de Rudolf Boer

Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer

BACKGROUND Cross-sectional studies showed that treatment with cisplatin chemotherapy for testicular cancer is associated with an increased incidence of cardiac dysfunction. We investigated longitudinal progression of and contributing factors to cardiac dysfunction in testicular cancer survivors. PATIENTS AND METHODS Cardiac assessments were carried out before 10 months (range 7-15 months) and 6.9 years (range 4.9-9.7 years) after start of cisplatin-based chemotherapy, consisting of echocardiography [systolic function (left ventricular ejection fraction, LVEF), diastolic function (myocardial tissue velocities; tissue velocity imaging of early diastole, TVI Et)] and plasma biomarkers (N-Terminal pro brain natriuretic peptide, NT-proBNP; galectin-3). RESULTS In 37 patients [median age 34 years (range 24-51 years)], the incidence of abnormal TVI Et increased from 0% at baseline and 4.5% at 10 months (in 27 patients) to 16.7% at 6.9 years post-chemotherapy (P = 0.03). One patient developed LVEF <50%; no other systolic abnormalities occurred. Hypertension, obesity and age were associated with larger decreases in TVI Et. Changes in NT-proBNP and galectin-3 were not related to echocardiographic abnormalities. CONCLUSIONS In this longitudinal cohort study, we observed a gradual decline in diastolic parameters after cisplatin-based chemotherapy for testicular cancer, whereas the rate of systolic dysfunction remains low. The association of larger declines in diastolic parameters with hypertension and obesity stresses the need to monitor and treat cardiovascular risk factors.

Neurohormonal profile of patients with heart failure and diabetes

Background. Neurohormonal activation is generally recognised to play an important role in the pathophysiology, prognosis and treatment of chronic heart failure (HF). While the number of patients with diabetes increases, little if anything is known about neurohormonal activation in HF patients with diabetes. Methods. The study population consisted of 371 patients with advanced HF who were enrolled in a multicentre survival trial. Ten different plasma neurohormones were measured (noradrenaline, adrenaline, dopamine, aldosterone, renin, endothelin, atrial natriuretic peptide [ANP], N-terminal (pro)ANP, brain natriuretic peptide [BNP] and N-terminal (pro)BNP. Comparisons were made between patients with diabetes (n=81) and those without (n=290). Results. At baseline, the two groups were comparable regarding age (mean 68 years), left ventricular ejection fraction (23%), severity and aetiology of HF, while body weight was higher in those with diabetes (77.4 vs. 74.2 kg, p=0.04). Most plasma neurohormones were similar between groups, but patients with diabetes had higher values of BNP (94 vs. 47 pmol/l, p=0.03), while a similar trend was observed for N-terminal (pro)BNP (750 vs. 554 pmol/l, p=0.10). During almost five years of follow-up, 51/81 patients with diabetes died (63%), as compared with 144 of 290 non-diabetic patients (50%) who died (p=0.046). Natriuretic peptides and noradrenaline were the most powerful predictors of mortality in both diabetic and non-diabetic HF patients. Conclusion. HF patients with diabetes have higher (N-terminal (pro)) BNP levels than non-diabetic patients, while other neurohormones are generally similar. Natriuretic peptides are also good prognostic markers in diabetic HF patients. (Neth Heart J 2010;18:190-6.)

Reduced regional myocardial perfusion reserve is associated with impaired contractile performance in idiopathic dilated cardiomyopathy

Background. In idiopathic dilated cardiomyopathy (IDC) an imbalance between myocardial oxygen consumption and supply has been postulated. Subclinical myocardial ischaemia may contribute to progressive deterioration of left ventricular function. The relation between regional myocardial perfusion reserve (MPR) and contractile performance was investigated.Methods. Patients with newly diagnosed IDC underwent positron emission tomography (PET) scanning using both 13N-ammonia as a perfusion tracer (baseline and dypiridamole stress), and 18F-fluorodeoxyglucose viability tracer and a dobutamine stress MRI. MPR (assessed by PET) as well as wall motion score (WMS, assessed by MRI) were evaluated in a 17-segment model.Results. Twenty-two patients were included (age 49±11 years; 15 males, LVEF 33±10%). With MRI, a total of 305 segments could be analysed. Wall motion abnormalities at rest were present in 127 (35.5%) segments and in 103 (29.9%) during dobutamine stress. Twenty-one segments deteriorated during stress and 43 improved. MPR was significantly higher in those segments that improved, compared with those that did not change or were impaired during stress (1.87±0.04 vs. 1.56± 0.07 p<0.01.)Conclusion. Signs of regional ischaemia were clearly present in IDC patients. Ischaemic regions displayed impaired contractility during stress. This suggests that impaired oxygen supply contributes to cardiac dysfunction in IDC. (Neth Heart J 2009;17:470–4.)

Identification of a specific pattern of downregulation in expression of isoforms of vascular endothelial growth factor in dilated cardiomyopathy

Recent work suggests that myocardial hypoxia or ischaemia are also pathophysiologic factors in idiopathic dilated cardiomyopathy (IDC).1 Besides several other factors (increased wall stress, endothelial dysfunction, decreased coronary reserve), the observed decreased capillarisation in IDC, disproportionate to the rate of hypertrophy, may further contribute to this oxygen demand–supply mismatch. The reason for this seemingly decreased angiogenic capacity remains unclear, however a role for microvascular abnormalities in heart failure is now recognised.2 Hypoxia is the key factor in the induction of vascular endothelial growth factor (VEGF). Increased expression of VEGF causes angiogenesis, and expression level of VEGF could therefore mediate the capillarisation in IDC. Recently, data have been reported on this issue,3 and the authors found a downregulation of VEGF165 and VEGF189 isoforms. The VEGF121 however was not investigated, although it has been suggested that this isoform in particular has powerful angiogenic capacities. Additionally, it is unclear whether VEGF expression is related to the severity of the disease. We analysed 28 patients with IDC. Patients had enlarged left ventricular end diastolic and systolic diameters (LVEDD 69 (2.1) mm, LVESD 61 (2.6) mm), and decreased left ventricular ejection fraction (LVEF) (0.27 (0.03)), and elevated wedge (15 (1.9) mm Hg) and left ventricular end diastolic pressures (14.1 (2.7) mm Hg). Echocardiography did not reveal cardiac disease in the 10 brain dead subjects, who served as controls. Endomyocardial biopsy taken from the right ventricle showed cardiomyocyte hypertrophy and interstitial …

Mycotic Aneurysm of the Aorta as an Unusual Complication of Coronary Angiography

INTRODUCTION Mycotic aneurysm of the aorta is a rare diagnosis with high mortality. REPORT Percutaneous coronary intervention was complicated by bacteraemia with Staphylococcus aureus and a mycotic aortic aneurysm, an unusual complication of coronary angiography. Combining CT and PET scan showed a hotspot in the thoracic aorta. After six months of antibiotic treatment she fully recovered. Repeated CT/PET scanning revealed complete abolishment of the aortic abnormalities. DISCUSSION This report suggests that diagnosing and follow-up of aortitis is feasible with combined CT/PET scan and may help in determining choice and duration of therapy.

High serum erythropoietin levels are related to heart failure development in subjects from the general population with albuminuria

In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown.

Apoptosis during CABG surgery with the use of cardiopulmonary bypass is prominent in ventricular but not in atrial myocardium

Objectives. We aimed to compare the rate of apoptosis after cardiopulmonary bypass (CPB) and cardioplegic arrest during coronary artery bypass grafting (CABG) surgery between atrial and ventricular tissue.Methods. During CABG surgery with CPB and cardioplegic arrest, sequential biopsies were taken from the right atrial appendage and left ventricular anterior wall before CPB and after aortic cross clamp release. Change in number of apoptotic cells and biochemical markers of myocardial ischaemia and renal dysfunction were assessed.Results. CPB was associated with a transient small, but significant increase in CK (1091±374%), CK-MB (128±38%), troponin-T (102±13%) and NT-proBNP (1308±372%) levels (all: p<0.05). A higher number of apoptotic cells as assessed by caspase-3 staining was found in the ventricular biopsies taken after aortic cross clamp release compared with the biopsies taken before CPB (5.3±0.6 vs. 14.0±1.5 cells/microscopic field, p<0.01). The number of apoptotic cells in the atrial appendage was not altered during CPB. Correlation between the duration of aortic cross clamp time and the change in caspase-3 positive cells in the left ventricular wall was of borderline significance (r of 0.58, p=0.08). Similar results were obtained from TUNEL staining for apoptosis.Conclusion. CABG surgery with CPB and cardioplegic arrest is associated with an elevated rate of apoptosis in ventricular but not in atrial myocardial tissue. Ventricular tissue may be more sensitive to detect changes than atrial tissue, and may be more useful to investigate the protective effects of therapeutic intervention. (Neth Heart J 2010;18:236-42.)

Telomere length and outcomes in ischaemic heart failure

Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth.

Meeting highlights from the 2010 European Society of Cardiology Heart Failure Association Winter Meeting

Like last year, the 2010 Translational Heart Failure Meeting of the Heart Failure Association of the ESC was again held in Les Diablerets, Switzerland. Not only was a very interesting scientific programme offered in this small winter resort in the Swiss Alps, close to Lake Geneva, but an intense social interaction was also guaranteed due to the limited group size and great surroundings. In this meeting report, we summarize some of the scientific presentations held during this wonderful meeting. The scientific programme started on Thursday with the Brutseart lecture delivered by R. Fischmeister (Paris, France), who addressed the importance of signalling microdomains with a focus on the different dynamics of cAMP signals in different cellular compartments. The role of PDE3A and the different PDE4 isoforms (A,B,D) in the rat heart was discussed and it was shown that these PDEs differentially regulate excitation–contraction coupling. PDE4B appeared dominant in the regulation of the L-type Ca2+ current. Importantly, PDE3A and PDE4A,B were down-regulated in cardiomyocytes from chronic heart failure animals, indicating that cAMP hydrolytic capacity is decreased, which could be an adaptive mechanism for the reduced cAMP synthesis during heart failure. This may alter overall cAMP signalling and compartmentalization. At the end of this session, L. Maier (Göttingen, Germany) discussed the role of Ca2+/calmodulindependent protein kinase II (CaMKII) in excitation–contraction coupling in cardiomyocytes. CaMKIIdelta-null mice generated in his laboratory showed attenuation of pathological cardiac hypertrophy and remodelling in response to pressure overload. Transgenic CaMKIIdelta mice, on the other hand, have heart failure and isoproterenol-inducible arrhythmias, most likely due to increased sarcoplasmatic reticulum Ca2+ leakage. CaMKII inhibition reduced arrhythmias suggesting that this could be a potential therapeutic target. In the second session on Thursday, the roles of histone deacetylases (HDACs) in cardiac function and heart failure were addressed. M. Gupta (Chicago, USA) discussed the role of the NAD-dependent class III HDACs, SIRT1 and SIRT3, and proposed a model in which SIRT3 deacetylates and thereby activates the LKB1 kinase. In turn, LKB1 activates the AMPK pathway resulting in Akt1 inactivation and anti-hypertrophic effects. Akt1 signalling was also inhibited by a second SIRT3-dependent mechanism, namely via upregulation of anti-oxidants. A role of SIRT1 in antihypertrophic mechanisms could not be established. Interestingly, pathophysiological hypertrophy and heart failure appeared to be associated with the depletion of intracellular NAD pools and supplementation of these pools by NAD infusion in a pathological mouse heart failure model could attenuate hypertrophy in an SIRT3dependent fashion. This may therefore open new treatment options. J. Sadoshima (NJ, USA) showed that cysteines in HDAC4 are rapidly oxidized in response to hypertrophic stimuli, resulting in its cytoplasmic relocalization and hence its inability to inhibit transcription factors such as NFAT and MEF2. Thioredoxin-1 can prevent hypertrophy-mediated oxidation of HDAC4 cysteines and hence attenuates hypertrophy. D. Oceandy (Manchester, UK) finished this session by suggesting that the balance of tumour suppressor and proto-oncogene activity could determine the balance between antiand prohypertrophic stimulation, similar to their role in maintaining the balance in proliferation. This idea was supported by the authors identification of the known tumour suppressor protein RASSF1A as a novel inhibitor of cardiac hypertrophy. This observation underscores the importance of thinking outside of the ‘cardiac’ box when studying cardiac hypertrophy and failure. The Friday morning session started with a special lecture in honour of Professor Helmut Drexler, who died suddenly last

Pharmacogenetics in heart failure

Pharmacotherapy remains the cornerstone in the treatment of heart failure. There is a wide variability in the individuals response to treatment, which is at least partially ascribed to genetic factors. Pharmacogenetics studies the differential clinical effects due to genetic variances. Some effects of the major neurohormonal inhibitors like angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers are importantly modulated by genetic polymorphisms. So far, however, this does not result in standard genetic testing before starting specific therapy. This review discusses several important pharmacogenetic targets. Furthermore, it is argued that new and sophisticated high-throughput genetic screens could be employed to develop pharmacogenetic screening further. Prospective large-scale pharmacogenetic studies are warranted as we believe that they will identify new targets for therapy and specific populations that benefit from specific treatments.Pharmacotherapy remains the cornerstone in the treatment of heart failure. There is a wide variability in the individuals response to treatment, which is at least partially ascribed to genetic factors. Pharmacogenetics studies the differential clinical effects due to genetic variances. Some effects of the major neurohormonal inhibitors like angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers are importantly modulated by genetic polymorphisms. So far, however, this does not result in standard genetic testing before starting specific therapy. This review discusses several important pharmacogenetic targets. Furthermore, it is argued that new and sophisticated high-throughput genetic screens could be employed to develop pharmacogenetic screening further. Prospective large-scale pharmacogenetic studies are warranted as we believe that they will identify new targets for therapy and specific populations that benefit from specific treatments.