Haroon Kamran

Cardiac repolarization indices in epilepsy patients.

Objectives: Although epilepsy may be associated with an increased risk for sudden cardiac death, its effects on Q-T intervals has not been established. Methods: To determine whether changes in Q-T interval duration (QTmax c, QTmin c) and dispersion (QTD c) occur in epileptic patients, we retrospectively studied 40 consecutive patients (age: 36.1 ± 22.2 years) who have had a seizure disorder for 14.0 ± 12.2 years and were seen in the Epilepsy Monitoring Unit, and 60 age-matched non-epileptic controls (age: 38.0 ± 15.6 years). Q-T intervals were calculated from a single 12-lead ECG. Results: QTmax c (425 ± 30 vs. 410 ± 36 ms, p = 0.040) and QTD c (63.1 ± 22.4 vs. 31.0 ± 17.2 ms, p = 0.000) were higher, and QTmin c (362 ± 36 vs. 379 ± 33 ms, p = 0.040) was lower in epilepsy patients. QTmax c was significantly correlated with disease duration (r = –0.35, p = 0.028) before, but not after age correction (r = –0.31, p = 0.053). Neither age nor reported recent seizure frequency was correlated with any repolarization index. Conclusions: QTmax c and QTD c are higher in epilepsy patients as compared to control subjects. While Q-T interval appears to be related to disease duration, particularly over the early history of disease, it is unrelated to patient age or recent reported seizure frequency.

Vagus nerve stimulation-induced bradyarrhythmias in rats

The autonomic consequences of seizures can be severe. Death can follow from autonomic overactivity that causes a parasympathetically mediated bradyarrhythmia. We studied the cardiovascular consequences of unilateral and bilateral stimulation of the distal segments of transected vagus nerve in rats anesthetized with urethane. The range of stimulation rates tested is comparable to the firing rates observed in vagus nerve during seizures. There was a consistent inverse relation between stimulus rate and heart rate with nodal block appearing at 5-10 Hz and minimum HR levels (cardiac standstill) occurring at 50 Hz. Cardiac standstill could last many seconds. Blood pressure during VNS was maintained during lower frequency VNS, but collapsed at frequencies > or =20 Hz to dramatically impair ventricular filling. Recovery of heart rate and blood pressure after VNS was rapid. In the presence of sympathetic co-activation (pharmacological or hypercapnia and/or hypoxia), mean arterial pressure was better maintained and there was much better ventricular filling, but cardiac performance was worse (e.g. ejection fraction derived from echocardiography). The combination of sympathetic and parasympathetic overactivity was sometimes associated with prolonged (> or =20 s) apneic periods during VNS. We conclude that an abrupt increase in parasympathetic activity on the order of 5 times the background of parasympathetic tone can produce transient bradyarrhythmias, and increases on the order of 20 times can produce cardiac standstill, sometimes accompanied by apnea. Our findings suggest that parasympathetically mediated bradyarrhythmia must be accompanied by airway obstruction to sustain parasympathetic overactivity and produce hypoxia to ultimately cause death.

Cardiac Lineage Protein-1 (CLP-1) Regulates Cardiac Remodeling via Transcriptional Modulation of Diverse Hypertrophic and Fibrotic Responses and Angiotensin II-transforming Growth Factor β (TGF-β1) Signaling Axis

Background: CLP-1 heterozygous mice exhibit enhanced susceptibility to cardiac stress. Results: Angiotensin-II-induced left ventricular hypertrophy and fibrosis were enhanced, and the Smad3 and Stat3 signaling was stimulated in CLP-1+/− mice. Conclusion: CLP-1 controls the hypertrophy and fibrotic response during cardiac remodeling. Significance: Our results offer the potential of targeting CLP-1 for therapeutic intervention in cardiac disease. It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-β1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an anti-fibrogenic and anti-hypertrophic role by blocking, among others, the TGF-β-induced nuclear localization of Smads. It is not clear how the hypertrophic and fibrotic responses are transcriptionally regulated. CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible-1 (HEXIM-1), regulates the pTEFb activity via direct association with pTEFb causing inhibition of the Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. It was recently reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3, suggesting that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis. In this study, we evaluated the role of CLP-1 in vivo in induction of left ventricular hypertrophy in angiotensinogen-overexpressing transgenic mice harboring CLP-1 heterozygosity. We observed that introduction of CLP-1 haplodeficiency in the transgenic α-myosin heavy chain-angiotensinogen mice causes prominent changes in hypertrophic and fibrotic responses accompanied by augmentation of Smad3/Stat3 signaling. Together, our findings underscore the critical role of CLP-1 in remodeling of the genetic response during hypertrophy and fibrosis.

Relation of autonomic and cardiac abnormalities to ventricular fibrillation in a rat model of epilepsy.

Cardiac autonomic, conduction, and structural changes may occur in epilepsy and may contribute to sudden unexpected death in epilepsy (SUDEP), e.g. by increasing the risk for ventricular fibrillation (VF). In a model of chronic seizures in rats, we sought to study (1) cardiac and autonomic derangements that accompany the epileptic state, (2) whether chronically seizing rats experienced more significant cardiac effects after severe acute seizures, and (3) the susceptibility of chronically seizing rats to VF arising from autonomic and hypoxemic changes, which commonly occur during seizures. Sprague-Dawely rats were injected with saline or kainic acid to induce chronic seizures. At 2-3 months or 7-11 months after injection, these rats were studied with both 12-lead electrocardiography (to assess heart rate variability and QT dispersion) and echocardiography under ketamine/xylazine or urethane anesthesia. Hearts were subsequently excised, weighed, and examined histologically. Epileptic rats exhibited decreased vagal tone, increased QT dispersion, and eccentric cardiac hypertrophy without significant cardiac fibrosis, especially at 7-11 months post-injection. Of these three findings, vagal tone was inversely correlated with heart weights. Epileptic rats exhibited diminished systolic function compared to controls after severe acute seizures. However, animals with long-standing chronic seizures were less susceptible to autonomic/hypoxemia-driven VF, and their susceptibility inversely correlated with mean left ventricular wall thickness on histology. On the basis of this model, we conclude that cardiac changes accompany epilepsy and these can lead to significant seizure-associated cardiac performance decreases, but these cardiac changes actually lower the probability of VF.

Effect of Reactive Hyperemia on Carotid-Radial Pulse Wave Velocity in Hypertensive Participants and Direct Comparison With Flow-Mediated Dilation: A Pilot Study

This pilot study assessed the effects of hyperemia on carotid-radial pulse wave velocity (PWV) in 39 normotensive (NT) and 23 hypertensive (HT) participants using applanation tonometry. Pulse wave velocity was measured at 1- and at 2-minute intervals. Baseline PWV was similar between the groups (P = .59). At 1 minute, PWV decreased (8.5 ± 1.2 to 7.1 ± 1.4 m/s, P < .001) in NT but not in HT (P = .83). Hyperemic PWV (ΔPWV) response differed between the groups (-16% vs + 1.0%, P < .001). On multivariate analysis, HT, not age or blood pressure was independently related to ΔPWV (R2 = .43, P < .01). Among patients with cardiovascular risk factors/disease, ΔPWV was inversely related to flow-mediated dilation (FMD; R 2 = .43, P < .003). Conclusion: hyperemia decreases PWV1min in NT but not in HT. ΔPWV is inversely related to FMD. Blunted hyperemic PWV response may represent impaired vasodilatory reserve.

Evaluation of arterial structure and function in pediatric patients with end‐stage renal disease on dialysis and after renal transplantation

Tawadrous H, Kamran H, Salciccioli L, Schoeneman MJ, Lazar J. Evaluation of arterial structure and function in pediatric patients with end‐stage renal disease on dialysis and after renal transplantation.

Relation of the Ankle Brachial Index to Left Ventricular Ejection Fraction

Low and high ankle brachial index (ABI) values are both a marker of peripheral arterial disease and associated with greater cardiovascular disease event rates. The objective of the present study was to determine whether the ABI is associated with left ventricular (LV) systolic function. We studied 175 patients (age 67 +/- 13 years, 58% men) referred for ABI determination who had had the LV ejection fraction (EF) determined using echocardiography within 14 days. The mean LVEF was 47 +/- 13%, mean ABI for the right leg was 0.93 +/- 0.32, and the mean ABI for the left leg was 0.94 +/- 0.26. Of the 175 patients, 91 (52%) had a low, 69 (39%) had a normal, and 15 (9%) had a high ABI. The mean LVEF increased in a stepwise manner from the low, to normal, to abnormally high ABI groups (43 +/- 13% vs 51 +/- 12% vs 57 +/- 5%, respectively; p <0.01). On ordinal regression analysis, ABI status was independently related to LVEF. For each 1% increase in LVEF, the odds of being in the higher category of ABI increased by 1.08 (95% confidence interval 1.02 to 1.12, p = 0.002). No significant interaction was seen between coronary artery disease and LVEF on the ABI (p = 0.48). In conclusion, the ABI might be influenced by LV systolic function, independent of coronary disease. LVEF should be considered when ABI values are used to evaluate and monitor cardiovascular risk in patients.

Passive leg raising induced brachial artery dilation: is an old technique a simpler method to measure endothelial function?

OBJECTIVES Passive leg raising (PLR) is a diagnostic maneuver that has been shown to cause brachial artery dilation (BAD). The objectives of this study were to compare BAD induced by PLR with flow mediated dilation (FMD), and to investigate the mechanism of PLR-BAD. We studied a total of 75 subjects with and without cardiovascular risk factors/disease in order to provide a wide range of FMD responses. METHODS Using ultrasound, PLR-BAD and FMD induced by release of arterial cuff occlusion were measured. RESULTS BA diameter increased from 0.33+0.06 at baseline to 0.35+/-0.06 cm (p<.001) (4.8% increase) upon PLR and from 0.33+/-0.06 to 0.37+/-0.06 (11.8%) upon hyperemia. PLR induced BAD was significantly correlated with FMD (r=.82, p<.001). On receiver operating characteristic analysis of the two techniques, the area under the curve was 0.86 (95% CI 0.79-0.94, p<.001). Heart rate variability measures remained unchanged upon PLR indicating minimal contributions from changes in autonomic activity. The combination of FMD and PLR did not result in greater BAD than did FMD alone consistent with a common underlying mechanism. Mean blood flow velocity increased prior to BAD suggesting that shear stress increases prior to BAD. CONCLUSIONS BAD occurs in response to PLR and is proportional to FMD, although the magnitude of PLR-BAD is less than half that of FMD. It appears to occur by the same endothelial dependent mechanism as FMD. PLR-BAD may be used as a surrogate measure of FMD to evaluate vascular function, and has the advantage of being simpler to perform.

Determinants of a blunted carotid-to-radial pulse wave velocity decline in response to hyperemia.

Carotid—radial pulse wave velocity (PWV) decreases in normal healthy individuals following hyperemia provoked by release of arterial cuff occlusion. To determine the effects of specific cardiovascular (CV) risk factors on the hyperemic PWV response, we measured PWV before and after brachial artery (BA) occlusion in 218 participants (66% males, age 56 ± 19 years), with and without CV risk factors/disease. ΔPWV ranged from -46% to +35% and values were normally distributed. On univariate analyses, ΔPWV correlated with age, hypertension (Htn), hypercholesterolemia, diabetes mellitus (DM), coronary disease, congestive heart failure (CHF), smoking, and mean arterial pressure (MAP). On multivariate analysis, ΔPWV was independently related to Htn (B = 4.56, P = .03) and CHF (B = 7.34, P = .008) and trended toward a higher MAP (B = .113, P = .067), DM (B = 4.01, P = .11), and hypercholesterolemia (B = 3.36, P = .12). In conclusion, hyperemic changes in carotid—radial PWV values are independently related to Htn and CHF and possibly DM and hyperlipidemia.

Comparison of passive leg raising and hyperemia on macrovascular and microvascular responses

Passive leg raising is a simple diagnostic maneuver that has been proposed as a measure of arterial vasodilator reserve and possibly endothelial function. While passive leg raising has previously been shown to lower blood pressure, increase flow velocity and cause brachial artery dilation, its effects on microvascular flow has not been well studied. Also, passive leg raising has been directly compared previously to upper arm but never to lower arm occlusion of blood flow induced hyperemia responses. We compared changes in macrovascular indices measured by brachial artery ultrasound and microvascular perfusion measured by Laser Doppler Flowmetry induced by passive leg raising to those provoked by upper arm and lower arm induced hyperemia in healthy subjects. Upper arm induced hyperemia increased mean flow velocity by 398%, induced brachial artery dilatation by 16.3%, and increased microvascular perfusion by 246% (p<.05 for all). Lower arm induced hyperemia increased flow velocity by 227%, induced brachial artery dilatation by 10.8%, and increased microvascular perfusion by 281%. Passive leg raising increased flow velocity by 29% and brachial artery dilatation by 5.6% (p<.05 for all), but did not change microvascular perfusion (-5%, p=ns). In conclusion, passive leg raising increases flow velocity orders of magnitude less than does upper arm or lower arm induced hyperemia. Passive leg raising-induced brachial artery dilatation is less robust than either of these hyperemic techniques. Finally, although upper arm and lower arm hyperemia elicits macrovascular and microvascular responses, passive leg raising elicits only macrovascular responses.