Generation of an induced pluripotent stem cell line (SHETi004-A) from a Chinese Han child with left bundle branch block.

Desmin (DES) is an important intermediate filament protein associated with the extrasarcomeric cytoskeleton and cellular function that was first reported to be associated with cardiac conduction disease and cardiomyopathy in 1998. We generated an induced pluripotent stem cell (iPSC) line from the left bundle branch block (LBBB) patient's peripheral blood mononuclear cells using Sendai virus-mediated reprogramming. The iPSCs exhibited stable amplification, expressed pluripotent markers, and spontaneously differentiated into three layers in vitro. Additionally, it showed a normal diploid karyotype and maintained the pathogenic mutation in DES. Hence, the iPSC line provided a platform for exploring LBBB mechanisms associated with DES mutations.

Impact of left bundle branch block on myocardial perfusion and metabolism: A positron emission tomography study.

BACKGROUND: Better understanding of pathophysiological changes, induced by left bundle branch block (LBBB), may improve patient selection for cardiac resynchronization therapy (CRT). Therefore, we assessed the effect of LBBB on regional glucose metabolism, 13N-NH3-derived absolute and semiquantitative myocardial blood flow (MBF), and their relation in non-ischemic CRT candidates. METHODS: Twenty-five consecutive non-ischemic patients with LBBB underwent 18F-FDG and resting dynamic 13N-NH3 PET/CT prior to CRT implantation. Regional 18F-FDG uptake, absolute MBF, and late 13N-NH3 uptake were analyzed and corresponding septal-to-lateral wall ratios (SLR) were calculated. Segmental analysis was performed to evaluate "reverse mismatch," "mismatch," and "match" patterns, based on late 13N-NH3/18F-FDG uptake ratios. RESULTS: A significantly lower 18F-FDG uptake was observed in the septum compared to the lateral wall (SLR 0.53 ± 0.17). A similar pattern was observed for MBF (SLR 0.68 ± 0.18), whereas late 13N-NH3 uptake showed a homogeneous distribution (SLR 0.96 ± 0.13). 13N-NH3/18F-FDG "mismatch" and "reverse mismatch" segments were predominantly present in the lateral (52%) and septal wall (61%), respectively. CONCLUSIONS: Non-ischemic CRT candidates with LBBB demonstrate lower glucose uptake and absolute MBF in the septum compared to the lateral wall. However, late static 13N-NH3 uptake showed a homogenous distribution, reflecting a composite measure of altered regional MBF and metabolism, induced by LBBB.

Main clinical determinants of the presence of coronary artery disease in patients with left bundle branch block.

BACKGROUND: Considering clinical parameters as main predictors for coronary artery dis-ease (CAD)in patients with left bundle branch block (LBBB) can be very helpful to explain high likelihood of ischemic events in LBBB conditions. In the present study, we attempted to identify major clinical determinants to predict CAD occurrence in patients with LBBB. METHODS: A retrospective chart review of 229 consecutive patients with the diagnosis of complete LBBB pattern on electrocardiograms was conducted. The final diagnosis of LBBB was based on the Criteria Committee of the New York Heart Association. The participants were also classified based on coronary angiography evidences into two groups including CAD patients (n =99) and non-CAD patients (n =130). RESULTS: Among 99 patients with CAD, 27 (27.3%) had single vessel disease, 30 (30.3%) had two-vessel disease and 42 (42.4%) had three-vessel disease. Also, only two of them had left main lesions. The number of diseased coronary vessels was significantly higher in men than in women so that three vessels disease in men was revealed in 28% and in women was observed in 10.9% (p = 0.002). Using a multivariable logistic regression analysis, male gender (2.445, 95% CI: 1.372-4.367, p = 0.002), advanced age (1.063, 95% CI: 1.032-1.095, p < 0.001), and cigarette smoking (4.112, 95% CI: 1.145-8.635, p = 0.012) were main predictors of CAD in LBBB patients. CONCLUSION: A notable number of patients with LBBB suffered concomitantly from CAD that the presence and severity of this ischemic event could be predicted by male gender, advanced age, and history of smoking in these patients.

Septal and anterior reverse mismatch of myocardial perfusion and metabolism in patients with coronary artery disease and left bundle branch block.

The effects of left bundle branch block (LBBB) on left ventricular myocardial metabolism have not been well investigated. This study evaluated these effects in patients with coronary artery disease (CAD).Sixty-five CAD patients with complete LBBB (mean age, 61.8 ±â€Š9.7 years) and 65 without LBBB (mean age, 59.9 ±â€Š8.4 years) underwent single photon emission computed tomography, positron emission tomography, and contrast coronary angiography. The relationship between myocardial perfusion and metabolism and reverse mismatch score, and that between QRS length and reverse mismatch score and wall motion score were evaluated.The incidence of left ventricular septum and anterior wall reverse mismatching between the two groups was significantly different (P < 0.001 and P = 0.002, respectively). The incidences of normal myocardial perfusion and metabolism in the left ventricular lateral and inferior walls were also significantly different between the two groups (P < 0.001 and P < 0.001, respectively). The incidence of septal reverse mismatching in patients with mild to moderate perfusion was significantly higher among those with LBBB than among those without LBBB (P < 0.001). In CAD patients with LBBB, septal reverse mismatching was significantly more common among those with mild to moderate perfusion than among those with severe perfusion defects (P = 0.002). The correlation between the septal reverse mismatch score and QRS length was significant (P = 0.026).In patients with CAD and LBBB, septal and anterior reverse mismatching of myocardial perfusion and metabolism was frequently present; the septal reverse mismatch score negatively correlated with the QRS interval.

Current concepts relating coronary flow, myocardial perfusion and metabolism in left bundle branch block and cardiac resynchronisation therapy.

Cardiac resynchronisation therapy (CRT) improves mortality and symptoms in heart failure patients with electromechanically dyssynchronous ventricles. There is a 50% non-response rate and reproducible biomarkers to predict non-response have not been forthcoming. Therefore, there has been increasing interest in the pathophysiological effects of dyssynchrony particularly focusing on coronary flow, myocardial perfusion and metabolism. Studies suggest that dyssynchronous electrical activation effects coronary flow throughout the coronary vasculature from the epicardial arteries to the microvascular bed and that these changes can be corrected by CRT. The effect of both electrical and mechanical dyssynchrony on myocardial perfusion is unclear with some studies suggesting there is a reduction in septal perfusion whilst others propose that there is an increase in lateral perfusion. Better understanding of these effects offers the possibility for better prediction of non-response. CRT appears to improve homogeneity in myocardial perfusion where heterogeneity is described in the initial substrate. Novel approaches to the identification of non-responders via metabolic phenotyping both invasively and non-invasively have been encouraging. There remains a need for further research to clarify the interaction of coronary flow with perfusion and metabolism in patients who undergo CRT.

Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally.

BACKGROUND: The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing ("cardiac resynchronization therapy", CRT) are unknown. METHODS: Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB). RESULTS: AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p=0.001, and aortic VTI by 11(SEM 3)%, p=0.002, but also increased MVO2 by 11(SEM 5)%, p=0.04. AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p=0.035 and aortic VTI by 4(SEM 1)%, p=0.017. MVO2 trended further up by 7(SEM 5)%, p=0.22. Mechanoenergetics at AV-40 were no different from LBBB. The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly >1 (p=0.02). CONCLUSIONS: Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect - which may therefore not be mainly "resynchronization".

Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions.

Left ventricular (LV) dyssynchrony reduces myocardial efficiency because work performed by one segment is wasted by stretching other segments. In the present study, we introduce a novel noninvasive clinical method that quantifies wasted energy as the ratio between work consumed during segmental lengthening (wasted work) divided by work during segmental shortening. The wasted work ratio (WWR) principle was studied in 6 anesthetized dogs with left bundle branch block (LBBB) and in 28 patients with cardiomyopathy, including 12 patients with LBBB and 10 patients with cardiac resynchronization therapy. Twenty healthy individuals served as controls. Myocardial strain was measured by speckle tracking echocardiography, and LV pressure (LVP) was measured by micromanometer and a previously validated noninvasive method. Segmental work was calculated by multiplying strain rate and LVP to get instantaneous power, which was integrated to give work as a function of time. A global WWR was also calculated. In dogs, WWR by estimated LVP and strain showed a strong correlation (r = 0.94) and good agreement with WWR by the LV micromanometer and myocardial segment length by sonomicrometry. In patients, noninvasive WWR showed a strong correlation (r = 0.96) and good agreement with WWR using the LV micromanometer. Global WWR was 0.09 ± 0.03 in healthy control subjects, 0.36 ± 0.16 in patients with LBBB, and 0.21 ± 0.09 in cardiomyopathy patients without LBBB. Cardiac resynchronization therapy reduced global WWR from 0.36 ± 0.16 to 0.17 ± 0.07 (P < 0.001). In conclusion, energy loss due to incoordinated contractions can be quantified noninvasively as the LV WWR. This method may be applied to evaluate the mechanical impact of dyssynchrony.

Relationship between mechanical and metabolic dyssynchrony with left bundle branch block: evaluation by 18-fluorodeoxyglucose positron emission tomography in patients with non-ischemic heart failure.

BACKGROUND: Ventricular dyssynchrony is a common finding in patients with heart failure (HF), especially in the presence of conduction delays. The loss of ventricular synchrony leads to progressive impairment of contractile function, which may be explained in part by segmental abnormalities of myocardial metabolism. However, the association of these metabolic disarrangements with parameters of ventricular dyssynchrony and electrocardiography (ECG) findings has not yet been studied. METHODS: Our aim was to determine the correlation between the presence of left bundle branch block (LBBB) with left ventricular (LV) mechanical synchrony assessed by multiple-gated acquisition scan (MUGA) and with patterns of 18-fluorodeoxyglucose (18FDG) uptake in patients with non-ischemic heart failure. Twenty-two patients with non-ischemic cardiomyopathy, LV ejection fraction (LVEF) ≤45% and New York Heart Association (NYHA) Functional Class II or III symptoms under standard medical therapy were included, along with 10 healthy controls matched for age and gender. A 12-lead ECG was obtained to measure the length of the QRS. Mechanical LV synchrony was assessed by MUGA using phase analysis. All patients and controls underwent positron emission tomography with 18FDG to determine the distribution of myocardial glucose uptake. The standard deviation of peak (18)FDG uptake was used as an index of metabolic heterogeneity. Student's t-test and Pearson's correlation were used for statistical analysis. RESULTS: The mean age of the patients with HF was 54 ± 12 years and 72% were male. The length of the QRS was 129 ± 31 milliseconds and LBBB was present in 9 patients. Patients with HF had decreased LV 18FDG uptake compared with controls (7.56 ± 3.36 vs. 11.63 ± 4.55 standard uptake value; p = 0.03). The length of the QRS interval correlated significantly with glucose uptake heterogeneity (r = 0.62; p = 0.002) and mechanical dyssynchrony (r = 0.63; p = 0.006). HF patients with LBBB showed marked glucose uptake heterogeneity compared with HF patients without LBBB (41.4 ± 10 vs 34.7 ± 4.9 ml/100 g/min, respectively; p = 0.01). CONCLUSIONS: Patients with non-ischemic heart failure exhibit a global decrease in myocardial glucose uptake. Within this group, subjects who also have LBBB exhibit a marked heterogeneity in segmental glucose uptake, which directly correlates with QRS duration.

The effect of connexin40 deficiency on ventricular conduction system function during development.

AIMS: The aim of this study was to characterize ventricular activation patterns in normal and connexin40-deficient mice in order to dissect the role of connexin40 in developing the conduction system. METHODS AND RESULTS: We performed optical mapping of epicardial activation between ED9.5-18.5 and analysed ventricular activation patterns and times of left ventricular activation. Mouse embryos deficient for connexin40 were compared with normal and heterozygous littermates. Morphology of the primary interventricular ring (PIR) was delineated with the help of T3-LacZ transgene. Four major types of ventricular activation patterns characterized by primary breakthrough in different parts of the heart were detected during development: PIR, left ventricular apex, right ventricular apex, and dual right and left ventricular apices. Activation through PIR was frequently present at the early stages until ED12.5. From ED14.5, the majority of hearts showed dual left and right apical breakthrough, suggesting functionality of both bundle branches. Connexin40-deficient embryos showed initially a delay in left bundle branch function, but the right bundle branch block, previously described in the adults, was not detected in ED14.5 embryos and appeared only gradually with 80% penetrance at ED18.5. CONCLUSION: The switch of function from the early PIR conduction pathway to the mature apex to base activation is dependent upon upregulation of connexin40 expression in the ventricular trabeculae. The early function of right bundle branch does not depend on connexin40. Quantitative analysis of normal mouse embryonic ventricular conduction patterns will be useful for interpretation of effects of mutations affecting the function of the cardiac conduction system.

Mutational spectrum in the Ca(2+)--activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.

Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndromes. In eight probands with atrioventricular block or right bundle branch block--five familial cases and three sporadic cases--a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients.

Myocardial structural, perfusion, and metabolic correlates of left bundle branch block mechanical derangement in patients with dilated cardiomyopathy: a tagged cardiac magnetic resonance and positron emission tomography study.

BACKGROUND: Left bundle branch block (LBBB) influences on regional left ventricular (LV) structure, perfusion, and metabolism have not yet been thoroughly investigated in dilated cardiomyopathy patients. METHODS AND RESULTS: Eleven dilated cardiomyopathy patients with LBBB (mean+/-SD age, 62+/-11 years; LV ejection fraction, 35+/-8%) and 7 dilated cardiomyopathy patients without LBBB (mean+/-SD age, 58+/-9 years; LV ejection fraction, 37+/-10%) were studied by cardiac magnetic resonance and positron emission tomography. The left ventricle was divided in 3 regions: septum, adjacent (anterior-inferior walls), and lateral. Regional midwall circumferential strain, maximum shortening, and strain rate were obtained from tagged cardiac magnetic resonance. The systolic stretch index was calculated as positive strain rate (stretching) divided by total strain rate. Myocardial metabolic rate of glucose and resting and hyperemic myocardial blood flow were quantified by 2-[(18)F]fluoro-2-deoxyglucose and [(13)N]ammonia positron emission tomography, respectively. Compared with non-LBBB patients, LBBB patients showed a highly inhomogeneous systolic deformation pattern that changed gradually, moving from a discoordinate [(systolic stretch index, 0.485 (0.284)] and poorly contracting (maximum shortening, -1.14+/-0.96%) septum to a coordinate [systolic stretch index, 0.002 (0.168)] and strongly contracting (maximum shortening, -13.63+/-2.58%) lateral region (both P<0.0001). This pattern was closely matched to the myocardial metabolic rate of glucose, disclosing lowest, intermediate, and highest values in the septum, adjacent, and lateral regions, respectively (P<0.0001). Septal-to-lateral thickness ratio was lower in LBBB than in non-LBBB patients (P=0.03). In both groups, the LV distribution of resting and hyperemic myocardial blood flow and myocardial blood flow reserve did not differ significantly. CONCLUSIONS: In dilated cardiomyopathy patients, the extensive LV contraction abnormalities induced by LBBB cause regional myocardial metabolic and structural remodeling, without consistent changes in blood flow.

Relationship of age and exercise performance in patients with heart failure: the HF-ACTION study.

BACKGROUND: More than three fourths of patients with heart failure (HF) are 65 years and older, and older age is associated with worse symptoms and prognoses than is younger age. Reduced exercise capacity is a chief HF complaint and indicates poorer prognosis, especially among elderly persons, but the mechanisms underlying functional decline in older patients with HF are largely unknown. METHODS: Baseline cardiopulmonary exercise testing data from the HF-ACTION trial were assessed to clarify age effects on peak oxygen consumption (VO(2)) and ventilation-carbon dioxide production (VE/VCO(2)) slope. RESULTS: Among 2,331 New York Heart Association class II-IV patients with HF, increased age corresponded to decreased peak VO(2) (-0.14 mL kg(-1) min(-1) per year >40 years; P < .0001) and increased VE/VCO(2) slope (0.30 U/y >70 years; P < .0001). In a multivariable model with 34 other potential determinants, age was the strongest independent predictor of peak VO(2) (partial R(2) 0.130, total R(2) 0.392; P < .001) and a significant but relatively weaker predictor of VE/VCO(2) slope (partial R(2) 0.037, total R(2) 0.199; P < .001). Blunted peak heart rate was also a strong predictor of peak VO(2). Although peak heart rate and age were strongly correlated, both were significant independent predictors of peak VO(2) when analyzed simultaneously in a model. Aggregate comorbidity increased significantly with age but did not account for age effects on peak VO(2). CONCLUSIONS: Age is the strongest predictor of peak VO(2) and a significant predictor of VE/VCO(2) slope in the HF-ACTION population. Age-dependent comorbidities do not explain changes in peak VO(2). Age-related changes in cardiovascular physiology, potentially magnified by the HF disease state, should be considered a contributor to the pathophysiology and a target for more effective therapy in older patients with HF.

Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.

Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.

Heterogeneous reduction of myocardial oxidative metabolism in patients with ischemic and dilated cardiomyopathy using C-11 acetate PET.

BACKGROUND: The 11C-acetate positron emission tomography can estimate myocardial oxidative metabolism, but previous studies have only evaluated small populations and the difference between ischemic (ICM) and idiopathic dilated cardiomyopathy (DCM) has not been fully investigated. The present aims were to evaluate global and regional myocardial oxidative metabolism in a well-characterized, large population with left ventricular (LV) dysfunction in order to clarify the metabolic differences between ICM and DCM. METHODS AND RESULTS: Seventy-eight patients with ejection fraction (EF) < or =50% (33 ICM; 45 DCM) were compared with 14 healthy controls. Myocardial oxidative metabolism was estimated with a clearance rate constant (K(mono)) and the coefficient of variation (CV) of regional K(mono). Patients with LV dysfunction had reduced K(mono) and higher CV (p<0.05). In the comparison of oxidative alterations with clinical variables there was a weak correlation between K(mono) and LVEF (r=0.27). Although K(mono) was reduced in both ICM and DCM, CV was more pronouncedly increased in ICM (p=0.001). In multivariate analysis, the presence of left bundle branch block (LBBB) was an independent predictor of heterogeneous oxidative metabolism in DCM (R2=0.30, p<0.0001). CONCLUSIONS: Global reduction of myocardial oxidative metabolism occurred in both ICM and DCM. Heterogeneous oxidative metabolism was observed in these patients, especially those with ICM. Furthermore, LBBB was the independent predictor of heterogeneous oxidative metabolism in patients with DCM.

Combination of cardiac conduction disease and long QT syndrome caused by mutation T1620K in the cardiac sodium channel.

AIMS: The aim of the present study was to elucidate the molecular mechanism underlying the concomitant occurrence of cardiac conduction disease and long QT syndrome (LQT3), two SCN5A channelopathies that are explained by loss-of-function and gain-of-function, respectively, in the cardiac Na+ channel. METHODS AND RESULTS: A Caucasian family with prolonged QT interval, intermittent bundle-branch block, sudden cardiac death, and syncope was investigated. Lidocaine (1 mg/kg i.v.) normalized the prolonged QT interval and rescued bundle-branch block. An SCN5A mutation analysis was performed that revealed a C-to-A mutation at position 4859 (exon 28), predicted to change a highly conserved threonine for a lysine at position 1620. Mutant channels were characterized both in Xenopus oocytes and HEK293 cells. The T1620K mutation remarkably altered the properties of Nav1.5 channels. In particular, the voltage-dependence of the current decay time constants was largely lost. As a consequence, mutant channels inactivated faster than wild-type channels at potentials negative to -30 mV, resulting in less Na+ inward current (loss-of-function), but significantly slower at potentials positive to -30 mV, resulting in an increased Na+ inward current (gain-of-function). Moreover, we found a hyperpolarized shift of steady-state activation and an accelerated recovery from inactivation (gain-of-function). At the same time, channel availability was significantly reduced at the resting membrane potential (loss-of-function). CONCLUSION: We conclude that lysine at position 1620 leads to both loss-of-function and gain-of-function properties in hNav1.5 channels, which may consequently cause in the same individuals impaired impulse propagation in the conduction system and prolonged QTc intervals, respectively.

Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a.

OBJECTIVE: Dilated cardiomyopathy (DCM) leads to dilation of the cardiac chambers and congestive heart failure. Recent reports have associated mutations in the SCN5A gene, which codes for the major cardiac sodium channel Nav1.5, with DCM. Although DCM is the most common form of cardiomyopathy, no animal studies have established this functional connection. METHODS AND RESULTS: We have produced transgenic mice that ectopically express the transcriptional repressor Snail in heart. These animals display severe DCM, ECG abnormalities, conduction defects, revealed by voltage-sensitive dye imaging, and significantly reduced voltage-gated sodium current as measured by patch clamping. There is a concomitant decrease in expression of the major cardiac sodium channel gene Scn5a, which we show by gene reporter assays and electrophoretic mobility shift assays is a direct target of Snail. CONCLUSIONS: Our findings indicate that a decrease in Scn5a expression and significant reduction in sodium current can result in DCM, and support the hypothesis that some mutations in the human SCN5A gene can lead to DCM.

Impact of intraventricular conduction delay on coronary haemodynamics: a study with intracoronary Doppler in patients with bundle branch blocks and normal coronary arteries.

AIMS: The impact of right bundle branch block (RBBB) and left bundle branch block (LBBB) on myocardial perfusion is not completely understood as data are often blurred by underlying cardiac disease. The present study investigates whether conduction delays per se affect coronary perfusion-an indirect measure of myocardial oxygen demand. METHODS AND RESULTS: Intracoronary Doppler and ultrasound were performed in 8 patients with RBBB, 10 patients with LBBB, and 10 control subjects. All patients had angiographically normal coronary arteries and normal left ventricular function. Baseline (bAPV) and adenosine-induced hyperaemic average flow velocity and coronary flow velocity reserve (CFVR) were measured in left anterior descending arteries. Intravascular ultrasound showed no difference in lumen cross-sectional area and plaque burden between groups. Patients with RBBB and LBBB had higher bAPV values than controls (19.0 +/- 4.9, 21.9 +/- 5.1, and 14.6 +/- 2.4 cm/s, respectively; ANOVA P = 0.003). There was no difference between patients with LBBB and RBBB compared with controls in CFVR (2.8 +/- 0.5, 3.0 +/- 1.0, and 3.4 +/- 0.7, respectively; ANOVA P = 0.21). CONCLUSION: Bundle branch blocks, in particular LBBB, are associated with an increased coronary flow velocity, which indicates enhanced myocardial oxygen demand on the basis of mechanoenergetic disturbance. This may contribute to the unfavourable outcome of patients with intraventricular conduction delay.

Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias.

Population pharmacokinetics (PK) of a sodium channel-blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed-effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS-like elevation of ST-segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant (P < .01) covariates of weight-normalized systemic clearance of pilsicainide. Patients who showed a BrS-like ECG pattern after the drug administration also showed a significantly (P < .01) greater prolongation in His-Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug-induced BrS-like ECG morphology may be associated with augmented ECG responses to pilsicainide.