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Biomedical subjects

Zoran B Popovic

Publications and source records attributed to Zoran B Popovic.

16 recordsLinked to original sources
PubMed2006

Stem cell therapy enhances electrical viability in myocardial infarction.

Clinical studies suggest increased arrhythmia risk associated with cell therapy for myocardial infarction (MI); however, the underlying mechanisms are poorly understood. We hypothesize that the degree of electrical viability in the infarct and border zone associated with skeletal myoblast (SKMB) or mesenchymal stem cell (MSC) therapy will determine arrhythmia vulnerability in the whole heart. Within 24 h of LAD ligation in rats, 2 million intramyocardially injected SKMB (n=6), intravenously infused MSC (n=7), or saline (n=7) was administered. One month after MI, cardiac function was determined and novel optical mapping techniques were used to assess electrical viability and arrhythmia inducibility. Shortening fraction was greater in rats receiving SKMB (17.8%+/-5.3%, p=0.05) or MSC (17.6%+/-3.0%, p<0.01) compared to MI alone (10.1%+/-2.2%). Arrhythmia inducibility score was significantly greater in SKMB (2.8+/-0.2) compared to MI (1.4+/-0.5, p=0.05). Inducibility score for MSC (0.6+/-0.4) was significantly lower than SKMB (p=0.01) and tended to be lower than MI. Optical mapping revealed that MSC therapy preserved electrical viability and impulse propagation in the border zone, but SKMB did not. In addition, injected SKMBs were localized to discrete cell clusters where connexin expression was absent. In contrast, infused MSCs engrafted in a more homogeneous pattern and expressed connexin proteins. Even though both MSC and SKMB therapy improved cardiac function following MI in rat, SKMB therapy significantly increased arrhythmia inducibility while MSC therapy tended to lower inducibility. In addition, only MSC therapy was associated with enhanced electrical viability, diffuse engraftment, and connexin expression, which may explain the differences in arrhythmia inducibility.

Animals↗
PubMed2006

Enhanced ventricular untwisting during exercise: a mechanistic manifestation of elastic recoil described by Doppler tissue imaging.

BACKGROUND: The cascade of events by which early diastolic left ventricular (LV) filling increases with exercise is not fully elucidated. Doppler tissue imaging (DTI) can detect myocardial motion, including torsion, whereas color M-mode Doppler (CMM) can quantify LV intraventricular pressure gradients (IVPGs). METHODS AND RESULTS: Twenty healthy volunteers underwent echocardiographic examination with DTI at rest and during submaximal supine bicycle exercise. We assessed LV long-/short-axis function, torsion, volume, inflow dynamics, and early diastolic IVPG derived from CMM data. LV torsion and untwisting velocity increased with exercise (torsion, 11+/-4 degrees to 24+/-8 degrees ; untwisting velocity, -2.0+/-0.7 to -5.6+/-2.3 rad/s) that was associated with an increase in IVPG (1.4+/-0.5 to 3.7+/-1.2 mm Hg). Untwisting in normal subjects occurred during isovolumic relaxation and early filling, significantly before long-axis lengthening or radial expansion. The clinical feasibility of this method was tested in 7 patients with hypertrophic cardiomyopathy (HCM); torsion was higher at rest but did not increase with exercise (16+/-4 degrees to 14+/-6 degrees), whereas untwisting was delayed and unenhanced (-1.6+/-0.8 to -2.3+/-1.2 rad/s). In concert, IVPG was similar at rest (1.2+/-0.3 mm Hg), but the exercise response was blunted (1.6+/-0.8 mm Hg). In normal subjects and HCM patients, there was a similar linear relation between IVPG and untwisting rate, with an overall correlation coefficient of r=0.75 (P<0.0001). CONCLUSIONS: LV untwisting appears to be linked temporally with early diastolic base-to-apex pressure gradients, enhanced by exercise, which may assist efficient LV filling, an effect that appears blunted in HCM. Thus, LV torsion and subsequent rapid untwisting appear to be manifestations of elastic recoil, critically linking systolic contraction to diastolic filling.

Adult↗
PubMed2006

Tissue synchronization imaging and optimal left ventricular pacing site in cardiac resynchronization therapy.

The optimal pacing site in cardiac resynchronization therapy (CRT) remains controversial. Tissue synchronization imaging is a novel echocardiographic technique that color-codes for areas of maximal delay in myocardial velocities. This study aimed to identify whether the left ventricular (LV) pacing lead position in CRT should be guided by a patient's area of maximal mechanical delay. Fifty-four patients with advanced heart failure were assessed echocardiographically before and 6 months after CRT. Response was analyzed according to the relation between the LV lead position and the area of maximal delay to peak velocity by tissue synchronization imaging in the first half of the ejection phase: group 1 (n = 22) had lead placement corresponding to the segment of maximal delay; group 2 (n = 13) had lead placement 1 segment adjacent; and group 3 (n = 19) had lead placement remote from this site. Evidence of LV reverse remodeling and improved systolic function was documented in group 1 (mean percentage decrease in end-systolic volume 23%) more than in group 2 (mean decrease 15%), and more than in group 3 (mean increase 8.9%, p <0.0001 compared with groups 1 and 2). In group 1, 16 of 22 patients had reverse remodeling (>15% decrease in end-systolic volume); reverse remodeling was seen in 7 of 13 patients in group 2 and 1 of 19 in group 3. The placing of the lead position proximal to the site of maximal delay by tissue synchronization imaging was correlated with reverse remodeling (r = 0.449, p = 001). Of 7 patients with delay confined to the septum and anterior wall only, none had evidence of reverse remodeling after CRT. In conclusion, pacing at the site of maximal mechanical delay was associated with reverse remodeling. Individually tailored LV lead positioning should be considered before CRT.

Adult↗
PubMed2006

Intraventricular pressure gradients in left ventricular aneurysms determined by color M-mode Doppler method: an animal study.

BACKGROUND: Left ventricular aneurysm (LVA) may affect diastolic intraventricular blood flow. Color M-mode (CMM) Doppler flow propagation patterns are abnormal in the presence of apical aneurysms. The aim of this study was to validate the accuracy of CMM echocardiography for assessing the existence and size of LVA and to determine the intraventricular pressure gradient in LVA. METHODS: CMM of the transmitral inflow in early diastole was obtained from the apical 4-chamber view in 19 sheep. The presence of the break point where the velocity decreased abruptly in the mitral inflow (point D) was determined and the distance between the apex and point D was measured. The intraventricular pressure difference between the base and the apex was measured by a catheter while it was calculated using CMM with the Euler equation. RESULTS: The presence of the break point D showed 84% sensitivity and 100% specificity for determining the existence of an LVA. Distance between the apex and point D correlated well with scar size. Catheter- and CMM-derived intraventricular pressure difference correlated and agreed well (y = 1.0 x -0.2, r = 0.94). CONCLUSIONS: The point of abrupt decrease in propagation velocity of the CMM recording indicated the presence and size of LVA. Intraventricular pressure gradients were determined noninvasively by CMM echocardiography with reasonable accuracy.

Animals↗
PubMed2006

Myocardial adaptation to short-term high-intensity exercise in highly trained athletes.

We aimed to clarify the myocardial adaptation to short-term high-intensity exercise among trained athletes. We screened 17 participants in the 2004 World Indoor Rowing Championships before and after a 2000-m sprint. Echocardiography included standard measurements and tissue Doppler-derived strain (epsilon), strain rate, and 2-dimensionally derived speckle-tracking imaging for left ventricular (LV) torsion. LV volumes and ejection fraction were unchanged after exercise. There was a reduction in early and an increase in late diastolic filling velocities and a decrease in the flow propagation velocity. Annular systolic velocities, slope of the systolic acceleration, septal and lateral epsilon, and speckle tracking-derived torsion were increased. The increased LV torsion was a result of increased basal and apical rotation. Right ventricular apical epsilon decreased. In conclusion, maximal intensity short-duration exercise was associated with attenuation of LV diastolic function, augmentation of LV systolic function, and a reduction in apical right ventricular contractility.

Adaptation, Physiological↗
PubMed2006

Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent.

Cell-based gene therapy to alter the myocardial tissue microenvironment has been shown to improve mechanical cardiac function, but little is known regarding its effects on arrhythmogenic risk. Clinical studies with skeletal myoblasts (SKMBs) have suggested a potential increase in arrhythmogenic risk. Therefore, we studied the functional mechanical and electrical effects of transient reestablishment of stem cell homing via transplantation of stromal-cell derived factor-1 (SDF-1)-expressing SKMBs. Eight weeks after anterior myocardial infarction, rats received in five divided doses into the periinfarct zone 1 million SKMBs transfected with AdSDF-1 (n=15) or AdGFP (n=8). Echocardiography was used to quantify changes in cardiac function, and optical mapping was used to determine the arrhythmogenic risk. Eight weeks after cell therapy, we observed a 54% (p=0.004) increase in shortening fraction in AdSDF-1:SKMB-treated rats, but only an 18.8% increase (p=not significant) with GFP:SKMB. SDF-1-treated hearts exhibited an increase in vascular density compared with control SKMBs (34.9+/-7.1 vs. 20.7+/-5.6 vessels/mm2; p<0.01). Optical mapping performed 8 weeks after cell therapy revealed that all animals that received SKMBs regardless of viral transfection had inducible ventricular tachycardia (VT) whereas only 50% of saline-treated animals had inducible VT (p<0.05). Transient reestablishment of stem cell homing via transplantation of modified SKMBs is sufficient to improve cardiac function. However, despite improved mechanical function, the risk of ventricular tachycardia increased. We propose that future studies on functional effects of cell-based gene therapies should address both mechanical and electrical consequences.

Adenoviridae↗
PubMed2005

Optical mapping of late myocardial infarction in rats.

Late myocardial infarction (MI) is associated with ventricular arrhythmias and sudden cardiac death. The exact mechanistic relationship between abnormal cellular electrophysiology, conduction abnormalities, and arrhythmogenesis associated with late MI is not completely understood. We report a novel, rapid dye superfusion technique to enable whole heart, high-resolution optical mapping of late MI. Optical mapping of action potentials was performed in normal rats and rats with anterior MI 7 days after left anterior descending artery ligation. Hearts from normal rats exhibited normal action potentials and impulse conduction. With the use of programmed stimulation to assess arrhythmia inducibility, 29% of hearts with late MI had inducible sustained ventricular tachycardia, compared with 0% in normal rats. A causal relationship between the site of infarction, abnormal action potential conduction (i.e., block and slow conduction), and arrhythmogenesis was observed. Optical mapping techniques can be used to measure high-resolution action potentials in a whole heart model of late MI. This experimental model reproduces many of the electrophysiological characteristics (i.e., conduction slowing, block, and ventricular tachycardia) associated with MI in patients. Importantly, the results of this study can enhance our ability to understand the interplay between cellular heterogeneity, conduction abnormalities, and arrhythmogenesis associated with MI.

Action Potentials↗
PubMed2005

Planimetric assessment of anatomic valve area overestimates effective orifice area in bicuspid aortic stenosis.

BACKGROUND: Although the continuity equation remains the noninvasive standard, planimetry using transesophageal echocardiography is often used to assess valve area for patients with aortic stenosis (AS). Not uncommonly, however, anatomic valve area (AVAA) obtained by planimetry overestimates continuity-derived effective valve area (AVAE) in bicuspid AS. METHODS: Transthoracic Doppler and transesophageal echocardiography were performed to obtain AVAE and AVAA in 31 patients with bicuspid AS (age 61 +/- 11 years) and 22 patients with degenerative tricuspid AS (age 71 +/- 13 years). Aortic root and left ventricular outflow tract dimensions and the directional angle of the stenotic jet were assessed in all patients. Using these data, a computational fluid dynamics model was constructed to test the effect of these variables in determining the relationship between AVAE and AVAA. RESULTS: For patients with tricuspid AS, the correlation between AVAA (1.15 +/- 0.36 cm2) and AVAE (1.13 +/- 0.46 cm2) was excellent (r = 0.91, P < .001, Delta = 0.02 +/- 0.21 cm2). However, AVAA was significantly larger (1.19 +/- 0.35 cm2) than AVAE (0.89 +/- 0.29 cm2) in the bicuspid AS group (r = 0.71, P < .001, Delta = 0.29 +/- 0.25 cm2). Computer simulation demonstrated that the observed discrepancy related to jet eccentricity. CONCLUSION: For a given anatomic orifice, functional severity tends to be greater in bicuspid AS than in tricuspid AS. This appears to be primarily related to greater jet eccentricity and less pressure recovery.

Anatomy, Cross-Sectional↗
PubMed2004

Effects of sodium nitroprusside in aortic stenosis associated with severe heart failure: pressure-volume loop analysis using a numerical model.

In the recently published clinical study [Use of Nitroprusside in Left Ventricular Dysfunction and Obstructive Aortic Valve Disease (UNLOAD)], sodium nitroprusside (SNP) improved cardiac function in patients with severe aortic stenosis (AS) and left ventricular (LV) systolic dysfunction. We explored the possible mechanisms of these findings using a series of numerical simulations. A closed-loop lumped parameters model that consists of 24 differential equations relating pressure and flow throughout the circulation was used to analyze the effects of varying hemodynamic conditions in AS. Hemodynamic data from UNLOAD study subjects were used to construct the initial simulation. Systemic vascular resistance (SVR), heart rate, and aortic valve area were directly entered into the model while end-systolic and end-diastolic pressure-volume (P-V) relationships were adjusted using previously published data to match modeled and observed end-systolic and end-diastolic pressures and volumes. Initial simulation of SNP treatment by a reduction of SVR was not adequate. To obtain realistic model hemodynamics that reliably reproduce SNP treatment effects, we performed a series of simulations while simultaneously changing end-systolic elastance (E(es)), end-systolic volume at zero pressure (V(0)), and diastolic P-V shift. Our data indicate that either an E(es) increase or V(0) decrease is necessary to obtain realistic model hemodynamics. In five patients, we corroborated our findings by using the model to duplicate individual P-V loops obtained before and during SNP treatment. In conclusion, using a numerical model, we identified ventricular function parameters that are responsible for improved hemodynamics during SNP infusion in AS with LV dysfunction.

Aortic Valve Stenosis↗
PubMed2004

Coupled pacing improves cardiac efficiency during acute atrial fibrillation with or without cardiac dysfunction.

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction (CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.

Acute Disease↗
PubMed2003

Determinants of LV diastolic function during atrial fibrillation: beat-to-beat analysis in acute dog experiments.

Left ventricular (LV) diastolic function during atrial fibrillation (AF) remains poorly understood due to the complex interaction of factors and beat-to-beat variability. The purpose of the present study was to elucidate the physiological determinants of beat-to-beat changes in LV diastolic function during AF. The RR intervals preceding a given cardiac beat were measured from the right ventricular electrogram in 12 healthy open-chest mongrel dogs during AF. Doppler echocardiography and LV pressure and volume beat-to-beat analyses were performed. The LV filling time (FT) and early diastolic mitral inflow velocity-time integral (E(vti)) were measured using the pulsed Doppler method. The LV end-diastolic volume (EDV), peak systolic LV pressure (LVP), minimum value of the first derivative of LV pressure curve (dP/dt(min)), and the time constant of LV pressure decay (tau) were evaluated with the use of a conductance catheter for 100 consecutive cardiac cycles. Beat-to-beat analysis revealed a cascade of important causal relations. LV-FT showed a significant positive linear relationship with E(vti) (r = 0.87). Importantly, there was a significant positive linear relationship between the RR interval and LV-EDV in the same cardiac beat (r = 0.53). Consequently, there was a positive linear relationship between LV-EDV and subsequent peak systolic LVP (r = 0.82). Furthermore, there were significant positive linear and negative curvilinear relationships between peak systolic LVP and dP/dt(min) (r = 0.95) and tau (r = -0.85), respectively, in the same cardiac beat. In addition, there was a significant negative curvilinear relationship between dP/dt(min) and tau (r = -0.86). We have concluded that the determinants of LV diastolic function in individual beats during AF depend strongly on the peak systolic LVP. This suggests that the major benefit of slower ventricular rate appears related to lengthening of LV filling interval, promoting subsequent higher peak systolic LVP and greater LV relaxation.

Animals↗
PubMed2003

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.

BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

Animals↗
PubMed2003

Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: The distribution and magnitude of left ventricular hypertrophy are not uniform in patients with hypertrophic cardiomyopathy (HCM). Previous echocardiographic studies have focused on global left ventricular function. Recently, myocardial Doppler strain (epsilon) imaging, a newly developed technique, has allowed the quantification of regional myocardial motion. The aim of this study was to characterize regional left ventricular systolic function by myocardial Doppler epsilon imaging in patients with HCM. METHODS: Included in this study were 31 patients with asymmetric septal hypertrophy and HCM, and 41 age-matched healthy patients. Regional longitudinal axial systolic epsilon was assessed at the basal, mid, and apical segments of the septal and lateral walls and compared between both groups. RESULTS: Patients with HCM had reduced epsilon at the ventricular septum (-10.3 +/- 5.7%) compared with control patients (-19.4 +/- 3.3%, P <.001). In the HCM group, epsilon in the midseptum (-1.3 +/- 8.2%) was significantly less than at the basal (-12.2 +/- 8.7%, P <.01) and apical septum (-17.3 +/- 10.4%, P <.01), and was also less than at the midlateral wall (-9.4 +/- 5.3%, P <.05). There was a significant correlation between midseptal epsilon and intraventricular septum to posterior wall thickness ratio (r = 0.81, P <.001). CONCLUSION: Midseptal longitudinal epsilon was markedly decreased, even reversed in patients with HCM (paradoxic longitudinal systolic expansion), which was directly related to the degree of septal hypertrophy. Myocardial Doppler epsilon imaging could offer a unique approach to quantify regional systolic dysfunction in these patients.

Adult↗
PubMed2002

Pulmonary venous flow determinants of left atrial pressure under different loading conditions in a chronic animal model with mitral regurgitation.

BACKGROUND: The aim of our study was to quantitatively compare the changes and correlations between pulmonary venous flow variables and mean left atrial pressure (mLAP) under different loading conditions in animals with chronic mitral regurgitation (MR) and without MR. METHODS: A total of 85 hemodynamic conditions were studied in 22 sheep, 12 without MR as control (NO-MR group) and 10 with MR (MR group). We obtained pulmonary venous flow systolic velocity (Sv) and diastolic velocity (Dv), Sv and Dv time integrals, their ratios (Sv/Dv and Sv/Dv time integral), mLAP, left ventricular end-diastolic pressure, and MR stroke volume. We also measured left atrial a, x, v, and y pressures and calculated the difference between v and y pressures. RESULTS: Average MR stroke volume was 10.6 +/- 4.3 mL/beat. There were good correlations between Sv (r = -0.64 and r = -0.59, P <.01), Sv/Dv (r = -0.62 and r = -0.74, P <.01), and mLAP in the MR and NO-MR groups, respectively. Correlations were also observed between Dv time integral (r = 0.61 and r = 0.57, P <.01) and left ventricular end-diastolic pressure in the MR and NO-MR groups. In velocity variables, Sv (r = -0.79, P <.001) was the best predictor of mLAP in both groups. The sensitivity and specificity of Sv = 0 in predicting mLAP 15 mm Hg or greater were 86% and 85%, respectively. CONCLUSION: Pulmonary venous flow variables correlated well with mLAP under altered loading conditions in the MR and NO-MR groups. They may be applied clinically as substitutes for invasively acquired indexes of mLAP to assess left atrial and left ventricular functional status.

Animals↗