Amir M. Nia

Ischemic Preconditioning for Prevention of Contrast Medium–Induced Nephropathy Randomized Pilot RenPro Trial (Renal Protection Trial)

Background— Contrast medium–induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium–induced acute kidney injury. Methods and Results— Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium–induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium–induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium–induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07–0.57; P =0.002). No major adverse events were related to remote ischemic preconditioning. Conclusions— Remote ischemic preconditioning before contrast medium use prevents contrast medium–induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. Clinical Trial Registration— URL: [http://www.germanctr.de][1]. Unique identifier: U1111-1118-8098. # Clinical Perspective {#article-title-44} [1]: http://www.germanctr.de.Background— Contrast medium–induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium–induced acute kidney injury. Methods and Results— Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium–induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium–induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium–induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07–0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. Conclusions— Remote ischemic preconditioning before contrast medium use prevents contrast medium–induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. Clinical Trial Registration— URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.

Remote Ischemic Preconditioning and Renoprotection: From Myth to a Novel Therapeutic Option?

There is currently no effective prophylactic regimen available to prevent contrast-induced AKI (CI-AKI), a frequent and life-threatening complication after cardiac catheterization. Therefore, novel treatment strategies are required to decrease CI-AKI incidence and to improve clinical outcomes in these patients. Remote ischemic preconditioning (rIPC), defined as transient brief episodes of ischemia at a remote site before a subsequent prolonged ischemia/reperfusion injury of the target organ, is an adaptational response that protects against ischemic and reperfusion insult. Indeed, several studies demonstrated the tissue-protective effects of rIPC in various target organs, including the kidneys. In this regard, rIPC may offer a novel noninvasive and virtually cost-free treatment strategy for decreasing CI-AKI incidence. This review evaluates the current experimental and clinical evidence for rIPC as a potential renoprotective strategy, and discusses the underlying mechanisms and key areas for future research.

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Arginine vasopressin (AVP) is the major physiological regulator of renal water excretion and blood volume. The AVP pathways of V1aR-mediated vasoconstriction and V2R-induced water retention represent a potentially attractive target of therapy for edematous diseases. Experimental and clinical evidence suggests beneficial effects of AVP receptor antagonists by increasing free water excretion and serum sodium levels. This review provides an update on the therapeutic implication of newly developed AVP receptor antagonists in respective disorders, such as chronic heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion.

Local Thrombolysis for Successful Treatment of Acute Stroke in an Adolescent with Cardiac Myxoma

Intracardiac myxomas are the most common benign cardiac tumors in adults. They are a rare source of cardiogenic embolisms and sudden death, especially in young patients. This report describes the case of a male adolescent who presented with right-sided paresis and aphasia. Magnetic resonance imaging of the brain revealed an ischemic stroke without evidence of acute bleeding. Intra-arterial local thrombolysis was immediately started. An echocardiographic screening after successful thrombolysis with a remarkable recovery of symptoms detected a thrombotic-like mass in the left atrium. The mass was excised surgically, confirmed as a benign atrial myxoma, and the patient was discharged with restitution ad integrum. Thus, contrary to some critical reports, thrombolytic therapy for acute ischemic strokes due to atrial myxomas may be safe and highly effective.

Impact of Rescue-Thrombolysis during Cardiopulmonary Resuscitation in Patients with Pulmonary Embolism

Background Cardiac arrest in patients with pulmonary embolism (PE) is associated with high morbidity and mortality. Thrombolysis is expected to improve the outcome in these patients. However studies evaluating rescue-thrombolysis in patients with PE are missing, mainly due to the difficulties of clinical diagnosis of PE. We aimed to determine the success influencing factors of thrombolysis during resuscitation in patients with PE. Methodology/Principal Findings We analyzed retrospectively the outcome of 104 consecutive patients with confirmed (n = 63) or highly suspected (n = 41) PE and monitored cardiac arrest. In all patients rtPA was administrated for thrombolysis during cardiopulmonary resuscitation. In 40 of the 104 patients (38.5%) a return of spontaneous circulation (ROSC) could be achieved successfully. Patients with ROSC received thrombolysis significantly earlier after CPR onset compared to patients without ROSC (13.6±1.2 min versus 24.6±0.8 min; p<0.001). 19 patients (47.5%) out of the 40 patients with initially successful resuscitation survived to hospital discharge. In patients with hospital discharge thrombolysis therapy was begun with a significantly shorter delay after cardiac arrest compared to all other patients (11.0±1.3 vs. 22.5±0.9 min; p<0.001). Conclusion Rescue-thrombolysis should be considered and started in patients with PE and cardiac arrest, as soon as possible after cardiac arrest onset.

Accuracy of Doppler-Echocardiographic Mean Pulmonary Artery Pressure for Diagnosis of Pulmonary Hypertension

Background The validity of Doppler echocardiographic (DE) measurement of systolic pulmonary artery pressure (sPAP) has been questioned. Recent studies suggest that mean pulmonary artery pressure (mPAP) might reflect more accurately the invasive pressures. Methodology/Principal Findings 241 patients were prospectively studied to evaluate the diagnostic accuracy of mPAP for the diagnosis of PH. Right heart catheterization (RHC) and DE were performed in 164 patients mainly for preoperative evaluation of heart valve dysfunction. The correlation between DE and RHC was better when mPAP (r = 0.93) and not sPAP (r = 0.81) was assessed. Bland-Altman analysis revealed a smaller variation of mPAP than sPAP. The following ROC analysis identified that a mPAP≥25.5 mmHg is useful for the diagnosis of PH. This value was validated in an independent cohort of patients (n = 50) with the suspicion of chronic-thromboembolic pulmonary hypertension. The calculated diagnostic accuracy was 98%, based on excellent sensitivity of 98% and specificity of 100%. The corresponding positive and negative predictive values were 100%, respectively 88%. Conclusion mPAP has been found to be highly accurate for the initial diagnosis of PH. A cut-off value of 25.5 mmHg might be helpful to avoid unnecessary RHC and select patients in whom RHC might be beneficial.

Beta1-Adrenoceptor Polymorphism Predicts Flecainide Action in Patients with Atrial Fibrillation

Background Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta1-adrenoceptor (β1AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different β1AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation. Methodology/Principal Findings In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual β1AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with β1AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34–8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18–1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03–2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10–0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110±2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8±2.4 bpm) and Gly389Gly (96.9±5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99–24.46; p<0.001). Conclusions The β1AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation.

Terry's nails: a window to systemic diseases.

n T a s d n Despite the enormous involvement of imaging tools in medicine, a focused physical examination still plays a pivotal role in all medical fields. During and after taking history, a detailed inspection and examination of the patient will direct to further key diagnostic tools. A wealth of information can be gained from shaking hands and examining the hands at the same time. This part of the examination, and in particular the examination of the nails, is often neglected, although it is simple to notice if the hands are warm and well perfused or sweaty and to examine the color of the nails. In some cases, nail shapes are directive for the diagnosis, such as clubbed fingers in pulmonary or cardiovascular disorders. This short report describes 2 patients with different systemic diseases but developing similar nail changes. The early recognition of this nail abnormality could have led to earlier treatment.

Torsades de pointes tachycardia induced by common cold compound medication containing chlorpheniramine.

Dear Editor, Chlorpheniramine (CPM) is a first generation histaminereceptor-1 antagonist registered in the World Health Organization Model List of Essential Medicines [1]. Due to its moderate degree of sedative effects, it is frequently used as a component of compound preparations for symptomatic treatment of common cold and influenza symptoms. CPM shows pronounced interindividual variability in pharmacokinetics, with an elimination half-life ranging from 2 to 43 h because of individual hepatic metabolism and the different activity of the involved cytochrome CYP2D6, which has a pronounced genetic polymorphism [2, 3]. Besides this mechanism, there are still unknown metabolic pathways that are involved in the disposition of CPM in humans [2]. CPM and its metabolites are excreted in a pH-dependent fashion in the urine with individual excretion dosages of unchanged CPM ranging from 0 to 34% [1, 4] (see also drug information). A 40-year-old woman (63 kg body weight; BMI 21 kg/m; Caucasian), otherwise healthy, was initially admitted to a primary care hospital after torsades de pointes tachycardia (TdP) that necessitated cardiopulmonary resuscitation. Repeated TdP was monitored there (Fig. 1a) in the first 24 h after administration and was treated successfully by magnesium infusions. At the second day after onset of TdP, the patient was referred to the cardiology department of the University of Cologne for further diagnostics. Laboratory values, including creatinine, were in normal ranges except for mildly elevated alanine aminotransferase and aspartate aminotransferase. The main pathological finding was detected by the retrospective evaluation of the documented electrocardiogram (ECG) during the inhospital observed TdP tachycardia: the corrected QT interval (QTc) using Bazett’s formula was prolonged up to 524 ms (Fig. 1a). Therefore the diagnosis of long-QT syndrome (LQTS) was made. The ECGs documented in our hospital revealed a borderline QTc of 440 ms (Fig. 1b). All other diagnostic procedures were normal including coronary angiogram, ventriculography, and complete invasive electrophysiological testing. The patient was on no permanent medication, denied abusing any other substances, was completely unremarkable on physical examination, and had no prior history of cardiac arrhythmias. She smoked regularly up to 5 cigarettes a day, drank small amounts of wine and had suffered from a common cold for some days, which she self-medicated with a compound medication taking two capsules three times a day. She had stopped self-medication the evening before the event. Each capsule contained 200 mg of acetaminophen, 150 mg of ascorbic acid, 25 mg of caffeine, and 2.5 mg of CPM. In animal experiments, CPM has been shown to present a dosedependent block of the delayed rectifier potassium channel IKr, and to lengthen the action potential, slow cardiac repolarization, and prolong the QTc interval [5–9]. The CPM-like drug diphenhydramine also significantly prolonged the QTc interval in healthy volunteers and in patients with coronary heart diseases [10]. The coincidence between drug intake and prolongation of the QT interval in our patient is highly suggestive of A. M. Nia :N. Gassanov : E. Erdmann : F. Er (*) Department of Internal Medicine III, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany e-mail: fikret.er@uk-koeln.de

Response to Letter Regarding Article, “Ischemic Preconditioning for Prevention of Contrast Medium–Induced Nephropathy: Randomized Pilot RenPro-Trial (Renal Protection Trial)”

We thank the authors for their interest in our study on the impact of remote ischemic preconditioning on contrast medium–induced acute kidney injury (CI-AKI).1 The incidence of CI-AKI varies substantially among several studies because of the lack of a uniform definition of CI-AKI.2 Rates of CI-AKI may be as high as 50% or even higher, depending on the presence of risk factors such as chronic renal insufficiency and diabetes mellitus. Although the definition of CI-AKI varies across the trials, the most commonly used definition includes an absolute increase in serum creatinine of 0.5 mg/dL or a 25% relative increase in …