Christian Funck-Brentano

Guidelines on the management of valvular heart disease (version 2012)

ACEn: angiotensin-converting enzymenAFn: atrial fibrillationnaPTTn: activated partial thromboplastin timenARn: aortic regurgitationnARBn: angiotensin receptor blockersnASn: aortic stenosisnAVRn: aortic valve replacementnBNPn: B-type natriuretic peptidenBSAn: body surface areanCABGn: coronary artery bypass graftingnCADn: coronary artery diseasenCMRn: cardiac magnetic resonancenCPGn: Committee for Practice GuidelinesnCRTn: cardiac resynchronization therapynCTn: computed tomographynEACTSn: European Association for Cardio-Thoracic SurgerynECGn: electrocardiogramnEFn: ejection fractionnEROAn: effective regurgitant orifice areanESCn: European Society of CardiologynEVERESTn: (Endovascularxa0Valvexa0Edge-to-Edge REpairxa0STudy)nHFn: heart failurenINRn: international normalized rationLAn: left atrialnLMWHn: low molecular weight heparinnLVn: left ventricularnLVEFn: left ventricular ejection fractionnLVEDDn: left ventricular end-diastolic diameternLVESDn: left ventricular end-systolic diameternMRn: mitral regurgitationnMSn: mitral stenosisnMSCTn: multi-slice computed tomographynNYHAn: New York Heart AssociationnPISAn: proximal isovelocity surface areanPMCn: percutaneous mitral commissurotomynPVLn: paravalvular leaknRVn: right ventricularnrtPAn: recombinant tissue plasminogen activatornSVDn: structural valve deteriorationnSTSn: Society of Thoracic SurgeonsnTAPSEn: tricuspid annular plane systolic excursionnTAVIn: transcatheter aortic valve implantationnTOEn: transoesophageal echocardiographynTRn: tricuspid regurgitationnTSn: tricuspid stenosisnTTEn: transthoracic echocardiographynUFHn: unfractionated heparinnVHDn: valvular heart diseasen3DEn: three-dimensional echocardiographynnGuidelines summarize and evaluate all evidence available, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well …

Rate-corrected QT interval: Techniques and limitations

The duration of the QT interval on the surface electrocardiogram represents the time required for all ventricular depolarization and repolarization processes to occur. Among the many physiologic and pathologic factors that contribute to the QT interval, heart rate plays a major role. Several approaches have been used to correct the QT interval, all of which take into account the heart rate at which the interval is measured. The simplest and most common approach to correcting the QT interval is to divide its value by the square root of the preceding RR interval expressed in seconds, i.e., by using Bazetts formula. This calculation provides a corrected QT (QTc) interval that represents the QT interval normalized for a heart rate of 60 beats/min. However, several studies have shown that Bazetts correction formula is not optimal. Fridericias cube-root formula has been shown to perform better in correcting the QT interval for heart rate. Other formulas require the measurement of several QT-RR pairs at various heart rates to obtain a reliable QTc interval and are therefore not easily usable. Any correction formula is likely to introduce an error in assessing the QTc interval. Although the importance of this error should not be minimized, the corrected QT interval remains useful in assessing the effects of drugs on the duration of repolarization. For this purpose, Fridericias cube-root formula is preferable to Bazetts square-root formula.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolongation of QTc Interval after Postoperative Nausea and Vomiting Treatment by Droperidol or Ondansetron

Background:At dosages above 0.1 mg/kg, droperidol inducesa dose-dependent QTc interval prolongation. Although subject to controversy, low-dose droperidol has recently been suspected to induce cardiac arrhythmias. Hence, 5-hydroxytryptamine type 3 antagonists have become the first-line drug for management of postoperative nausea and vomiting. These drugs are also known to prolong the QTc interval at high dosages. This study describes QTc interval changes associated with postoperative nausea and vomiting treatment by droperidol or ondansetron at low doses. Methods:Eighty-five patients with postoperative nausea and vomiting were included in this prospective, single-blind study. Patients received either 0.75 mg intravenous droperidol (n = 43) or 4 mg intravenous ondansetron (n = 42). Electrocardiographic recordings were obtained before administration of antiemetic drug and then 1, 2, 3, 5, 10, and 15 min after. Electrocardiographic monitoring was maintained for 3 h in eight patients in each group. Results:The QTc interval was prolonged (> 450 ms in men, > 470 ms in women) in 21% of the patients before antiemetic drug administration. This was significantly correlated with lower body temperature and longer duration of anesthesia. Compared with predrug QTc measurement, both antiemetics were associated with a significant QTc interval prolongation (P < 0.0001). The mean maximal QTc interval prolongation was 17 ± 9 ms after droperidol occurring at the second minute and 20 ± 13 ms after ondansetron at the third minute (both P < 0.0001). Compared with predrug measurement, the QTc interval was significantly lower after the 90th minute in both groups. Conclusions:Droperidol and ondansetron induced similar clinically relevant QTc interval prolongations. When used in treatment of postoperative nausea and vomiting, a situation where prolongation of the QTc interval seems to occur, the safety of 5-hydroxytryptamine type 3 antagonists may not be superior to that of low-dose droperidol.

The Role of Genetically Determined Polymorphic Drug Metabolism in the Beta-Blockade Produced by Propafenone

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenones beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drugs beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Pharmacokinetic‐pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers

Ivabradine (S‐16257) is a new bradycardic agent with a direct effect on the sinus node. Its N‐dealkylated metabolite, S‐18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers.

Can We Override Clopidogrel Resistance

Clopidogrel, a thienopyridine antiplatelet agent, has been used alone or in association with aspirin to prevent vascular complications in atherothrombotic patients. It is also, in combination with aspirin, the key treatment to prevent stent thrombosis in patients who have undergone percutaneous coronary intervention. It is estimated that >40 million patients worldwide receive clopidogrel. Recent investigations into genetic mechanisms that influence clopidogrel efficacy suggest that a common variant present in ≈30% of whites has the potential to identify patients with a deficient clopidogrel metabolic activation who are consequently at risk of recurrent cardiovascular events, including stent thrombosis.1–3 Stent thrombosis is the most serious complication of coronary stent implantation, often leading to empiric modifications of antiplatelet treatments, although stent thrombosis pathogenesis is complex and the weight of the various factors involved is not known.4 We report 7 recent cases of stent thrombosis with demonstrated platelet resistance to clopidogrel, and we describe a novel clinical approach using pharmacodynamic and genetic information to override clopidogrel resistance.nn### Patient Selection and CharacteristicsnnThe clinical characteristics of 7 patients who presented with stent thrombosis on clopidogrel treatment (75 mg maintenance dose [MD]) are presented in the Table. Stent thrombosis was angiographically proven in all patients and occurred on days 1, 3, 5, 6 (2 patients), 11, and 70, with a median time from stent implantation to stent occlusion of 6 days (interquartile range, 4 to 8.5 days). Clinical presentation was ST-elevation myocardial infarction in all cases, and 4 of 7 patients had a history of myocardial infarction. Stent thrombosis occurred in 6 patients with a bare metal stent and 1 patient with a drug-eluting stent. Primary percutaneous coronary intervention revascularization of stent thrombosis was performed with a new bare metal stent in 6 patients; in the remaining patient, a drug-eluting stent was implanted. nnView this table:nnTable. Baseline Characteristics of the …

Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Dofetilide on QT-Interval Duration and Dispersion at Various Heart Rates During Exercise in Humans

BACKGROUNDnThe objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects.nnnMETHODS AND RESULTSnDofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax-QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P < .01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P < .05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate.nnnCONCLUSIONSnDofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.

QT interval measurement: evaluation of automatic QTc measurement and new simple method to calculate and interpret corrected QT interval.

Background:Assessment of repolarization duration is often recommended to avoid administration of QT-prolonging drugs in patients with prolonged QTc interval, a frequent situation in the postoperative period. Bazett QT correction inappropriately increases QTc when heart rate is increased, and the use of the Fridericia formula may avoid a falsely prolonged QTc interval. The authors assessed automatic QT interval measurement to detect prolonged QTc interval (women >450 ms; men >440 ms) in the postoperative setting. Methods:Automatic and manual electrocardiograms were performed in 108 patients after anesthesia. Automatic electrocardiographic measurement used the Bazett formula. Manual measurements were made from each electrocardiogram and used as the reference. Agreement between the two methods was analyzed. Bazett and Fridericia QT corrections were compared in this population. Results:Agreement between automatic and manual measurements was low. The Fridericia correction, but not the Bazett correction, was independent from heart rate and allowed adequate QT correction. Sensitivity of automatic measurements to detect prolonged QTc-Bazett interval was 54%. Automatic QTc-Bazett interval less than 430 ms ruled out a manual prolonged QTc interval. When automatic QTc-Bazett was greater than 430 ms, this value was converted according to Fridericia. Automatic QTc-Fridericia greater than 430 ms identified all patients with prolonged manual QTc with a negative predictive error of 0% (95% confidence interval, 0–7%). QTc-Fridericia can be approximated by respectively adding or subtracting 5% to the uncorrected QT for each increase or decrease by 10 beats/min in heart rate from 60 beats/min. Conclusions:Automatic QTc-Bazett measurement, if abnormal, associated with calculation of QTc-Fridericia reliably identifies patients in whom manual QTc measurement must be performed to confirm postoperative prolonged QTc interval.

Pharmacogenetics of acenocoumarol pharmacodynamics.

The aim of this study was to investigate the respective contribution of the different cytochrome P450 (CYP) 2C9 genetic polymorphisms to the interindividual variability of acenocoumarol pharmacodynamic response.