Physical Exercise in Patients with Fabry Disease - a Pilot Study.

The aim of this study was to assess the extent of exercise intolerance in Fabry disease (FD) patients and to report individual effects of physical exercise. Exercise capacity and strength of 14 patients (mean age 46 years, 6 females) were determined using cycle ergometry and isokinetic measurements. Patients performed a strength/circuit exercise training protocol for 12 months. The mean relative maximum performance of the group was low at baseline and increased by 12.1% (baseline: 1.9 [0.9-3.4] W·kg-1vs. re-test: 2.1 [1.1-3.8] W·kg-1; p=0.035) during the study. Patients' mean baseline maximum performance blood lactate of 5.4 [1.3-9.9] mmol·L-1 increased to a mean of 7.2 (2.4-10.2) mmol·L-1 (p=0.038). Mean strength of the lower limbs (left/right extensors and flexors, total work of 5 sets) changed from 2269 (1017-2913) kg·m2·s - 2 to 2325 (1359-3107) kg·m2·s-2 (not significant). Patients reported increased well-being, daily activity and reduced fatigue during the study. Our results indicate that exercise intolerance in FD patients often results from physical inactivity. FD patients may perform exercise training to improve exercise capacity and muscle strength. Future studies will address the clinical benefits of exercise in FD.

Renal Contrast-Enhanced Sonography Findings in a Model of Acute Cellular Allograft Rejection.

Noninvasive methods to diagnose and differentiate acute cellular rejection from acute tubular necrosis or acute calcineurin inhibitor toxicity are still missing. Because T lymphocytes play a decisive role in early states of rejection, we investigated the suitability and feasibility of antibody-mediated contrast-enhanced ultrasound by using microbubbles targeted to CD3(+) , CD4(+) , or CD8(+) T cells in different models of renal disease. In an established rat renal transplantation model, CD3-mediated ultrasound allows the detection of acute rejection as early as on postoperative day 2. Ultrasound signal intensities increased with the severity of inflammation. Further, an early response to therapy could be monitored by using contrast-enhanced sonography. Notably, acute tubular necrosis occurring after ischemia-reperfusion injury as well as acute calcineurin inhibitor toxicity could easily be differentiated. Finally, the quantified ultrasound signal correlated significantly with the number of infiltrating T cells obtained by histology and with CD3 mRNA levels, as well as with chemokine CXCL9, CXCL11, and CCL19 mRNA but not with KIM-1 mRNA expression, thereby representing the severity of graft inflammation but not the degree of kidney injury. In summary, we demonstrate that antibody-mediated contrast-enhanced ultrasound targeting T lymphocytes could be a promising tool for an easy and reproducible assessment of acute rejection after renal transplantation.

[Congestive heart failure: reverse cardiac remodeling mediated by left ventricular assist devices]. / Chronische Herzinsuffizienz: Partielle Reversibilität durch linksventrikuläre mechanische Unterstützungssysteme.

Left ventricular assist devices (LVAD) are currently used to treat patients with terminal congestive heart failure as a bridge to transplantation or as destination therapy in individuals with contraindications for cardiac transplantation. The LVADs are pulsatile or non-pulsatile systems that transport blood from the left ventricle to the ascending aorta parallel to the circulation thus providing a profound volume and pressure reduction in the left ventricle. The use of LVADs is associated with a considerable decrease of cardiac hypertrophy and dilation with significantly improved cardiac performance in a small subset of patients. The underlying process is termed reverse cardiac remodelling and is characterized by a significant decrease in the size of cardiomyocytes and reversible regulation of numerous molecular systems in the myocardium.

Blockade of I(Ca) suppresses early afterdepolarizations and reduces transmural dispersion of repolarization in a whole heart model of chronic heart failure.

BACKGROUND AND PURPOSE Chronic heart failure (CHF) is associated with action potential prolongation and Ca(2+) overload, increasing risk of ventricular tachyarrhythmias (VT). We therefore investigated whether I(Ca) blockade was anti-arrhythmic in an intact perfused heart model of CHF. EXPERIMENTAL APPROACH CHF was induced in rabbits after 4 weeks of rapid ventricular pacing. Hearts from CHF and sham-operated rabbits were isolated and perfused (Langendorff preparation), with ablation of the AV node. VT was induced by erythromycin and low [K(+) ] (1.5mM). Electrophysiology of cardiac myocytes, with block of cation currents, was simulated by a mathematical model. KEY RESULTS Repolarization was prolonged in CHF hearts compared with sham-operated hearts. Action potential duration (APD) and overall dispersion of repolarization were further increased by erythromycin (300 µM) to block I(Kr) in CHF hearts. After lowering [K(+) ] to 1.5mM, CHF and sham hearts showed spontaneous episodes of polymorphic non-sustained VT. Additional infusion of verapamil (0.75 µM) suppressed early afterdepolarizations (EAD) and VT in 75% of sham and CHF hearts. Verapamil shortened APD and dispersion of repolarization, mainly by reducing transmural dispersion of repolarization via shortening of endocardial action potentials. Mathematical simulations showed that EADs were more effectively reduced by verapamil assuming a state-dependent block than a simple block of I(Ca) . CONCLUSIONS AND IMPLICATIONS Blockade of I(Ca) was highly effective in suppressing VT via reduction of transmural dispersion of repolarization and suppression of EAD. Such blockade might represent a novel therapeutic option to reduce risk of VT in structurally normal hearts and also in heart failure. LINKED ARTICLE This article is commented on by Stams et al., pp. 554-556 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01818.x.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years' follow-up from the University Hospital Münster.

BACKGROUND: 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. METHODS: 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. RESULTS: 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)]. CONCLUSION: 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.

[Heart transplantation. Pathology, clinical work-up and therapy]. / Herztransplantation. Pathologie, Klinik und Therapie.

Since the first heart transplantation in 1967, the procedure has become an established therapy in the treatment of terminal heart failure. Constant advances in the development of potent immunosuppressive drugs, as well as greater clinical experience and pathological diagnostics have improved patient survival dramatically. The first grading system for rejection was published in 1990 by the International Society for Heart and Lung Transplantation (ISHLT) and revised in 2004. The 2004 grading system comprises three grades of severity (1R, 2R, 3R), whereby the former grade 2 in the 1990 system has been incorporated in the new grade 1R. Recommendations are made for the histological diagnosis of acute antibody-mediated rejection using immunohistochemical staining against C4d and macrophages. To the present day, the pathological examination of endomyocardial biopsies remains the gold standard for post-transplant diagnostic procedures. Whether or not non-invasive diagnostic approaches (e.g. gene array profile analysis on leukocytes) can replace morphological investigations needs to be clarified in randomised, prospective clinical studies.

Sex mismatch in heart transplantation is associated with increased number of severe rejection episodes and shorter long-term survival.

BACKGROUND: Heart transplantation is the criterion standard for treating end-stage heart failure. Male sex of both the donor organ and the recipient is advantageous for survival, possibly owing to hemodynamic or immunologic reasons. The effect of sex mismatch on long-term survival in male heart transplant recipients is less known. PATIENTS AND METHODS: In this prospective single-center study, we reviewed follow-up data for 57 sex-mismatched and 179 sex-matched men who underwent orthotopic heart transplantation between 1990 and 2002. RESULTS: Median survival was significantly shorter in the sex-mismatched group (8.1 vs 12.9 years; P < .04). Subgroup analysis revealed that this was even more pronounced in male heart recipients with coronary artery disease (2.4 vs 12.9 years; P < .001). Female donor organs were significantly smaller (left ventricular end-diastolic diameter 49 vs 51 mm; P < .05), and recipients more often experienced clinically relevant episodes of cellular rejection during the first 3 months posttransplantation (International Society for Heart and Lung Transplantation grade 3, 5.6% vs 3.1%; P < .001). Global left ventricular function, and immunosuppressive and inflammatory parameters did not differ. CONCLUSION: In male orthotopic heart transplant recipients, sex mismatch is associated with adverse outcome owing to increased number and severity of episodes of graft rejection.

Aminoterminal B-type pro-natriuretic peptide as a marker of recovery after high-risk coronary artery bypass grafting in patients with ischemic heart disease and severe impaired left ventricular function.

BACKGROUND: Aminoterminal B-type pro-natriuretic peptide (NT-proBNP) is a reliable indicator of heart failure severity. Levels of NT-proBNP are markedly increased in patients with coronary artery disease (CAD) and severely impaired left ventricular (LV) function. The aim of our study was to assess the impact of NT-proBNP levels after high-risk coronary artery bypass grafting (CABG) with regard to recovery potential. METHODS: Between 1998 and 2004, 121 patients with CAD and severely impaired LV function, who were undergoing CABG, were investigated. Their mean age was 64 +/- 11 years. All patients were in New York Heart Association (NYHA) Class III/IV status; LV ejection fraction (EF) was 20 +/- 6%. All survivors underwent follow-up (59 +/- 34 months) spiroergometric, electrocardiographic (ECG) and echocardiographic assessment and were tested for routine blood controls and NT-proBNP levels (Roche, Mannheim, Germany). RESULTS: The survival rate after 8 years was 70%. All survivors received follow-up assessment. Among survivors the median NT-proBNP level at follow-up was 896 (521 to 1,687) pg/ml. The maximum oxygen uptake was 14.6 +/- 4.9 ml/min/kg, and EF increased to 42% at follow-up among all survivors. On dichotomizing survivors into two groups with NT-proBNP levels above and below the median, the post-operative body mass index was significantly higher in the high NT-proBNP group (p = 0.036). EF (p = 0.028) and NYHA classification (p < 0.05) improved significantly in both groups, with a tendency toward higher EF in the low NT-proBNP group. CONCLUSIONS: Patients undergoing a high-risk CABG procedure have a survival rate comparable to heart transplantation patients and show a potential for clinical and myocardial recovery. NT-proBNP use a useful marker for recovery after a high-risk CABG procedure, with significant correlation with clinical parameters.

Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early afterdepolarizations in an intact heart model of LQT3.

BACKGROUND: In long QT syndrome (LQTS), prolongation of the QT-interval is associated with sudden cardiac death resulting from potentially life-threatening polymorphic tachycardia of the torsade de pointes (TdP) type. Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS. We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3. METHODS AND RESULTS: In 8 Langendorff-perfused rabbit hearts, veratridine (0.1 microM), an inhibitor of sodium channel inactivation, led to a marked increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p < 0.05) thereby mimicking LQT3. In bradycardic (AV-blocked) hearts, simultaneous recording of up to eight epi- and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p < 0.05) and reverse frequency-dependence. After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts. Additional infusion of verapamil (0.75 microM) suppressed EADs and consecutively TdP in all hearts. Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization. CONCLUSIONS: Verapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3. These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.

Cardiothoracic surgery after heart and heart-lung transplantation.

OBJECTIVE: We sought to examine our management and the outcomes of cardiothoracic procedures after heart and heart lung transplantation. METHODS: We performed a retrospective review of cardiothoracic surgical procedures carried out between 1990 and 2004 in patients who had previously undergone heart or heart-lung transplantation at our institution. RESULTS: Twenty-one out of 340 patients (6.2 %) were identified. Cardiothoracic surgery was performed 44.4 +/- 33 months (range 1 - 115 months) after transplantation. Predominant types of surgery were coronary artery bypass grafting due to allograft vasculopathy (n = 5), aortic surgery due to acute dissection (n = 3), biventricular assist device implantation due to acute rejection (n = 1), tricuspid valve repair (n = 1), multiple cardiac surgical procedures including coronary artery bypass grafting, retransplantation, and tricuspid valve replacement (n = 2), explantation of a functionless heterotopic transplanted heart (n = 1). Lung surgery was performed in six patients due to pneumonia (n = 2), primary lung carcinoma (n = 3), lung torsion following heart-lung transplantation (n = 1). All patients underwent either lobectomy or segmental lung resection. Single lung retransplantation (n = 2) after prior heart-lung transplantation due to bronchiolitis obliterans was performed. In one patient a pneumonectomy (n = 1) due to severe chronic rejection of the contralateral lung was performed. Six subsequent deaths after cardiothoracic procedures were recorded after 1, 4, 78, 163, 205, and 730 days, respectively. Causes of death were advanced carcinoma (n = 1), multi-organ failure due to sepsis (n = 2), sudden heart death (n = 2), and advanced heart failure (n = 1). Fifteen out of 21 patients having undergone cardiothoracic procedures (71.4 %) survived the observation period of 56.6 +/- 34 months (range 1 - 114). CONCLUSIONS: Reasons for cardiothoracic procedures after prior heart or heart-lung transplantation were allograft vasculopathy, aortic dissections years after transplantation, chronic rejection, and either lung infections or malignancies. Surgical repair can be performed with an acceptable operative risk and good long-term survival rates.

Primary left atrial angiosarcoma mimicking severe mitral valve stenosis.

Primary cardiac tumours are quite rare and most of these tumours are benign. In this report, a patient presented with heart failure symptoms attributable to severe mitral valve stenosis. Echocardiography showed a dense left atrial mass causing functional mitral valve obstruction. The morphological and intraoperative presentation was highly suggestive of a myxoma but histopathological examination found a primary pedunculated cardiac angiosarcoma. The role of two dimensional and transoesophageal echocardiography in the assessment of cardiac masses and tumours is discussed.

Stroke volume and mitral annular velocities. Insights from tissue Doppler imaging.

The aim of this study was to assess the impact of stroke volume (SV) on mitral annular velocities derived from tissue Doppler imaging (TDI). To this end, conventional echocardiographic variables and TDI derived mitral annular velocities (S', E', A') were obtained in 14 patients (pts) with increased SV (due to primary mitral (n=12) (ISV group)), in 41 pts with reduced SV (due to ischemic (n=27) or dilated cardiomyopathy (n=9) or hypertensive heart disease (n=5) (RSV group)) and 29 asymptomatic controls with normal SV (CON group). Systolic (S') and early diastolic (E') mitral annular velocities were elevated in the ISV group in the comparison to the CON group, but were significantly reduced in the RSV group. Late diastolic annular velocities (A') did not differ between the ISV and the CON group, but were lowest in the RSV group. On simple linear regression analysis, SV was significantly related to S' (r=0.74, p<0.001), to E' (r=0.74, p<0.001) and to A' (r=0.43, p<0.01). On multiple regression analysis, SV was a stronger independent predictor of S' and E' than conventional systolic or diastolic echocardiographic variables. Thus, stroke volume has a significant impact on TDI derived systolic (S') and early diastolic (E') mitral annular velocities. This should be considered, when TDI is used in the evaluation of LV performance or in the estimation of filling pressures.

[Myocardial alterations with mechanical left ventricular assist devices]. / Myokardiale Veränderungen unter mechanischer linksventrikulärer Unterstützungstherapie.

Left ventricular assist devices (LVAD) have been used to "bridge" patients with end-stage heart failure to transplantation. Although several reports have suggested that the native ventricular function recovers after long-term LVAD support, a process called "reverse remodeling", the underlying biological mechanisms are still unclear. Various molecular pathways of the human myocardium associated with apoptosis, response to stress, or matrix changes are known to be altered under conditions of heart failure, and some have been shown to be reversibly regulated during left ventricular mechanical support, suggesting that the descriptive term "reverse remodeling" is, at least in parts, a reversible mechanism. The reduction of volume and pressure overload with a decrease of ventricular wall stress leading to an improvement of myocardial blood supply under mechanical circulatory assistance, may be one explanation for the molecular myocardial changes and may reflect one possible cause for the phenomenon of "reverse remodeling".

Naloxone prevents increased atrial natriuretic peptide release during regional myocardial ischaemia and stunning in awake dogs.

BACKGROUND: Atrial natriuretic peptide (ANP) release is increased in patients with ischaemic left ventricular dysfunction. A beneficial effect of naloxone on recovery from myocardial stunning was shown previously. The aim of this study was to investigate the effects of naloxone on ANP release during regional myocardial ischaemia and stunning in awake dogs. METHODS: Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic, and left ventricular pressure (LVP), LV dP x dtmax/min(-1), and myocardial wall-thickening fraction. An occluder around the left anterior descending artery (LAD) allowed induction of reversible ischaemia in the LAD-perfused myocardium. Each dog underwent two ischaemic episodes (randomized crossover fashion; separate days): 10 min of LAD occlusion (1) after application of naloxone (63 microg kg(-1)), and (2) without naloxone. ANP levels were measured at baseline (BL) and at predetermined time points until complete recovery of myocardial stunning occurred. RESULTS: LAD ischaemia-induced release of ANP (peak level: 182 (30) vs 27 (7) pg ml(-1) BL) only in the control group without naloxone. Between 1 and 180 min of reperfusion, ANP levels were significantly higher only in the control group (P<0.05). CONCLUSION: Pre-ischaemic application of naloxone prevents this ischaemia-induced ANP-release in conscious dogs.

Does a suitable animal model for research on partial left ventriculectomy exist? Animal models for PLV.

Partial left ventriculectomy is a new surgical option quickly introduced into clinical use worldwide for treating end-stage heart failure in patients with dilated cardiomyopathy. Due to the overwhelming success of this new kind of surgical treatment for dilated cardiomyopathy, experimental research on the physiological and pathophysiological basis was initially not performed. Now, demands for an appropriate animal model have arisen more and more since the outcome of patients treated by partial left ventriculectomy has differed considerably. This review summarizes available experimental models for heart failure in large animals, and discusses their suitability for research on partial left ventriculectomy.

Naloxone improves functional recovery of myocardial stunning in conscious dogs through its action on the central nervous system.

This study tests the hypothesis that naloxone, but not its quarternary salt, naloxone methiodide (which does not enter the central nervous system), improves recovery from myocardial stunning in conscious dogs. Twenty dogs were chronically instrumented for measurement of heart rate, left atrial, aortic and left ventricular pressure (LVP), LV dP x dtmax(-1) and myocardial wall thickening fraction (WTF). Regional myocardial blood flow was determined with coloured microspheres. Occluder around the left anterior descending artery (LAD) allowed induction of reversible LAD ischaemia. Each of the 20 dogs underwent two LAD ischaemic challenges. Experiments (performed on separate days, in crossover fashion) were: (i) 10 min of LAD occlusion after application of naloxone 63 microg kg(-1) or naloxone methiodide 63 microg kg(-1) and (ii) occlusion without naloxone or naloxone methiodide. WTF was measured at baseline and until complete recovery occurred. LAD ischaemia significantly reduced LAD WTF with (mean (SD) 54 (15)% lower than baseline) and without naloxone (55 (16)% lower than baseline), without significant haemodynamic differences. Between I to 30 min of reperfusion, WTF was significantly higher with naloxone (P < 0.05). There was no difference in WTF with or without naloxone methiodide. We conclude that naloxone improved recovery from myocardial stunning in conscious dogs, and that this was centrally mediated.