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Arshad Jahangir

Publications and source records attributed to Arshad Jahangir.

At least 19 recordsLinked to original sources
PubMed2006

Left ventricular structure and function: basic science for cardiac imaging.

The myofiber geometry of the left ventricle (LV) changes gradually from a right-handed helix in the subendocardium to a left-handed helix in the subepicardium. In this review, we associate the LV myofiber architecture with emerging concepts of the electromechanical sequence in a beating heart. We discuss: 1) the morphogenesis and anatomical arrangement of muscle fibers in the adult LV; 2) the sequence of depolarization and repolarization; 3) the physiological inhomogeneity of transmural myocardial mechanics and the apex-to-base sequence of longitudinal and circumferential deformation; 4) the sequence of LV rotation; and 5) the link between LV deformation and the intracavitary flow direction observed during each phase of the cardiac cycle. Integrating the LV structure with electrical activation and motion sequences observed in vivo provides an understanding about the spatiotemporal sequence of regional myocardial performance that is essential for noninvasive cardiac imaging.

Aging↗
PubMed2006

Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.

Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4-S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1-S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current I(Kur) vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.

Animals↗
PubMed2006

Targeted therapy for short QT syndrome.

Identified in 2000, short QT syndrome is an electrical disease of the heart characterised as a channelopathy. At first considered extremely rare, families with this disease have been found in Brazil, Finland, Germany, Spain, the Netherlands, France, Turkey, Italy and the US. The focus of the paper is to present a current review of short QT syndrome, as well as providing an overview upon the potential molecular target-based strategies for management of this very deadly disease. Abnormalities in three different potassium channels have been recognised as the cause of the disease and targets for therapy will be discussed for each potassium channel individually. In addition to pharmacological strategies, gene therapy with transfer of genes coding for specific ion channel subunits or regulatory proteins are discussed.

Arrhythmias, Cardiac↗
PubMed2005

Apex-to-base dispersion in regional timing of left ventricular shortening and lengthening.

OBJECTIVES: We investigated whether the onset and progression of regional left ventricular (LV) shortening and lengthening parallel the apex-to-base differences in depolarization and repolarization. BACKGROUND: Limited information exists regarding apex-to-base differences in longitudinal and circumferential deformation sequence of the LV. METHODS: The apex-to-base differences in electric activation and the progression of longitudinal and circumferential shortening and lengthening sequences were determined in 8 porcine beating hearts in situ by implanting bipolar electrodes and an array of 14 sonomicrometry crystals in the LV free wall. RESULTS: Electric activation started at the apical subendocardium and showed significant delay in reaching the LV base. The onsets of mechanical activation and subsequent 20%, 40%, and 80% peak longitudinal shortenings required longer time to occur at base compared to the apex. The repolarization sequence propagated in reverse, with the base repolarizing before the apex. Subendocardial longitudinal shortening at base and subepicardial circumferential shortening at apex continued beyond the period of LV ejection, resulting in an apex-to-base gradient in the onset of lengthening. This gradient correlated with the duration of isovolumic relaxation (r = 0.85, p = 0.004) and the time required for reaching the lowest LV diastolic pressure (r = 0.70, p = 0.04). CONCLUSIONS: Apex-to-base delay in mechanical shortening of LV parallels the apex-to-base direction of the electric activation sequence. Basal subendocardial and apical subepicardial regions deform through a characteristic phase of postsystolic shortening. Short-lived apex-to-base and subendocardial-to-subepicardial relaxation gradients at the onset of diastole may have a physiologic significance in facilitating active restoration of the LV cavity in diastole.

Animals↗
PubMed2005

Score indices for predicting electrophysiologic outcomes in patients with unexplained syncope.

INTRODUCTION: Our ability to predict a positive electrophysiologic (EP) study in the evaluation of unexplained syncope is suboptimal. AIMS: In patients with unexplained syncope, we defined clinical predictors of bradyarrhythmia and ventricular tachycardia (VT) diagnosed during EP study, constructed diagnostic score indices for bradyarrhythmia and VT, and evaluated the predictive power of each score index. METHODS: All patients evaluated in the Arrhythmia Clinic for unexplained syncope from January 1, 1996, through December 31, 1998, were identified and enrolled in the study. Five hundred eight patients (325 [64%] men; mean+/-SD age, 64+/-17 years) underwent EP testing. We analyzed elements from historical data and noninvasive laboratory findings as predictors of bradyarrhythmia and VT diagnosed on EP study. RESULTS: Fifty-eight patients (11%) had sinus node dysfunction, 94 (19%) had atrioventricular (AV) node disease, 92 (18%) had His-Purkinje system disease, and 101 (20%) had VT. Models were fit using logistic regression analysis. Predictors were assigned weighted scores, and a score index was formulated. The area under the curve associated with sinus node dysfunction, AV node disease, His-Purkinje system disease, and VT models was 0.64, 0.60, 0.84, and 0.60, respectively. CONCLUSIONS: We have constructed diagnostic score indices for EP outcomes of bradyarrhythmia and VT in syncope. Of all the score indices, the model for His-Purkinje system disease has the highest predictive power.

Arrhythmias, Cardiac↗
PubMed2005

Use of advanced mapping systems to guide ablation in complex cases: experience with noncontact mapping and electroanatomic mapping systems.

OBJECTIVE: This report describes our experience with noncontact mapping and electroanatomic mapping in complex ablations, which are defined as ablations done after failure of conventional ablation. MATERIAL AND METHODS: Patients were included (N = 68; 49% with structural heart disease) in whom previous ablation failed and in whom a second procedure was done with advanced mapping. Non-contact mapping was used in 17 patients, electroanatomic mapping in 36, and both noncontact and electroanatomic mapping in 15. Arrhythmias included focal atrial tachycardia (n = 16), reentrant atrial tachycardia (n = 14), right ventricular outflow tachycardia (n = 10), post-myocardial infarction ventricular tachycardia (n = 9), and others (n = 19). RESULTS: Acute success at the second ablation was achieved in 79% of patients. At 20 +/- 9 months after the procedure, 69% of these patients reported having significantly fewer symptoms than before the second ablation, and 51% were free of symptoms. Only 16% were using antiarrhythmic medications. Complications included a small pericardial effusion in two patients, hypotension in one patient, and a femoral pseudoaneurysm in another. CONCLUSIONS: Advanced mapping is a useful and safe adjunct for catheter ablation after ablation has failed in patients with complex substrate.

Arrhythmias, Cardiac↗
PubMed2005

Acute blood pressure changes after the onset of atrioventricular nodal reentrant tachycardia: a time-course analysis.

INTRODUCTION: We aimed to characterize blood pressure (BP) response at the beginning of atrioventricular nodal reentrant tachycardia (AVNRT) and its relationship to orthostatic challenge and variable atrioventricular interval. METHODS AND RESULTS: In this prospective study of 17 consecutive patients with documented AVNRT, mean BP was analyzed in the supine and upright positions during sinus rhythm, AVNRT, and pacing with atrioventricular delay of 150 msec (AV150) and 0 msec (AV0). Mean BPs were compared at 3-5 seconds, 8-10 seconds, and 28-30 seconds after the onset of AVNRT or pacing. BP decreased immediately after AVNRT initiation, with gradual recovery during the first 30 seconds from 71.9 +/- 16.5 mmHg to 86 +/- 13.8 mmHg, P < 0.01. A similar pattern was observed during AV0, but not during AV150, pacing. While supine, mean BP decrease was more pronounced during AVNRT and AV0 pacing (-26.1% and -32.1%, respectively) than during AV150 pacing (-8%, P = 0.02 and P = 0.07, respectively). This difference subsided 30 seconds after the onset of AVNRT or pacing. When upright, the mean BP time course was similar, but mean BP recovery during AVNRT was slower, and the difference between mean BP during AVNRT and AV150 persisted at 30 seconds. CONCLUSIONS: The initial mean BP decrease during AVNRT recovered gradually within 30 seconds. A short atrioventricular interval is associated with a greater mean BP decrease at the onset of tachycardia. These observations may explain clinical symptoms immediately after the onset of AVNRT.

Adult↗
PubMed2004

Syncope Evaluation in the Emergency Department Study (SEEDS): a multidisciplinary approach to syncope management.

BACKGROUND: The primary aim and central hypothesis of the study are that a designated syncope unit in the emergency department improves diagnostic yield and reduces hospital admission for patients with syncope who are at intermediate risk for an adverse cardiovascular outcome. METHODS AND RESULTS: In this prospective, randomized, single-center study, patients were randomly allocated to 2 treatment arms: syncope unit evaluation and standard care. The 2 groups were compared with chi2 test for independence of categorical variables. Wilcoxon rank sum test was used for continuous variables. Survival was estimated with the Kaplan-Meier method. One hundred three consecutive patients (53 women; mean age 64+/-17 years) entered the study. Fifty-one patients were randomized to the syncope unit. For the syncope unit and standard care patients, the presumptive diagnosis was established in 34 (67%) and 5 (10%) patients (P<0.001), respectively, hospital admission was required for 22 (43%) and 51 (98%) patients (P<0.001), and total patient-hospital days were reduced from 140 to 64. Actuarial survival was 97% and 90% (P=0.30), and survival free from recurrent syncope was 88% and 89% (P=0.72) at 2 years for the syncope unit and standard care groups, respectively. CONCLUSIONS: The novel syncope unit designed for this study significantly improved diagnostic yield in the emergency department and reduced hospital admission and total length of hospital stay without affecting recurrent syncope and all-cause mortality among intermediate-risk patients. Observations from the present study provide benchmark data for improving patient care and effectively utilizing healthcare resources.

Aged↗
PubMed2004

Age- and sex-related atrial electrophysiologic and structural changes.

Age and gender dependence of the 3 major variables--left atrial (LA) dimension, effective refractory period (ERP), and atrial conduction--that govern the development of atrial fibrillation (AF) were examined in 76 women and 39 men without structural heart disease. A significant positive correlation was found between age and LA dimension, mainly because of a strongly positive correlation in women not taking hormone replacement therapy but not in women on hormone replacement therapy. Men had a significantly greater average LA dimension than women. Neither ERP nor atrial conduction estimated by normalized P-wave duration demonstrated any significant correlation with either age or gender. It was concluded that LA size is greater in the elderly and in men, which may increase their risk for AF.

Adult↗
PubMed2004

Potassium channel openers are uncoupling protonophores: implication in cardioprotection.

Excessive build-up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability a proposed countermeasure. Here, we demonstrate that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitated transmembrane proton translocation generating H(+)-selective current through planar phospholipid membrane. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained in K(+)-free conditions and shared with the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4-dinitrophenol, but not 2,4-dinitrotoluene lacking protonophoric properties, preserved functional recovery of ischemic heart. The identified protonophoric property of potassium channel openers, thus, implicates a previously unrecognized component in their mechanism of cardioprotection.

Animals↗
PubMed2004

A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs.

BACKGROUND: The human cardiac SCN5A gene encodes for the alpha subunit of the human cardiac voltage-dependent sodium channel hNav1.5 [Neuron 28 (2) (2000) 365] and carries inward Na current (INa). Mutations in SCN5A cause arrhythmia syndromes including Brugada syndrome (BrS) and congenital long QT syndrome subtype 3 (LQT3). Here, we report a trafficking defective BrS-causing SCN5A mutation that was drug-rescued. METHODS AND RESULTS: A 14-year-old Caucasian male was diagnosed with BrS with typical ECG pattern for BrS and ventricular fibrillation was easily induced. He also had significant HV interval delay ( approximately 65 ms) and high (31 J) defibrillation thresholds (DFTs). Genomic analysis revealed the SCN5A mutation (G1743R). We engineered G1743R into the cardiac Na channel and transfected HEK-293 cells for functional studies. The mutant channel yielded nearly undetectable sodium channel currents. Coexpression with the beta1 subunit, or incubation at low temperature did not increase current density. However, mexiletine, a sodium channel blocker, increased current density 93-fold in G1743R, but only twofold in WT. CONCLUSIONS: This study identifies an expression-defective BrS mutation in SCN5A with pharmacological rescue. The profoundly decreased sodium current associated with the G1743R suggests a molecular basis for the delayed His-Purkinje conduction and elevated DFTs observed in the proband. Whether the mutant channel may be rescued in vivo by mexiletine and normalize the patient's electrophysiologic parameters remains to be tested.

Adolescent↗
PubMed2004

Genetic disruption of Kir6.2, the pore-forming subunit of ATP-sensitive K+ channel, predisposes to catecholamine-induced ventricular dysrhythmia.

Metabolic-sensing ATP-sensitive K+ channels (KATP channels) adjust membrane excitability to match cellular energetic demand. In the heart, KATP channel activity has been linked to homeostatic shortening of the action potential under stress, yet the requirement of channel function in securing cardiac electrical stability is only partially understood. Here, upon catecholamine challenge, disruption of KATP channels, by genetic deletion of the pore-forming Kir6.2 subunit, produced defective cardiac action potential shortening, predisposing the myocardium to early afterdepolarizations. This deficit in repolarization reserve, demonstrated in Kir6.2-knockout hearts, translated into a high risk for induction of triggered activity and ventricular dysrhythmia. Thus, intact KATP channel function is mandatory for adequate repolarization under sympathetic stress providing electrical tolerance against triggered arrhythmia.

Adenosine Triphosphate↗
PubMed2003

Significant effects of atrioventricular node ablation and pacemaker implantation on left ventricular function and long-term survival in patients with atrial fibrillation and left ventricular dysfunction.

Control of ventricular rate by atrioventricular node ablation and pacemaker implantation in patients with drug-refractory atrial fibrillation (AF) is associated with improved left ventricular (LV) function. The objective of this study was to determine the effect of atrioventricular node ablation on long-term survival in patients with AF and LV dysfunction. Survival was determined by the Kaplan-Meier method for 56 study patients with LV ejection fraction (EF) < or =40% who underwent atrioventricular node ablation and pacemaker implantation and 56 age- and gender-matched control patients with AF and LVEF >40%, and age- and gender-matched control subjects from Minnesota. Groups were compared using the log-rank test. In study patients (age 69 +/- 10 years; 45 men), LVEF was 26% +/- 8% and 34% +/- 13% (p <0.001) before and after ablation, respectively. During follow-up (40 +/- 23 months), 23 patients died. Observed survival was worse than that of normal subjects (p <0.001) and control patients (p = 0.005). After ablation, LVEF nearly normalized (> or =45%) in 16 study patients (29%), in whom observed survival was comparable to that of normal subjects (p = 0.37). Coronary artery disease, hyperlipidemia, chronic renal failure, previous myocardial infarction, and coronary artery operation were independent predictors for mortality. Near normalization of LVEF occurred in 29% of study patients, suggesting that AF-induced EF reduction is reversible in many patients. Normal survival in patients with reversible LV dysfunction highlights potential survival benefits of rate control. Poor survival in patients with persistent LV dysfunction confirms the importance of optimal medical therapy.

Aged↗
PubMed2003

Familial atrial fibrillation is a genetically heterogeneous disorder.

OBJECTIVES: The aims of this study were to identify and characterize familial cases of atrial fibrillation (AF) in our clinical practice and to determine whether AF is genetically heterogeneous. BACKGROUND: Atrial fibrillation is not generally regarded as a heritable disorder, yet a genetic locus for familial AF was previously mapped to chromosome 10. METHODS: Of 2,610 patients seen in our arrhythmia clinic during an 18-month study period, 914 (35%) were diagnosed with AF. Familial cases were identified by history and medical records review. Four multi-generation families with autosomal dominant AF (FAF 1 to 4) were tested for linkage to the chromosome 10 AF locus. RESULTS: Fifty probands (5% of all AF patients; 15% of lone AF patients) were identified with lone AF (age 41 +/- 9 years) and a positive family history (1 to 9 additional relatives affected). In FAF 1 to 3, AF was associated with rapid ventricular response. In contrast, AF in FAF-4 was associated with a slow ventricular response and, with progression of the disease, junctional rhythm and cardiomyopathy. Genotyping of FAF 1 to 4 with deoxyribonucleic acid markers spanning the chromosome 10q22-q24 region excluded linkage of AF to this locus. In FAF-4, linkage was also excluded to the chromosome 3p22-p25 and lamin A/C loci associated with familial AF, conduction system disease, and dilated cardiomyopathy. CONCLUSIONS: Familial AF is more common than previously recognized, highlighting the importance of genetics in disease pathogenesis. In four families with AF, we have excluded linkage to chromosome 10q22-q24, establishing that at least two disease genes are responsible for this disorder.

Adult↗
PubMed2003

Deletion of mtDNA disrupts mitochondrial function and structure, but not biogenesis.

The role of nuclear DNA (nDNA)-encoded proteins in the regulation of mitochondrial fission and fusion has been documented, yet the role of mitochondrial DNA (mtDNA) and encoded proteins in mitochondrial biogenesis remains unknown. Long-term treatment of a lymphoblastoid cell line Molt-4 with ethidium bromide generated mtDNA-deficient rho0 mutants. Depletion of mtDNA in rho0 cells produced functional and morphological changes in mitochondria without affecting the nuclear genome and encoded proteins. Indeed, the gene encoding subunit II of mitochondrial cytochrome c oxidase (COX II), a prototypical mitochondrial gene, was reduced in rho0 mutants blunting the activity of mitochondrial cytochrome coxidase. Yet, the amount of the nuclear beta-actin gene and the activity of citrate synthase, a mitochondrial matrix enzyme encoded by nDNA, remained unaffected in rho0 cells. Loss of mtDNA in rho0 cells was associated with significant distortion of mitochondrial structure, decreased electron density of the matrix and disorganized inner and outer membranes, resulting in the appearance of 'ghost-like' mitochondria. However, the number of mitochondria-like structures was not significantly different between mtDNA-deficient and parental cells. Thus, we conclude that cells lacking mtDNA still generate mitochondrial scaffolds, albeit with aberrant function.

Journal Article↗