the variability between cardiac progenitors derived from independent iPS lines was minimal. The NKX2-5-GFP(+) iPS cells formed cardiomyocytes by numerous induction protocols and could survive upon transplantation into the infarcted mouse heart without formation of teratomas. CONCLUSIONS: Despite the line-to-line variability of gene expression in the undifferentiated state of ES and iPS cells, the variance narrows significantly in lineage-specific iPS-derived cardiac progenitors, and these progenitor cells can be isolated and used for transplantation without generation of unwanted cell types.

Eicosapentaenoic acid disrupts the balance between Tregs and IL-17+ T cells through PPARγ nuclear receptor activation and protects cardiac allografts.

Eicosapentaenoic acid (EPA) is one of n-3 polyunsaturated fatty acids that possesses a wide array of anti-inflammatory effects but its effects, on transplantation in general and on Tregs and IL-17(+) T cells in particular, are not well studied. We treated recipient mice of heart transplantation with EPA and examined the effect of EPA on the ratio of Tregs/IL-17(+) T cells in an allogeneic heart transplant model. The hearts from BALB/c (H-2d) mice were transplanted into C57BL/6 (H-2b) mice, and the recipients were administered EPA (500 mg/kg/d, 250 mg/kg/d, or 100 mg/kg/d) from d 1 to 3 post-transplant. The survival of cardiac allografts in mice treated with EPA was significantly protracted. Further examination of donor hearts in EPA-treated group demonstrated that infiltrating Foxp3(+) T cells were increased, IL-17(+) T cells were decreased, and expression of PPARγ was up-regulated. In mixed lymphocytes reaction (MLR), incubation with EPA significantly inhibited the proliferation of IL-17(+) T cells and promoted the proliferation of Tregs, while PPARγ antagonists GW9662 could reverse the results. Our study demonstrated that EPA can effectively protect cardiac allografts and disrupt the balance between Tregs and IL-17(+) T cells in a murine model. This effect is partially mediated by PPARγ nuclear receptor activation.

The profile of inflammatory and metabolic response in children undergoing heart transplantation.

Inflammatory and metabolic response is an important factor to determine clinical outcomes. However, it remains unknown in children undergoing heart transplantation (HTx). We examined the perioperative changes in the inflammatory and metabolic response markers C-reactive protein (CRP) and prealbumin (PA) in 38 heart-transplanted children. Data obtained prior to and within one month after HTx included CRP, PA, total and differential white blood cell counts, doses of inotropes and immunosuppressants, cultures of blood and body fluids, duration of cardiopulmonary bypass (CPB), aortic cross clamp and donor heart ischemia, and days in the intensive care unit (ICU) and hospital. CRP was 32±49 mg/L before HTx, increased to 130±55 mg/L on postoperative day 1-2, and decreased to 21±31 mg/L by one month after HTx. PA was 0.15±0.06 g/L before HTx, decreased to 0.12±0.03 g/L on postoperative day 1-2, and then gradually increased to 0.21±0.10 g/L by one month after HTx. Postoperative CRP positively correlated with epinephrine dosage and CPB duration. PA positively correlated with age. In conclusion, inflammatory and metabolic response is present before HTx and acutely intensified after HTx. It may be mainly influenced by CPB duration and cardiovascular function status.

Arrhythmias in heart transplant recipients.

The suture between the recipient and donor atrium in a heart transplant patient usually gives complete electric isolation. In this case report, we describe two transplant patients with an atrial tachycardia in the recipient atrium. In the first patient there was no conduction to the donor atrium, whereas the second patient had a breakthrough with 2-to-1 conduction.

Unloading the infarcted heart affect MMPs-TIMPs axis in a rat cardiac heterotopic transplantation model.

Ventricular assist devices may function as a bridge to recovery or heart transplantation, however, little is known about its mechanisms. This study examined the role of matrix metalloproteinases (MMP)-tissue inhibitors of metalloproteinases (TIMP) axis in the process of recovery after unloading in a rat ischemic-induce heart failure (HF) model. Myocardial infarction model was created with the coronary artery ligation. The infarcted rats hearts were unloaded by heterotopic cardiac transplantation (n=14). 2 weeks later, the function of normal and infarcted hearts with or without loading was evaluated by Langendorff perfusion model. The hearts were then harvested and prepared for the study of expression of MMPs and TIMPs. Developed pressure in the unloading group was higher than the loading group (P=0.0074). Unloading increased the ratio of TIMP-1-MMP-1(1.38±0.11 vs. 0.76±0.09, P<0.05), TIMP-2-MMP-2 (1.06±0.10 vs. 0.33±0.07, P<0.01), TIMP-3-MMP-9(1.07±0.08 vs. 0.59±0.06, P<0.05). Although MMP-1, 2, 9 were downregulated (P<0.01, 0.01, 0.05, respectively), TIMP-2 and TIMP-3 upregulated (P<0.01, 0.05, respectively), MMP-7 and TIMP-1 was not affected significantly. The infarcted cardiac function could be improved by unloading. It was attributed to downregulation of MMP-1, 2 and 9, and upregulation of TIMP-2 and -3, and furthermore, the ratio of TIMPs to MMPs was increased, which might be more sensitive than sole MMPs or TIMPs for the judgment of myocardial matrix homeostasis.

Multiple interatrial electrical connection after heart transplantation.

A 62-year-old woman who underwent heart transplantation 6 years later presented a regular atrial tachycardia. Electrophysiologic evaluation showed an atrial arrhythmia in the recipient atrium with 2:1 conduction to the donor atrium, with a confusing electroanatomical map. With the suspect of alternant conduction through two different breakthroughs, the map was split in two concordant maps, corresponding to two connections that were successfully ablated. Later on, a third connection was detected and therefore ablated.

Wait, treat and see: echocardiographic monitoring of brain-dead potential donors with stunned heart.

BACKGROUND: Heart transplantation is limited by a severe donor organ shortage. Potential donors with brain death (BD) and left ventricular dysfunction due to neurogenic stunning are currently excluded from donation--although such abnormalities can be reversible with aggressive treatment including Hormonal Treatment (HT) and deferred organ retrieval. AIM: To assess the recovery of left ventricular dysfunction in potential brain-dead donors with hemodynamic instability treated by aggressive treatment and HT. METHODS: In a single-center, observational study design, we evaluated 15 consecutive brain-dead potential donors (DBD) (8 males, age = 48 ± 15 years) with hemodynamic instability. All underwent standard hemodynamic monitoring and transthoracic 2-dimensional echo (2-DE) with assessment of Ejection Fraction (EF). Measurements were obtained before BD and after BD within 6 h, at 24 h and within 48 h. HT (with insulin, methylprednisolone, vasopressin and T3) was started as soon as possible to treat hemodynamic instability and avoid administration of norepinephrine (NE). Eligible potential heart donors underwent coronary angiography. RESULTS: After HT, we observed a normalization of hemodynamic conditions with improvement of mean arterial pressure (pre = 68 ± 8 mmHg vs post = 83 ± 13 mmHg, p < .01), cardiac index (pre = 2.4 ± 0.6 L/min/m2 vs post 3.7 ± 1.2 L/min/m2, p < .05), EF (pre = 48 ± 15 vs post = 59 ± 3%, p < .01) without administration of norepinephrine (NE) in 67% of cases. Five potential donors were excluded from donation (opposition, n = 3, tubercolosis n = 1, malignancy n = 1). At pre-harvesting angiography, coronary artery stenosis was present in 2 of the 10 consented donors. Eight hearts were uneventfully transplanted. No early graft failure occurred and all eight recipients were alive at 6-month follow-up. CONCLUSION: In BD donors, intensive treatment including HT is associated with improvement of regional and global LV function and reverse remodeling detectable by transthoracic 2DE. Donor hearts with recovered LV function may be eligible for uneventful heart transplant. The wait (in brain death), treat (with HT) and see (with 2D echo) strategy can help rescue organs suitable for heart donation.

Sensing of 2 atrial rhythms by a pacemaker in a transplanted heart.

A patient who had undergone orthotopic heart transplantation received a VDD pacemaker for AV block. The pacemaker sensed both the recipient and donor atrial rhythms. The atrial lead must be implanted in the donor atrium: a double atrial electrogram requires a different atrial site unless programmable atrial sensitivity can establish preferential sensing of donor P waves.

[Toxoplasmic cyst and heart transplant: a case report of serological reactivation in an acute graft rejection context]. / Kyste toxoplasmique et transplant cardiaque : cas d'une réactivation sérologique dans un contexte de rejet de greffe.

We describe the case of a serological reactivation in a Toxoplasma-seropositive subject, following a cardiac transplantation transmitting cysts contained in the myocardial tissue. In a context of acute graft rejection, primary chemoprophylaxis enables to avoid onset of opportunistic toxoplasmosis, emerging with immunodepletion performed by high-dose steroids. Then, we draw up a brief review of the bibliographical literature about pathophysiological mechanisms of toxoplasmic reactivation in heart transplants.

SPECT/CT lymphoscintigraphy of heterotopic cardiac grafts reveals novel sites of lymphatic drainage and T cell priming.

The normal function of lymphatic vessels is to facilitate the trafficking of antigen presenting cells to draining lymph nodes where they evoke an immune response. Donor lymphatic vessels are not connected to that of recipients' during organ transplantation. The pathophysiology of this disruption has received little attention. Murine heterotopic cardiac transplantation has been used extensively in transplantation research. Following vascularized organ transplantation, the main site of allosensitization is thought to be in the spleen of the recipient as a result of migration of donor passenger leukocytes via blood. Here, using Single Photon Emission Computed Tomography/Computerized Tomography (SPECT/CT) lymphoscintigraphy, we studied the pattern of lymphatic flow from mouse heterotopic abdominal cardiac grafts and identified mediastinal lymph nodes as the draining nodes for the donor graft. Staining with HY tetramer after transplantation of HY mismatched heart grafts and ELISPOT following allogeneic grafts to detect donor specific T cells revealed them as important sites for allosensitization. Our data indicates that mediastinal lymph nodes play a crucial role in the alloimmune response in this model, and should be used for ex vivo and adoptive transfer studies after transplantation in addition to the spleen.

Causal relationships between heart period and systolic arterial pressure during graded head-up tilt.

In physiological conditions, heart period (HP) affects systolic arterial pressure (SAP) through diastolic runoff and Starling's law, but, the reverse relation also holds as a result of the continuous action of baroreflex control. The prevailing mechanism sets the dominant temporal direction in the HP-SAP interactions (i.e., causality). We exploited cross-conditional entropy to assess HP-SAP causality. A traditional approach based on phases was applied for comparison. The ability of the approach to detect the lack of causal link from SAP to HP was assessed on 8 short-term (STHT) and 11 long-term heart transplant (LTHT) recipients (i.e., less than and more than 2 yr after transplantation, respectively). In addition, spontaneous HP and SAP variabilities were extracted from 17 healthy humans (ages 21-36 yr, median age 29 yr; 9 females) at rest and during graded head-up tilt. The tilt table inclinations ranged from 15 to 75° and were changed in steps of 15°. All subjects underwent recordings at every step in random order. The approach detected the lack of causal relation from SAP to HP in STHT recipients and the gradual restoration of the causal link from SAP to HP with time after transplantation in the LTHT recipients. The head-up tilt protocol induced the progressive shift from the prevalent causal direction from HP to SAP to the reverse causality (i.e., from SAP to HP) with tilt table inclination in healthy subjects. Transformation of phases into time shifts and comparison with baroreflex latency supported this conclusion. The proposed approach is highly efficient because it does not require the knowledge of baroreflex latency. The dependence of causality on tilt table inclination suggests that "spontaneous" baroreflex sensitivity estimated using noncausal methods (e.g., spectral and cross-spectral approaches) is more reliable at the highest tilt table inclinations.

Mismatch of right- and left-sided filling pressures in chronic heart failure.

BACKGROUND: In patients with advanced heart failure (HF), elevated jugular venous pressure (JVP) is the most reliable sign of elevated left-sided filling pressures. However, discordance between right- and left-sided filling pressures (R-L mismatch) could lead to inadequate or excessive therapy guided by JVP. We determined the prevalence of R-L mismatch in the current era and investigated whether mismatch might be identified from clinical information. METHODS AND RESULTS: Right-sided heart catheterization was performed in 537 consecutive patients hospitalized with advanced HF during complete transplantation evaluation. Patients with high filling pressures were categorized as matched (right atrial pressure (RAP) ≥10 mm Hg and pulmonary wedge pressure (PCWP) ≥22 mm Hg), high-R mismatch (RAP ≥10 but PCWP <22 mm Hg) or high-L mismatch (PCWP ≥22 but RAP <10 mm Hg). Among all of the patients, 195 (36%) were matched low and 194 (36%) were matched high, and 148 (28%) had R-L mismatch. Among patients with high filling pressures, 194 (57%) were matched high and 82 (24%) had high-L and 66 (19%) high-R mismatch. Mismatches were not associated with differences in demographic or clinical data, including pulmonary and hepatic function, or severity of valvular regurgitation and right ventricular function by echo. However, among all patients with RAP ≥10 mm Hg, pulmonary artery systolic pressure (PASP) was higher in those patients with matched high left- and right-sided pressures (59 ± 12 mm Hg) versus high-R mismatch (41 ± 13 mm Hg; P < .0001). Similarly among all patients with low RAP, PASP was lower in patients with matched low right- and left-side pressures (33 ± 11 mm Hg) versus high-L mismatch (53 ± 13 mm Hg; P < .0001). CONCLUSIONS: R-L mismatch was present in >1 in 4 total patients, and >1 in 3 with elevated filling pressures. Regardless of clinical history, when empiric therapy to optimize volume status to JVP is not effective, additional measurement should be considered to establish the R-L relationship.

Effects of exercise training in heart transplant recipients: a meta-analysis.

OBJECTIVES: Muscle wasting and exercise intolerance are common in heart transplant recipients. Most studies on the effects of exercise training have used relatively small sample sizes and are heterogeneous in nature. The purpose of this meta-analysis was to systematically review the relevant studies and investigate the effects of exercise training on exercise capacity and muscle strength in heart transplant recipients. METHODS: A systematic search was adopted from electronic databases and relevant references, using medical subject heading key words related to heart transplantation and exercise. Only randomized controlled trials with exercise intervention versus usual care were included. The data were expressed as the weighted mean differences with 95% confidence intervals (CIs). RESULTS: Altogether 6 studies were included. Peak oxygen consumption (VO(2)) was reported in 4 trials (117 patients), and muscle strength was reported in 3 trials (67 patients). Peak VO(2) was significantly increased by 2.34 ml/kg/min (95% CI 0.63-4.05). One-repetition maxima of the chest press (23.28 kg, 95% CI 0.64-45.91) and leg press (28.84 kg, 95% CI 5.70-51.98) were significantly improved by exercise training. CONCLUSION: Exercise training is recommended for heart transplant recipients to improve peak VO(2) and muscle strength despite the small number of trials included in this meta-analysis.

Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy.

The cardiac response to increased work includes a reactivation of fetal genes. The response to a decrease in cardiac work is not known. Such information is of clinical interest, because mechanical unloading can improve the functional capacity of the failing heart. We compared here the patterns of gene expression in unloaded rat heart with those in hypertrophied rat heart. Both conditions induced a re-expression of growth factors and proto-oncogenes, and a downregulation of the 'adult' isoforms, but not of the 'fetal' isoforms, of proteins regulating myocardial energetics. Therefore, opposite changes in cardiac workload in vivo induce similar patterns of gene response. Reactivation of fetal genes may underlie the functional improvement of an unloaded failing heart.

Hypertension after heart and heart/lung transplantation in childhood--study on the evolution of short-term blood pressure regulation.

Arterial hypertension complicates the follow-up of heart- and heart/lung-transplanted children. We investigated the evolution of BRS as short-time BP regulation mechanism and BP after heart and heart/lung transplantation. Twenty patients (15 males; mean age 15.1 ± 4.3 yr) were studied twice at intervals of 2.96 ± 0.87 yr. BRS was calculated using non-invasive beat-to-beat BP measurement system. HRV was calculated (LF, sympathetic influence; HF, parasympathetic influence). BRS increased in 10 patients (3.67 ± 1.43 ms/mmHg vs. 7.59 ± 3.40 mmHg, p = 0.005) (group 1). Six of 10 patients received antihypertensive medication. BRS decreased or remained unchanged in 10 patients (8.93 ± 7.9 ms/mmHg vs. 5.32 ± 6.6 ms/mmHg, p = 0.008) (group 2) with 9/10 patients necessitating antihypertensive medication. Group 1 showed LF/HF increase (LF/HF 1.03 ± 0.9 vs. 4.36 ± 2.32, p = 0.03); group 2 showed LF/HF decrease (LF/HF 3.7 ± 2.1 vs. 1.84 ± 1.1, p = 0.023). Evolution of BRS after heart and heart/lung transplantation in childhood seems to influence the necessity of antihypertensive medication. With time, increasing short-time BP regulation involving sympathetic reinnervation may improve BP.

Changes in exercise capacity induced by heart transplantation: prognostic and therapeutic implications.

Survival and exercise performance are key targets of heart transplantation (HT). We designed this study to help in identifying (1) patients with chronic heart failure (CHF) at risk of poor exercise capacity after HT and (2) HT recipients presenting risk factors modifiable with exercise showing a potential impact on outcome. We enrolled 49 HT recipients (age 52 ± 12 years, 84% males) who underwent a cardiopulmonary exercise test before (9 ± 6 months) and after (20 ± 14 months) HT. In the CHF phase, lower peak oxygen consumption (VO(2) ) (odds ratio 0.69, P=0.017) independently predicted peak VO(2) improvement after HT. In the post-HT phase, body mass index (BMI) [adjusted hazard ratio (HR) 1.16, P=0.034] and VE (ventilation)/VCO(2) (carbon dioxide production) slope (adjusted HR 1.07, P=0.031) independently predicted mortality. In conclusion, CHF patients with only a moderate impairment of peak VO(2) are at a risk of failing to achieve a significant improvement of exercise performance after HT. In the post-HT phase, a BMI≥28 and/or a VE/VCO(2) slope ≥47 represent risk factors for death, which are potentially modifiable with exercise. Prospective randomized studies are needed to analyze the effects of training on functional capacity and outcome in the different subsets of HT recipients.