Publications by authors named "Kazi T Haq"

10 Publications

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Competing risks in patients with primary prevention implantable cardioverter-defibrillators: Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study.

Heart Rhythm 2021 Mar 6. Epub 2021 Mar 6.

Oregon Health & Science University, Portland, Oregon. Electronic address:

Background: Global electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear.

Objective: This purpose of this study was to investigate whether GEH is associated with sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies in patients with heart failure and PP ICDs.

Methods: We conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral on preimplant 12-lead electrocardiograms. Survival analysis using cause-specific hazard functions compared the strength of associations with 2 competing outcomes: sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies.

Results: We analyzed 2668 patients (mean age 63 ± 12 years; 23% female; 78% white; 43% nonischemic cardiomyopathy; left ventricular ejection fraction 28% ± 11% from 6 academic medical centers). After adjustment for demographic, clinical, device, and traditional electrocardiographic characteristics, SVG elevation (hazard ratio [HR] per 1SD 1.14; 95% confidence interval [CI] 1.04-1.25; P = .004), SVG azimuth (HR per 1SD 1.12; 95% CI 1.01-1.24; P = .039), SVG magnitude (HR per 1SD 0.75; 95% CI 0.66-0.85; P < .0001), and QRS-T angle (HR per 1SD 1.21; 95% CI 1.08-1.36; P = .001) were associated with appropriate ICD therapies. Sum absolute QRST integral had different associations in infarct-related cardiomyopathy (HR 1.29; 95% CI 1.04-1.60) and nonischemic cardiomyopathy (HR 0.78; 95% CI 0.62-0.96) (P = .022).

Conclusion: In patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with 2 competing outcomes.
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March 2021

Characteristics of Cardiac Memory in Patients with Implanted Cardioverter-defibrillators: The Cardiac Memory with Implantable Cardioverter-defibrillator (CAMI) Study.

J Innov Card Rhythm Manag 2021 Feb 15;12(2):4395-4408. Epub 2021 Feb 15.

Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.

This study sought to determine factors associated with cardiac memory (CM) in patients with implantable cardioverter-defibrillators (ICDs). Patients with structural heart disease [n = 20; mean age: 72.6 ± 11.6 years; 80% male; mean left ventricular ejection fraction (LVEF): 31.7 ± 7.6%; history of myocardial infarction in 75% and nonsustained ventricular tachycardia (NSVT) in 85%] and preserved atrioventricular conduction received dual-chamber ICDs for primary (80%) or secondary (20%) prevention. Standard 12-lead electrocardiograms were recorded in AAI and DDD modes before and after seven days of right ventricular (RV) pacing in DDD mode with a short atrioventricular delay. The direction (azimuth and elevation) and magnitude of spatial QRS, T, and spatial ventricular gradient vectors were measured before and after seven days of RV pacing. CM was quantified as the degree of alignment between QRS and T vectors (QRS -T angle). Circular statistics and mixed models with a random slope and intercept were adjusted for changes in cardiac activation, LVEF, known risk factors, and the use of medications known to affect CM occurring on days 1 through 7. The QRS-T angle strongly correlated (circular r = -0.972; p < 0.0001) with a T-T angle. In the mixed models, CM-T azimuth changes [+132° (95% confidence interval (CI): 80°-184°); p < 0.0001] were counteracted by the history of MI [-180° (95% CI: -320° to -40°); p = 0.011] and female sex [-162° (95% CI: -268° to -55°); p = 0.003]. A CM-T area increase [+15 (95% CI: 6-24) mV*ms; p < 0.0001] was amplified by NSVT history [+27 (95% CI: 4-46) mV*ms; p = 0.007]. These findings suggest that preexistent electrical remodeling affects CM in response to RV pacing, that CM exhibits saturation behavior, and that women reach CM saturation more easily than men.
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February 2021

Sex differences in vectorcardiogram of African-Americans with and without cardiovascular disease: a cross-sectional study in the Jackson Heart Study cohort.

BMJ Open 2021 01 31;11(1):e042899. Epub 2021 Jan 31.

Department of Medicine, Cardiovascular Division, Oregon Health & Science University School of Medicine, Portland, Oregon, USA

Objectives: We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH.

Design: Cross-sectional, cohort study.

Setting: Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000-2004 enrolled residents of the Jackson, Mississippi metropolitan area.

Participants: Participants from the JHS with analysable ECGs recorded in 2009-2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors' magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured.

Outcome: Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke.

Results: In adjusted mixed linear models, women had a smaller spatial QRS-T angle (-12.2 (95% CI -19.4 to -5.1)°; p=0.001) and SAI QRST (-29.8 (-39.3 to -20.3) mV*ms; p<0.0001) than men, but larger SVG azimuth (+16.2(10.5-21.9)°; p<0.0001), with a significant random effect between families (+20.8 (8.2-33.5)°; p=0.001). SAI QRST was larger in women with CVD as compared with CVD-free women or men (+15.1 (3.8-26.4) mV*ms; p=0.009). Men with CVD had a smaller T area (by 5.1 (95% CI 1.2 to 9.0) mV*ms) and T peak magnitude (by 44 (95%CI 16 to 71) µV) than CVD-free men. T vectors pointed more posteriorly in women as compared with men (peak T azimuth + 17.2(8.9-25.6)°; p<0.0001), with larger sex differences in T azimuth in some families by +26.3(7.4-45.3)°; p=0.006.

Conclusions: There are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation.
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January 2021

Applying Artificial Intelligence to ECG Analysis: Promise of a Better Future.

Circ Arrhythm Electrophysiol 2020 08 4;13(8):e009111. Epub 2020 Aug 4.

Knight Cardiovascular Institute, Department of Medicine, Oregon Health & Science University, School of Medicine, Portland.

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August 2020

Mechanisms of Arrhythmogenicity in Hypertrophic Cardiomyopathy: Insight From Non-invasive Electrocardiographic Imaging.

Front Physiol 2020 24;11:344. Epub 2020 Apr 24.

Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States.

Background: Mechanisms of arrhythmogenicity in hypertrophic cardiomyopathy (HCM) are not well understood.

Objective: To characterize an electrophysiological substrate of HCM in comparison to ischemic cardiomyopathy (ICM), or healthy individuals.

Methods: We conducted a prospective case-control study. The study enrolled HCM patients at high risk for ventricular tachyarrhythmia (VT) [ = 10; age 61 ± 9 years; left ventricular ejection fraction (LVEF) 60 ± 9%], and three comparison groups: healthy individuals ( = 10; age 28 ± 6 years; LVEF > 70%), ICM patients with LV hypertrophy (LVH) and known VT ( = 10; age 64 ± 9 years; LVEF 31 ± 15%), and ICM patients with LVH and no known VT ( = 10; age 70 ± 7 years; LVEF 46 ± 16%). All participants underwent 12-lead ECG, cardiac CT or MRI, and 128-electrode body surface mapping (BioSemi ActiveTwo, Netherlands). Non-invasive voltage and activation maps were reconstructed using the open-source SCIRun (University of Utah) inverse problem-solving environment.

Results: In the epicardial basal anterior segment, HCM patients had the greatest ventricular activation dispersion [16.4 ± 5.5 vs. 13.1 ± 2.7 (ICM with VT) vs. 13.8 ± 4.3 (ICM no VT) vs. 8.1 ± 2.4 ms (Healthy); = 0.0007], the largest unipolar voltage [1094 ± 211 vs. 934 ± 189 (ICM with VT) vs. 898 ± 358 (ICM no VT) vs. 842 ± 90 μV (Healthy); = 0.023], and the greatest voltage dispersion [median (interquartile range) 215 (161-281) vs. 189 (143-208) (ICM with VT) vs. 158 (109-236) (ICM no VT) vs. 110 (106-168) μV (Healthy); = 0.041]. Differences were also observed in other endo-and epicardial basal and apical segments.

Conclusion: HCM is characterized by a greater activation dispersion in basal segments, a larger voltage, and a larger voltage dispersion through LV.

Clinical Trial Registration: Unique identifier: NCT02806479.
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April 2020

Eligibility for subcutaneous implantable cardioverter-defibrillator in congenital heart disease.

Heart Rhythm 2020 05;17(5 Pt B):860-869

Oregon Health & Science University, Knight Cardiovascular Institute, Portland, Oregon. Electronic address:

Background: Adult congenital heart disease (ACHD) patients can benefit from a subcutaneous implantable cardioverter-defibrillator (S-ICD).

Objective: The purpose of this study was to assess left- and right-sided S-ICD eligibility in ACHD patients, use machine learning to predict S-ICD eligibility in ACHD patients, and transform 12-lead electrocardiogram (ECG) to S-ICD 3-lead ECG, and vice versa.

Methods: ACHD outpatients (n = 101; age 42 ± 14 years; 52% female; 85% white; left ventricular ejection fraction [LVEF] 56% ± 9%) were enrolled in a prospective study. Supine and standing 12-lead ECG were recorded simultaneously with a right- and left-sided S-ICD 3-lead ECG. Peak-to-peak QRS and T amplitudes; RR, PR, QT, QTc, and QRS intervals; Tmax, and R/Tmax (31 predictor variables) were tested. Model selection, training, and testing were performed using supine ECG datasets. Validation was performed using standing ECG datasets and an out-of-sample non-ACHD population (n = 68; age 54 ± 16 years; 54% female; 94% white; LVEF 61% ± 8%).

Results: Forty percent of participants were ineligible for S-ICD. Tetralogy of Fallot patients passed right-sided screening (57%) more often than left-sided screening (21%; McNemar χP = .025). Female participants had greater odds of eligibility (adjusted odds ratio [OR] 5.9; 95% confidence interval [CI] 1.6-21.7; P = .008). Validation of the ridge models was satisfactory for standing left-sided (receiver operating characteristic area under the curve [ROC AUC] 0.687; 95% CI 0.582-0.791) and right-sided (ROC AUC 0.655; 95% CI 0.549-0.762) S-ICD eligibility prediction. Validation of transformation matrices showed satisfactory agreement (<0.1 mV difference).

Conclusion: Nearly half of the contemporary ACHD population is ineligible for S-ICD. The odds of S-ICD eligibility are greater for female than for male ACHD patients. Machine learning prediction of S-ICD eligibility can be used for screening of S-ICD candidates.
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May 2020

Bringing Critical Race Praxis Into the Study of Electrophysiological Substrate of Sudden Cardiac Death: The ARIC Study.

J Am Heart Assoc 2020 02 30;9(3):e015012. Epub 2020 Jan 30.

Knight Cardiovascular Institute Oregon Health and Science University Portland OR.

Background Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological substrate with SCD varies between black and white individuals. Methods and Results Participants from the ARIC (Atherosclerosis Risk in Communities) study with analyzable ECGs (n=14 408; age, 54±6 years; 74% white) were included. Electrophysiological substrate was characterized by ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease, risk factors, and incident nonfatal cardiovascular disease. At the baseline visit, adjusted for age, sex, and study center, blacks had larger spatial ventricular gradient magnitude (0.30 mV; 95% CI, 0.25-0.34 mV), sum absolute QRST integral (18.4 mV*ms; 95% CI, 13.7-23.0 mV*ms), and Cornell voltage (0.30 mV; 95% CI, 0.25-0.35 mV) than whites. Over a median follow-up of 24.4 years, SCD incidence was higher in blacks (2.86 per 1000 person-years; 95% CI, 2.50-3.28 per 1000 person-years) than whites (1.37 per 1000 person-years; 95% CI, 1.22-1.53 per 1000 person-years). Blacks with hypertension had the highest rate of SCD: 4.26 (95% CI, 3.66-4.96) per 1000 person-years. Race did not modify an association of ECG variables with SCD, except QRS-T angle. Spatial QRS-T angle was associated with SCD in whites (hazard ratio, 1.38; 95% CI, 1.25-1.53) and hypertension-free blacks (hazard ratio, 1.52; 95% CI, 1.09-2.12), but not in blacks with hypertension (hazard ratio, 1.15; 95% CI, 0.99-1.32) (-interaction=0.004). Conclusions Race did not modify associations of electrophysiological substrate with SCD and non-SCD. Electrophysiological substrate does not explain racial disparities in SCD rate.
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February 2020

Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain-Specific Interaction: Implications for Purkinje Cell-Dependent Ventricular Arrhythmias.

Circ Arrhythm Electrophysiol 2018 01;11(1):e005800

From the Division of Cardiovascular Medicine and the Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison (R.V., H.V.E., S.E., E.C.M., L.L.E.); and Department of Pharmacology, University of California Davis (K.T.H., S.M., E.G.).

Background: In human cardiac ventricle, is mainly comprised Kir2.1, but Kir2.2 and Kir2.3 heterotetramers occur and modulate . Long-QT syndrome-9-associated mutations cause decreased Kir2.1 current density, but Kir2.x heterotetramers have not been studied. Here, we determine the effect of long-QT syndrome-9- mutation F97C on Kir2.x homo- and heterotetramers and model-associated arrhythmia mechanisms.

Methods And Results: Super-resolution microscopy, co-immunoprecipitation, cellular electrophysiology, on-cell Western blotting, and simulation of Purkinje and ventricular myocyte mathematical models were used. Kir2.x isoforms have unique subcellular colocalization in human cardiomyocytes and coimmunoprecipitate with Cav3. F97C-Cav3 decreased peak inward Kir2.2 current density by 50% (-120 mV; =0.019) and peak outward by 75% (-40 mV; <0.05) but did not affect Kir2.3 current density. FRET (Förster resonance energy transfer) efficiency for Kir2.2 with Cav3 is high, and on-cell Western blotting demonstrates decreased Kir2.2 membrane expression with F97C-Cav3. Cav3-F97C reduced peak inward and outward current density of Kir2.2/Kir2.1 or Kir2.2/Kir2.3 heterotetramers (<0.05). Only Cav3 scaffolding and membrane domains co-immunoprecipitation with Kir2.1 and Kir2.2 and Kir2.x-N-terminal Cav3 binding motifs are required for interaction. Mathematical Purkinje, but not ventricular, myocyte model incorporating simulated current reductions, predicts spontaneous delayed after-depolarization-mediated triggered activity.

Conclusions: Kir2.x isoforms have a unique intracellular pattern of distribution in association with specific Cav3 domains and that critically depends on interaction with N-terminal Kir2.x Cav3-binding motifs. Long-QT syndrome-9- mutation differentially regulates current density and cell surface expression of Kir2.x homomeric and heteromeric channels. Mathematical Purkinje cell model incorporating experimental findings suggests delayed after-depolarization-type triggered activity as a possible arrhythmia mechanism.
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January 2018

Cardiac expression of ryanodine receptor subtype 3; a strategic component in the intracellular Ca release system of Purkinje fibers in large mammalian heart.

J Mol Cell Cardiol 2017 03 20;104:31-42. Epub 2017 Jan 20.

Faculty of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland, St. John's, NL, Canada. Electronic address:

Background: Three distinct Ca release channels were identified in dog P-cells: the ryanodine receptor subtype 2 (RyR2) was detected throughout the cell, while the ryanodine receptor subtype 3 (RyR3) and inositol phosphate sensitive Ca release channel (InsP3R) were found in the cell periphery. How each of these channels contributes to the Ca cycling of P-cells is unclear. Recent modeling of Ca mobilization in P-cells suggested that Ca sensitivity of Cainduced Carelease (CICR) was larger at the P-cell periphery. Our study examined whether this numerically predicted region of Ca release exists in live P-cells. We compared the regional Ca dynamics with the arrangement of intracellular Ca release (CR) channels.

Methods: Gene expression of CR channels was measured by qPCR in Purkinje fibers and myocardium of adult Yucatan pig hearts. We characterized the CR channels protein expression in isolated P-cells by immuno-fluorescence, laser scanning confocal microscopy, and 3D reconstruction. The spontaneous Ca activity and electrically-evoked Ca mobilization were imaged by 2D spinning disk confocal microscopy. Functional regions of P-cell were differentiated by the characteristics of local Ca events. We used the Ca propagation velocities as indicators of channel Ca sensitivity.

Results: RyR2 gene expression was identical in Purkinje fibers and myocardium (6 hearts) while RyR3 and InsPR gene expressions were, respectively, 100 and 16 times larger in the Purkinje fibers. Specific fluorescent immuno-staining of Ca release channels revealed an intermediate layer of RyR3 expression between a near-membrane InsP3R-region and a central RyR2-region. We found that cell periphery produced two distinct forms of spontaneous Ca-transients: (1) large asymmetrical Ca sparks under the membrane, and (2) typical Ca-wavelets propagating exclusively around the core of the cell. Larger cell-wide Ca waves (CWWs) appeared occasionally traveling in the longitudinal direction through the core of Pcells. Large sparks arose in a micrometric space overlapping the InsP3R expression. The InsP3R antagonists 2-aminoethoxydiphenyl borate (2-APB; 3μM) and xestospongin C (XeC; 50μM) dramatically reduced their frequency. The Ca wavelets propagated in a 5-10μm thick layered space which matched the intermediate zone of RyR3 expression. The wavelet incidence was unchanged by 2-APB or XeC, but was reduced by 60% in presence of the RyR3 antagonist dantrolene (10μM). The velocity of wavelets was two times larger (86±16μm/s; n=14) compared to CWWs' (46±10μm/s; n=11; P<0.05). Electric stimulation triggered a uniform and large elevation of Ca concentration under the membrane which preceded the propagation of Ca into the interior of the cell. Elevated Ca propagated at 150μm/s (147±34μm/s; n=5) through the region equivalent to the zone of RyR3 expression. This velocity dropped by 50% (75±24μm/s; n=5) in the central region wherein predominant RyR2 expression was detected.

Conclusion: We identified two layers of distinct Ca release channels in the periphery of Pcell: an outer layer of InsPRs under the membrane and an inner layer of RyR3s. The propagation of Ca events in these layers revealed that Ca sensitivity of Ca release was larger in the RyR3 layer compared to that of other sub-cellular regions. We propose that RyR3 expression in P-cells plays a role in the stability of electric function of Purkinje fibers.
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March 2017

Evoked centripetal Ca(2+) mobilization in cardiac Purkinje cells: insight from a model of three Ca(2+) release regions.

J Physiol 2013 Sep 29;591(17):4301-19. Epub 2013 Jul 29.

B. D. Stuyvers: Memorial University, Faculty of Medicine, Division of BioMedical Sciences, 300 Prince Phillip Bd, St John's, NL, A1B 3V6, Canada.

Despite strong suspicion that abnormal Ca(2+) handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca(2+) cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca(2+) handling system. Notably complex spontaneous Ca(2+) activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca(2+) release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca(2+) transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca(2+) dynamics which was then used to reproduce numerically the Ca(2+) activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca(2+) release nodes arranged, respectively, into three consecutive adjacent regions. A system of partial differential equations (PDEs) expressed numerically the principal cellular functions that modulate the local cytosolic Ca(2+) concentration (Cai). The apparent node-to-node progression of elevated Cai was obtained by combining Ca(2+) diffusion and 'Ca(2+)-induced Ca(2+) release'. To provide the modelling with a reliable experimental reference, we first re-examined the Ca(2+) mobilization in swine stimulated P-cells by 2D confocal microscopy. As reported earlier for the dog and rabbit, a centripetal Ca(2+) transient was readily visible in 22 stimulated P-cells from six adult Yucatan swine hearts (pacing rate: 0.1 Hz; pulse duration: 25 ms, pulse amplitude: 10% above threshold; 1 mm Ca(2+); 35°C; pH 7.3). An accurate replication of the observed centripetal Ca(2+) propagation was generated by the model for four representative cell examples and confirmed by statistical comparisons of simulations against cell data. Selective inactivation of Ca(2+) release regions of the computational array showed that an intermediate layer of Ca(2+) release nodes with an ~30-40% lower Ca(2+) activation threshold was required to reproduce the phenomenon. Our computational analysis was therefore fully consistent with the activation of a triple layered system of Ca(2+) release channels as a mechanism of centripetal Ca(2+) signalling in P-cells. Moreover, the model clearly indicated that the intermediate Ca(2+) release layer with increased sensitivity for Ca(2+) plays an important role in the specific intracellular Ca(2+) mobilization of Purkinje fibres and could therefore be a relevant determinant of cardiac conduction.
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September 2013