Christoph Schukro

Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. PATIENTS AND METHODS In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. RESULTS A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. CONCLUSION Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.

Detection of High-grade Stenoses With Multislice Computed Tomography in Heart Transplant Patients

BACKGROUND Post-transplant follow-up of heart transplant patients consists of repeated coronary angiography, which is associated with high costs, discomfort and risk. We sought to determine whether multislice computed tomography (MSCT) permits the exclusion or progression of coronary artery disease in heart transplant patients. METHODS MSCT scanning (Philips CT MX 8000 IDT) and invasive coronary angiography were performed on 66 consecutive heart transplant patients. One hundred milliliters of non-ionic iodinated contrast medium was applied for CT angiography. For MSCT analysis, coronary arteries and side branches with a diameter > or =1.5 mm were assessed for the presence of luminal narrowing of >70%. MSCT results were compared with those of quantitative coronary angiography analysis. RESULTS Ten patients (17%) had one significant stenosis, whereas 3 patients (5%) had 2-vessel disease and none had 3-vessel disease. MSCT was performed successfully on 60 patients enrolled in our analysis. Forty-two of 44 patients (95%) who were estimated to be fully evaluable for MSCT were correctly classified. On per-segment-based analysis, sensitivity, specificity and positive and negative predictive values were 59%, 94%, 91% and 99.43%, respectively. After exclusion of unevaluable segments, sensitivity and specificity increased to 71% and 99.86%, respectively. On per-patient-based analysis, sensitivity, specificity and positive and negative predictive values were 88%, 97%, 88% and 97%, respectively, in evaluable transplant recipients. CONCLUSIONS MSCT with its high specificity and high negative predictive value allows the exclusion of significant coronary artery vasculopathy in evaluable patients. From the clinical point of view, this might spare additional invasive coronary angiography in heart transplant patients.

Impact of accelerated ventricular tachyarrhythmias on mortality in patients with implantable cardioverter-defibrillator therapy

BACKGROUND Anti-tachycardia pacing (ATP) and shock delivery may induce or accelerate tachyarrhythmias in patients with implantable cardioverter-defibrillator (ICD). We investigated the incidence, triggers and impact on mortality of accelerated ventricular tachyarrhythmias. METHODS Database analysis concerning ventricular tachyarrhythmias accelerated by ATP or shock in 1275 ICD patients (age at implantation 59.7 ± 14.0 years; 81% male). RESULTS Within a mean follow-up period of 5.3 ± 4.0 years, intracardiac electrograms were available in 1170 patients (91.8%). Overall 157 episodes of accelerated ventricular tachyarrhythmias were found in 100 of 1170 patients (8.5%). Termination of tachyarrhythmias was achieved by shock delivery in 153 episodes (96.8%). Triggers of accelerated tachyarrhythmias were appropriate ATP in 139 (88.5%) and inappropriate ATP in 14 (8.9%), as well as appropriate and inappropriate shocks in 2 (1.3%) episodes, respectively. Chronic heart failure was significantly correlated with the occurrence and recurrence of acceleration (p<0.001). Patients with accelerated ventricular tachyarrhythmia and subsequent shock therapy revealed higher all-cause mortality (HR 1.760; 95% CI 1.286-2.410; p<0.001) as well as higher cardiac mortality (HR 2.555; 95% CI 1.446-4.513; p=0.001). The correlation between acceleration and all-cause mortality was independent of left ventricular function (HR 2.076; 95% CI 1.633-2.639; p<0.001). CONCLUSIONS Ventricular ATP with arrhythmia acceleration and subsequent shock delivery is a frequent and serious complication of ICD therapy that predominantly occurs in patients with reduced left ventricular function. Finally, occurrence of accelerated ventricular tachyarrhythmias was associated with increased all-cause mortality.

Multicenter assessment of coronary allograft vasculopathy by intravascular ultrasound-derived analysis of plaque composition

Background Coronary allograft vasculopathy is a severe complication of heart transplantation. We used virtual histology intravascular ultrasound to characterize plaque burden and tissue composition over time in heart transplant recipients.Methods We recruited patients undergoing heart transplantation in four centers in Europe and the US between 2004 and 2006. We used intravascular ultrasound to obtain morphological plaque measurements and to perform virtual histology in the left anterior descending coronary artery. Data were characterized according to the duration between transplantation and intravascular ultrasound assessment: ≤24, >24–60, >60–120 and >120–192 months.Results We assessed vessels from 152 patients (mean age 58 ± 12 years) a mean of 70 ± 53 months (range 1 week to 16 years) after transplantation. Plaque burden of >40% was observed in 26% of vessels analyzed, with increases from baseline being seen in all time categories. If assessed >24 months after transplantation, necrotic core and dense calcified volumes were significantly greater than at baseline (P = 0.0005 and P = 0.01, respectively). Time since heart transplantation and donor age and recipient age were independent predictive factors of increased necrotic core content. Necrotic core volume >2.01 mm3, diabetes mellitus, donor age older than 40 years, follow-up from transplantation longer than 5 years and recipient age older than 58 years were associated with the need for revascularization.Conclusions In coronary allograft vasculopathy, plaque burden and composition change over time and seem to affect clinical outcome. This relationship might facilitate identification of high-risk patients in whom the value of more aggressive medical therapy should be tested.

Regional prevalence and clinical benefit of implantable cardioverter defibrillators in Brugada syndrome

BACKGROUND Brugada syndrome (BS) is associated with an increased risk of sudden cardiac death (SCD) caused by ventricular tachyarrhythmia. Thus, implantable cardioverter defibrillators (ICD) became the main therapeutic option in these patients. We aimed to investigate the prevalence of BS in the Eastern Alps as well as the benefit of ICD therapy in this collective. METHODS During physical examination before military service, 47,606 Austrian men were screened for Brugada ECG pattern. Furthermore, we followed 4491 patients with arrhythmia during the last two decades, of which 26 patients (20 male; age at diagnosis: 43.2 ± 11.6 years) revealed BS. Diagnosis was based on characteristic ECG either at rest (11 patients) or after provocation with Ajmaline (15 patients). RESULTS The nationwide screening revealed one individual with Brugada ECG (prevalence of 2.10/100,000 inhabitants). Prior to diagnosis of BS, syncope and SCD survival were observed in 7 and 4 patients, respectively; the remaining 15 patients were asymptomatic. ICD were implanted in 17 patients (15 male). Three asymptomatic patients received no ICD because no tachyarrhythmia was inducible on programmed stimulation. Six asymptomatic patients without family history of sudden death refused further evaluation. Mean ICD follow-up period was 57.0 ± 32.2 months. Two patients (11.7%) needed defibrillation therapy. Four patients (23.5%) received exclusively inappropriate shocks (three due to T-wave oversensing, one due to atrial fibrillation). CONCLUSIONS Brugada syndrome has a low prevalence in the Eastern alpine region. Patients with BS benefit from ICD implantation, but less frequently than anticipated. The problem of inappropriate ICD discharges is still of major concern.

Single, remote-magnetic catheter approach for pulmonary vein isolation in patients with paroxysmal and non-paroxysmal atrial fibrillation.

BACKGROUND The aim of the study was to investigate the safety and efficacy of a single, remote-magnetic catheter navigation system (MNS) for pulmonary vein isolation (PVI). METHODS A total of 107 PVI procedures in 71 patients with paroxysmal (32%), persistent (38%) and longstanding-persistent (30%) atrial fibrillation (AF) were analyzed. A wide area circumferential radiofrequency ablation PVI was performed with either an 8mm MNS (first 35 procedures) or an irrigated MNS (last 36 procedures) catheter. Electrical isolation was confirmed with circular pacing/sensing using the MNS catheter and a coronary sinus catheter. Our follow-up strategy in the first year and upon symptoms thereafter was: clinical check plus 12-lead ECG (100%) and 24 h-ECG recordings (76%) at 3 month intervals, trans-telephonic ECG (79%) twice daily and upon symptoms (4 weeks every 3 months), or ECG monitoring via implanted devices (9%). RESULTS The mean procedure time at 1st PVI was 247±61 min, and mean fluoroscopy time was 44±18 min. The overall complication rate was 2%. Success rates did not differ at the 1st PVI regarding catheter type (p=0.931) but were dependent on history of AF: patients with paroxysmal AF had the highest success rates of 58% and 29% after 1 and 3 years of follow-up, respectively (p=0.0084). CONCLUSION PVI with a single MNS catheter is safe and is associated with short fluoroscopy exposition. Despite a rigorous follow-up strategy success rates favorably compare with recently published data on hand-held PVI. Thus, multipolar catheters or a 2nd trans-septal puncture may not be mandatory.

Selection for atrial fibrillation ablation: Importance of diastolic function grading.

BACKGROUND Pulmonary vein isolation (PVI) has become an accepted therapy for patients with atrial fibrillation (AF) and the indications have widened to include non-paroxysmal AF-patients. Maintenance of sinus rhythm after PVI can be adversely affected by clinical or echocardiographic parameters, which should be clearly identified. METHODS AND RESULTS After baseline clinical and echocardiographic evaluations, PVI was performed in patients with paroxysmal or non-paroxysmal AF. The follow-up strategy after PVI included: (1) clinical follow up, 12-lead electrocardiography (ECG) and 24-h ECG every 3 months, (2) trans-telephonic ECGs twice daily and when symptomatic (over 4 weeks) every 3 months, or (3) continuous monitoring via implanted devices. A recurrence was an atrial arrhythmia lasting >30s. All 340 PVI procedures of 229 patients were analyzed. On average, 1.5 PVI procedures per patient (range, 1-6 PVI) were performed. The mean age was 58±11 years (73% male) with 109 paroxysmal and 120 non-paroxysmal AF cases. Clinical follow-up with 12-lead ECGs, 24-h ECGs, trans-telephonic ECGs, and implanted devices was complete in 100%, 63%, 51%, and 16% of cases, respectively. The overall one-year recurrence rate of 59% (range, 24-82%) was dependent on grades of diastolic function (normal - dysfunction grade III) in a multivariable analysis model. Patients with normal diastolic function had the lowest recurrence rates of 24% and 49% after 1 and 3 years of follow-up, respectively (p<0.0001). CONCLUSION Diastolic function could serve as a simple summary predictor for AF recurrence, and would facilitate clinical decision-making in AF treatment.

Left ventricular hypertrabeculation/non-compaction in a Duchenne/Becker muscular dystrophy carrier with epilepsy

Left ventricular hypertrabeculation (LVHT), also known as non-compaction, is an abnormality of the left ventricular myocardium,characterised by separation of the left ventricular wall into acompacted, thin outer layer and a thicker, crenated, inner layer,predominantly of the apex and the lateral wall, distally to thepapillary muscles [1]. LVHT is frequently associated with other car-diac abnormalities, chromosomal abnormalities, or neuromusculardisorders [2]. LVHT patients carry an increased risk to developmalignant arrhythmias [3], heart failure [4], or possibly peripheralembolism. Though LVHT has been reported in patients with Duchennemuscular dystrophy (DMD) [5], it is unknown in female carriers of thisdisorder.The patient is a 42‐year old Vietnamese female, height 150 cm,weight 55 kg, with an uneventful cardiologic history, who was admit-ted because of dyspnoea for about three weeks. Blood pressure wasnormal but ECG showed sinus-tachycardia, and X-ray of the lung anenlarged heart, pleural effusion on the right side, and basal pulmo-nary congestion bilaterally. Liver function parameters and creatine-kinasevalues were slightlybut pro-BNPmarkedly elevated. Transtho-racic echocardiography showed an enlarged left ventricle, severely

Specific indications and clinical outcome in patients with subcutaneous implantable cardioverter-defibrillator (ICD) – A nationwide multicentre registry

Background Subcutaneous implantable cardioverter-defibrillators (S-ICD) are an innovative and less invasive alternative to transvenous ICD (TV-ICD) in selected patients. We aimed to investigate the underlying diseases and the specific indications for implanting S-ICD in clinical practice, as well as the prevalence of shock delivery and complications.BACKGROUND Subcutaneous implantable cardioverter-defibrillators (S-ICD) are an innovative and less invasive alternative to transvenous ICD (TV-ICD) in selected patients. We aimed to investigate the underlying diseases and the specific indications for implanting S-ICD in clinical practice, as well as the prevalence of shock delivery and complications. METHODS AND RESULTS From December 2012, data of 236 patients (30,5% female; age 48,6±16,8years) were gathered from 12 centres in Austria. Follow-up data over a period of 1,7±1,1years were available for 231 patients (in total 359,2 patient-years). Predominant underlying diseases were ischemic cardiomyopathy (iCMP; 32,0%), idiopathic ventricular fibrillation (22,6%) and dilated cardiomyopathy (dCMP; 17,3%). The most frequent indications for implantation were sudden cardiac death survival (27,4%), primary prevention for iCMP (23,9%) and for dCMP (12,8%), and previous explantation of TV-ICD (12,4%). Appropriate shocks were documented in 16 patients (6,9%), iCMP being the predominant underlying disease. Arrhythmia conversion was successful in all patients, efficacy of the first shock was 96%. Inappropriate shock rate was 5,2%, predominantly caused by oversensing of T wave or artefacts. A device upgrade to an ICD system with pacing function was necessary in <1%. Clinical complications needing surgical revision occurred in 8 patients (3,5%). CONCLUSIONS S-ICD were mostly implanted for primary prevention, one fourth of our cases were sudden death survivors. Clinical and functional complication rate was relatively low. In conclusion, S-ICD is a safe and efficient alternative in a larger population of ICD candidates, when no cardiac pacing is needed. EC-number: C-136-17.

Assessment of the Safety and Efficacy of the Novel Tetrapeptide ITF-1697 on Infarct Size after Primary PTCA in Acute Myocardial Infarction

AbstractObjective and design:ITF-1697 is a chemically modified LYS-Pro tetrapeptide that corresponds to sequence 113–116 of C-reactive protein. Previous studies have demonstrated significant anti-ischaemic and antithrombotic activity of this tetrapeptide. The aim of this prospective, randomised, double-blind study in patients with acute myocardial infarction undergoing coronary revascularisation was to investigate the safety and efficacy of prolonged intravenous (IV) infusion of ITF-1697 at different doses on reduction of infarct size, as assessed by radionuclide imaging. Patients and methods:Injection of technetium-99m (Tc99m) was followed by injection of ITF-1697 or placebo bolus and 24-hour infusion in patients with acute myocardial infarction. Percutaneous transluminal coronary angioplasty (PTCA) was performed and succeeded by radionuclide imaging. A second Tc99m injection and radionuclide imaging was performed 7 days after the PTCA or at hospital discharge. The primary efficacy variable was set as the ratio between the myocardial salvage (size of the initial perfusion defect minus the final size of the infarct) and the initial area at risk (myocardial salvage index). Twenty-three patients were included in the study protocol, of whom nine were randomised to the ITF-1967 dose 1 group (loading dose 55 μg/kg IV, infusion 0.5 μg/kg/min for 24 hours), a further nine to the ITF-1697 dose 2 group (loading dose 110 μg/kg IV, infusion 1.0 μg/kg/min for 24 hours), and the remaining five to the placebo group. Results: The defined safety variables (adverse events, laboratory parameters, vital signs and clinical outcome) exhibited no relationship to the application of ITF-1697. Comparison of myocardial salvage index revealed no statistical difference within the three groups (p = 0.65). Hypothesis testing on the myocardial salvage as well as the empirical and bias-correct confidence intervals (CIs) revealed significant differences between the ITF-1697 dose 2 group and the placebo group (95% CI 2.75, 18.07). Conclusion: The application of the tetrapeptide ITF-1697 during acute myocardial infarction to reduce infarct size was found to be feasible and safe in this pilot trial.