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ABSTRACT: Myocardial restoration using tissue-engineered grafts to regenerate the ischemic myocardium offers improved donor cell retention, yet a limited cell survival resulting from poor vascularization needs to be addressed. A cell type derived from the subamnion, namely, cord-lining mesenchymal stem cells (CL-MSC), has recently been identified. Here we present a restorative strategy that combines a fibrin graft containing human CL-MSC and omental flap providing, thereby, cell-, structural-, and angiogenic support to the injured myocardium. The graft consisted of a mixture of 2×106 CL-MSC-GFP-Fluc and fibrin. Myocardial infarction (MI) was induced in nude rats and following confirmation of ensued heart failure with echocardiography 2 weeks after injury, therapeutic intervention was performed as follows: untreated (MI, n=7), CL-MSC graft (CL-MSCG, n=8), CL-MSCG and omental flap (CL-MSCG+OM, n=11), and omental flap (OM, n=8). In vivo bioluminescence imaging at 1, 3, 7, and 14 days post-treatment indicated comparable early donor cell viability between the CL-MSCG and CL-MSCG+OM. Treatment with CL-MSCG+OM improved the myocardial function as assessed by the measurement of end-diastolic left ventricular (LV) pressure (3.53±0.34 vs. 5.21±0.54 mmHg, p<0.05), contractility (+dP/dt, 3383.8±250.78 mmHg vs. 2464.9±191.8 mmHg, p<0.05), and the relaxation rate (-dP/dt, -2707.2±250.7 mmHg vs. 1948.7±207.8 mmHg, p<0.05), compared to MI control 6 weeks after ischemic injury. Furthermore, evidence of a 20.32% increase in the ejection fraction was observed in CL-MSCG+OM rats from week 2 to 6 after injury. Both CL-MSCG and CL-MSCG+OM led to an enhanced cardiac output (p<0.05), and attenuated the infarct size (35.7%±4.2% and 34.7%±4.8%), as compared to MI (60.7%±3.1%; p<0.01 and p<0.001, respectively). All treated groups had a higher arteriole density than controls. Yet, a higher amount of functional blood vessels, and a 20-fold increase in arteriole numbers were found in CL-MSCG+OM. Altogether, CL-MSCGs supplemented with vascular supply have the potential to repair the failing, chronically ischemic heart by improving myocardial revascularization, attenuating remodeling, and ameliorating cardiac dysfunction.
Tissue Engineering Part A 02/2013; · 4.64 Impact Factor
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Journal of the American College of Cardiology 01/2012; 59(2):e3. · 14.16 Impact Factor
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ABSTRACT: Angiogenesis plays a key role in post-ischaemic myocardial repair. We hypothesized that epicardial implantation of an ascorbic acid (AA)-enriched myocardial artificial graft (MAG), which has been prevascularized in the recipients' own body, promotes restoration of the ischaemic heart. Gelatin patches were seeded with GFP-luciferase-expressing rat cardiomyoblasts and enriched with 5 μ m AA. Grafts were prevascularized in vivo for 3 days, using a renal pouch model in rats. The MAG patch was then implanted into the same rat's ischaemic heart following myocardial infarction (MI). MAG-treated animals (MAG group, n = 6) were compared to untreated infarcted animals as injury controls (MI group, n = 6) and sham-operated rats as healthy controls (healthy group, n = 7). In vivo bioluminescence imaging indicated a decrease in donor cell survival by 83% during the first week post-implantation. Echocardiographic and haemodynamic assessment 4 weeks after MI revealed that MAG treatment attenuated left ventricular (LV) remodelling (LV end-systolic volume, 0.31 ± 0.13 vs 0.81 ± 0.01 ml, p < 0.05; LV end-diastolic volume 0.79 ± 0.33 vs 1.83 ± 0.26 ml, p < 0.076) and preserved LV wall thickness (0.21 ± 0.03 vs 0.09 ± 0.005 cm, p < 0.05) compared to the MI group. Cardiac output was higher in MAG than MI (51.59 ± 6.5 vs 25.06 ± 4.24 ml/min, p < 0.01) and comparable to healthy rats (47.08 ± 1.9 ml/min). Histology showed decreased fibrosis, and a seven-fold increase in blood vessel density in the scar area of MAG compared to MI group (15.3 ± 1.1 vs 2.1 ± 0.3 blood vessels/hpf, p < 0.0001). Implantation of AA-enriched prevascularized grafts enhanced vascularity in ischaemic rat hearts, attenuated LV remodelling and preserved LV function. Copyright © 2011 John Wiley & Sons, Ltd.
Journal of Tissue Engineering and Regenerative Medicine 10/2011; · 3.28 Impact Factor
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ABSTRACT: Previous studies have demonstrated that mitral annulus early diastolic (e') velocity is increased in constrictive pericarditis (CP) and reduced in restrictive cardiomyopathy. However, those studies did not comprehensively evaluate mitral and tricuspid annular velocities before and after pericardiectomy.
We performed comprehensive echocardiography before and after pericardiectomy in 99 patients with CP, 52 with primary (idiopathic or postpericarditis etiology) and 47 with secondary CP (due to surgery or radiation). Overall, mean ± SD mitral medial, mitral lateral, and tricuspid lateral e' velocities were 12.2 ± 4.2, 10.0 ± 5.4, and 11.6 ± 3.5 cm/s, respectively; annular late diastolic velocities were 10.3 ± 4.3, 12.2 ± 4.9, and 11.7 ± 5.4 cm/s, respectively; and annular systolic (s') velocities were 7.8 ± 2.8, 8.2 ± 2.1, and 11.2 ± 3.8 cm/s, respectively. Medial e' was equal to or greater than mitral lateral e' in 74% of analyzable cases. With the exception of tricuspid s', there were significant differences in all s' and e'velocities between primary and secondary CP before pericardiectomy. After pericardiectomy, all annular velocities decreased significantly (P < 0.02 for all comparisons). The reduction in medial e' velocity was greater than that of mitral lateral e' velocity (P < 0.0001 and P = 0.0004, respectively), and the mitral lateral/medial e' ratio normalized (P = 0.0002).
The mitral lateral/medial e' ratio is reversed in three fourths of patients with CP. All annular velocities are lower in secondary compared to primary CP before pericardiectomy. After pericardiectomy, there is reduction of all annular velocities and normalization of the mitral lateral/medial e' ratio.
Circulation Cardiovascular Imaging 05/2011; 4(4):399-407. · 5.94 Impact Factor
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ABSTRACT: Most patients with constrictive pericarditis have normal measures of left ventricular function when assessed by the ejection phase index of ejection fraction, yet there is a wide spectrum of outcome after pericardiectomy. We hypothesized that parameters of non-ejection indexes of cardiac function (+dP/dt and tau) may predict postoperative prognosis.
The immediate and long-term outcomes of pericardiectomy were analyzed in 40 patients (30 male, mean age 62 years) with surgically confirmed constrictive pericarditis who underwent preoperative cardiac catheterization using high-fidelity micromanometer pressures. Left ventricular pressures were digitized at 5-msec intervals during end expiration, from which peak positive dp/dt and tau measurements were obtained. Patients were classified into 3 groups: Group 1 (n = 13) included those with abnormal +dP/dt and tau (defined as +dP/dt < 1200 mm Hg/s, tau > 50 msec); group 2 (n = 11) included those with either abnormal +dP/dt or tau; and group 3 (n = 16) included those with normal +dP/dt and tau.
There were no significant differences of gender, New York Heart Association class, duration of symptoms, and underlying cause among the 3 groups. Group 1 patients had lower preoperative ejection fraction and higher left and right ventricular end-diastolic pressures. Postoperative inotropic support was more frequently needed in group 1, and postoperative mortality was higher in group 1 than in groups 2 and 3. All postoperative deaths but 1 were in group 1. The median postoperative follow-up was 2.4 years. The postoperative long-term survival of group 1 was significantly lower compared with that of groups 2 and 3.
In patients with constrictive pericarditis undergoing pericardiectomy, those with abnormal left ventricular contractility and relaxation properties assessed by cardiac catheterization before surgery incur higher operative mortality and poor long-term outcome after surgery.
The Journal of thoracic and cardiovascular surgery 12/2008; 136(5):1136-41. · 3.41 Impact Factor
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ABSTRACT: B-type natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) are biomarkers of cardiovascular disease that is common in patients with chronic kidney disease (CKD). Conflicting data on the influence of glomerular filtration rate (GFR) on BNP and NT-proBNP levels in CKD may stem from failure to account fully for the effects of coexistent cardiac disease, dysfunction, and volume overload.
Prospective head-to-head comparison of plasma BNP and NT-proBNP in ambulatory euvolemic CKD patients with normal LV ejection fraction and no manifest cardiac or vascular disease. GFR was estimated by the Modification of Diet in Renal Disease formula, BNP and NT-proBNP measured using Abbott AxSYM and Roche Elecsys assays, respectively, and cardiac morphology and function assessed by transthoracic echocardiography.
In 142 patients (42% female) of mean age 60 +/- 11 yr, mean left ventricular ejection fraction was 71% +/- 6%, GFR 38 +/- 14 ml/min per 1.73 m(2), and median BNP and NT-proBNP level 59 and 311 pg/ml, respectively. Multivariate predictors of NT-proBNP level were GFR, beta-blocker usage, LV mass index, and hemoglobin level. Plasma BNP was independently predicted by LV mass index and beta-blocker usage but not GFR. In the 74 patients without diastolic dysfunction, there was a significant rise in NT-proBNP but not BNP as GFR declined.
Unlike NT-proBNP, plasma BNP level is relatively independent of GFR. BNP may therefore be the more appropriate biomarker to screen for cardiac dysfunction in CKD.
Clinical Journal of the American Society of Nephrology 11/2008; 3(6):1644-51. · 5.23 Impact Factor
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ABSTRACT: Left ventricular mass (LVM) is an independent risk factor for cardiovascular outcome. We aimed to define normal reference values of LVM/body surface area (BSA) in a multiethnic Southeast Asian population across ages, and define demographic parameters that predict LVM/BSA.
198 subjects (44% men, mean age 40 +/- 14 years, 82% Chinese, 13% Malay and 5% Indian) with no cardiovascular comorbidity and had normal echo images for age were included in the analysis. Echo LVM was calculated as: 1.04 x[(left ventricular internal diameter at end-diastole [LVIDd]+ interventricular septal thickness at end-diastole [IVSd]+ left ventricular posterior wall thickness at end-diastole [LVPWd])(3)- LVIDd(3)x 0.8]+ 0.6(1), indexed by BSA (LVM/BSA)* and expressed as g/m(2).
BSA and blood pressure (BP) were comparable between dichotomous age groups < or >or= 50 years within the same gender. Women aged >or= 50 years had larger IVSD, LVPWd, LVM and LVM/BSA compared to younger cohort. (p < 0.01 for all variables). The 95th percentile of LVM in men and women were 189 g and 148 g respectively; corresponding values for LVM/BSA were 106 and 96 g/m(2). These values are consistently smaller than published values from the West. Age (r = 0.27, P < 0.001), gender (r =-0.30, P < 0.001), and systolic BP (r = 0.25, P = 0.003) were significant univariate predictors of LVM/BSA.
We therefore propose a different cutoff value for the diagnosis of LV hypertrophy among Southeast Asians.
Echocardiography 10/2008; 25(8):805-11. · 1.24 Impact Factor
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ABSTRACT: Intact left atrial booster pump function helps maintain cardiac compensation in patients with aortic valve stenosis (AS). Because late diastolic mitral annular (A') velocity reflects left atrial systolic function, we hypothesized that A' velocity correlates with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level and clinical outcome in AS.
We prospectively enrolled 53 consecutive patients (median age 74 years) with variable degrees of AS, in sinus rhythm, and left ventricular ejection fraction greater than 50%. Indices of valvular stenosis, left ventricular diastolic dysfunction, and mitral annular motion were correlated with plasma NT-proBNP and a composite clinical end point comprising cardiac death and symptom-driven aortic valve replacement.
Tissue Doppler echocardiographic parameters, including early diastolic (E') velocity and A' velocity and ratio of early diastolic transmitral (E) to E' velocity (E/E') at the annular septum correlated better with NT-proBNP levels than body surface area-indexed aortic valve area. Eighteen patients had the composite end point, which was univariately predicted by body surface area-indexed aortic valve area, NT-proBNP, and all tissue Doppler echocardiographic indices. This outcome was most strongly predicted by the combination of septal A' velocity and E/E' ratio in bivariate Cox modeling. Septal annular A' velocity less than 9.6 cm/s was associated with significantly reduced event-free survival (Kaplan Meier log rank = 27.3, P < .0001) and predicted the end point with a sensitivity, specificity, and accuracy of 94%, 80%, and 85%, respectively.
In patients with AS and normal ejection fraction, annular tissue Doppler echocardiographic indices may better reflect the physiologic consequences of afterload burden on the left ventricle than body surface area-indexed aortic valve area. Lower A' velocity is a predictor of cardiac death and need for valve surgery, suggesting an important role for compensatory left atrial booster pump function.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 05/2008; 21(5):475-81. · 2.98 Impact Factor
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ABSTRACT: Little is known regarding the tissue Doppler characteristics and clinical significance of mitral annular motion during diastasis (L' wave).
In consecutive patients with left ventricular hypertrophy and normal ejection fraction, standard Doppler and Doppler tissue imaging were performed. Patients were followed up for heart failure (HF) hospitalization.
Of 177 patients, 53 (30%) had an L', detected most frequently at the lateral mitral annulus, whereas 35 (20%) had middiastolic transmitral flow (L wave), which almost invariably coexisted with the L'. The L' predicted increased left ventricular filling pressure with 74% sensitivity and 82% specificity, and increased risk of future HF (hazard ratio 3.9 [P = .030]), even after adjusting for baseline clinical differences (hazard ratio 6.5 [P = .024]). When associated with an L wave, HF risk increased further.
Middiastolic annular motion, detectable in almost a third of patients with left ventricular hypertrophy, may be an early marker of diastolic dysfunction and a prognostic marker for HF.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 03/2008; 21(2):165-70. · 2.98 Impact Factor
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ABSTRACT: Detection of viable myocardium (VM) has important therapeutic implications for chronic ischemic left ventricular (LV) systolic dysfunction. We compared the ability of nitroglycerin-dobutamine echocardiography (NTG-DE), intracoronary myocardial contrast echocardiography (MCE), and rest-redistribution thallium 201 single-photon emission computed tomography (RRT-SPECT) to detect VM in this setting.
Patients with LV ejection fraction (LVEF) <40% and multivessel coronary disease suitable for revascularization underwent NTG-DE, MCE, RRT-SPECT, and radionuclide ventriculography to determine baseline LVEF. Myocardial contrast echocardiography was performed using intracoronary injection of Albunex. Patients who underwent revascularization had 3-month postprocedural radionuclide ventriculography and transthoracic echocardiography to assess functional recovery.
Of 512 myocardial segments in the 32 patients studied, 309 were akinetic or dyskinetic at baseline. Nitroglycerin alone increased regional thickening in 20% of segments with contractile reserve. By RRT-SPECT, 93% of nitroglycerin-responsive segments were viable. Myocardial contrast echocardiography had up to 85% sensitivity and 74% specificity for detection of VM diagnosed by RRT-SPECT. In the 23 patients who underwent revascularization, 54% of akinetic segments showed improved contractility, and mean LVEF increased from 32% to 37% (P = .04). Sensitivities and specificities for detecting functional recovery were 95% and 37% for RRT-SPECT, up to 87% and 48% for MCE, and 63% and 83% for a biphasic response during NTG-DE.
In patients with chronic ischemic LV dysfunction, RRT-SPECT had the highest sensitivity, and NTG-DE, the best specificity for detection of VM. Nitroglycerin facilitated detection of VM and may be a useful adjunct to dobutamine stimulation.
American heart journal 04/2006; 151(4):882-9. · 4.65 Impact Factor
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International Journal of Cardiology 03/2006; 107(1):123-5. · 7.08 Impact Factor
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ABSTRACT: We sought to examine the relationship of the mitral L wave with echocardiographic indexes of diastolic function and heart failure (HF) events in patients with left ventricular (LV) hypertrophy (LVH).
The L wave, representing middiastolic transmitral flow, is of unknown clinical and prognostic significance in patients with LVH. Methods Consecutive echocardiograms performed during a 6-month period were screened for patients with LVH, normal LV ejection fraction, in sinus rhythm, and no significant valvular disease. Clinical and echocardiographic characteristics were analyzed, and patients were followed up for incident HF.
Of 177 patients, the L wave was present in 35 (20%) (group I) and absent in 142 (group II). Patients in group I had higher early (E) to late (A) transmitral flow velocity (E/A) ratio (1.2 vs 0.8), shorter mitral E wave deceleration time (201 vs 225 milliseconds), lower pulmonary venous systolic/diastolic velocity ratio (1.1 vs 1.6), shorter LV isovolumic relaxation time (83 vs 94 milliseconds), larger left atrial volume (36 vs 23 mL/m 2 ), and higher E to early mitral annular velocity (E/E') ratio (septal E/E', 12.2 vs 9.1; lateral annular E/E', 10.9 vs 7.8) compared with group II (all P < .05). The difference between pulmonary venous atrial reversal and mitral A wave durations was > or = 30 milliseconds in more patients of group I (70% vs 6%, P < .001). During a mean follow-up of 12.0 months, 11 patients were hospitalized for HF. The L wave was associated with a hazard ratio of 4.7 ( P = .011) for incident HF, and remained a significant predictor (hazard ratio 4.2, P = .026) after adjustment for cardiovascular risk factors.
In patients with LVH, the mitral L wave appears to be a marker of pseudonormal LV filling and predictor of future HF events.
Journal of the American Society of Echocardiography 05/2005; 18(4):336-41. · 3.71 Impact Factor
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Advances in cardiology 02/2004; 41:95-107.
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ABSTRACT: Respiratory variation of 25% or more in transmitral early diastolic filling (E) velocity is a well-recognized diagnostic feature of constrictive pericarditis (CP) that is useful for distinguishing it from restrictive cardiomyopathy. However, a subset of patients with CP do not exhibit the typical respiratory change. Recent data showed that mitral annular (E') velocity measured by Doppler tissue echocardiography (DTE) is markedly reduced in patients with restrictive cardiomyopathy whereas E' velocity is well-preserved in CP. This study evaluated the role of DTE for the diagnosis of CP when there is no characteristic respiratory variation of E velocity. From September 1999 to March 2001, 19 patients (17 men, 2 women; mean age, 57 +/- 13 years) with surgically confirmed CP underwent comprehensive echocardiography preoperatively, including pulsed wave and DTE examination with simultaneous recording of respiration. Nine (47%) of the 19 patients had less than 25% respiratory variation in E velocity. There was no significant difference in mitral inflow peak velocity, deceleration time, early-to-late ventricular filling ratio, and E' velocity between patients with and patients without respiratory variation of E velocity of 25% or more. Regardless of the presence or absence of a significant respiratory variation of E velocity, E' velocity was relatively normal (mean, 12 +/- 4 cm/s) in all patients with CP. In conclusion, E' velocity is well preserved in patients with isolated CP even when there is no characteristic respiratory variation of E velocity. Thus, when the respiratory variation in Doppler E velocity is blunted or absent during the evaluation of suspected CP in patients with restrictive mitral inflow velocity, preserved E' velocity shown by DTE should support the diagnosis of CP over a primary myocardial disease.
Journal of the American Society of Echocardiography 01/2003; 15(12):1468-71. · 3.71 Impact Factor
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ABSTRACT: The study was done to define the incidence, determinants and prognostic implications of onset of atrial fibrillation (AF) during follow-up of mitral regurgitation (MR) initially in sinus rhythm.
The rates and clinical implications of AF in MR are undefined.
We analyzed the occurrence of AF under conservative management in two populations of patients with degenerative MR in sinus rhythm at diagnosis: 1) 360 patients (65 +/- 13 years, 74% men) with MR due to flail leaflets; and 2) 89 residents of Olmsted County, Minnesota (67 +/- 17 years, 56% men) with grade 3 or 4 MR due to simple mitral valve prolapse (MVP) diagnosed echocardiographically.
In patients with MR due to flail leaflets, AF rates at 5 and 10 years were 18 +/- 3% and 48 +/- 6%, respectively, and the linearized rate was 5.0 +/- 0.7% per year. Development of AF during follow-up was independently associated with high risk of cardiac death or heart failure (adjusted risk ratio 2.23, p = 0.025). The AF rate at 10 years was higher in patients >or=65 years (75 +/- 10% vs. 24 +/- 6%, p < 0.0001) and in those with baseline left atrial (LA) dimension >or=50 mm (67 +/- 8% vs. 37 +/- 9%, p < 0.001). In multivariate analysis, independent baseline predictors of AF were age and LA diameter (both p < 0.01). In patients with MR due to MVP, similar rates of AF (41 +/- 7% vs. 44 +/- 6% at nine years, p > 0.50) and predictors of AF (age and LA dimension, both p < 0.006) were noted.
In patients with degenerative MR in sinus rhythm at diagnosis, the incidence of AF occurring under conservative management is high and similar whether the cause of MR is flail leaflet or simple MVP. After onset of AF, an increased cardiac mortality and morbidity are both observed under conservative management. The risk of AF increases with advancing age and larger LA dimension. These data suggest that the clinical management of MR should take into account the high incidence, excess risk, and predictors of AF.
Journal of the American College of Cardiology 08/2002; 40(1):84-92. · 14.16 Impact Factor
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ABSTRACT: Objectives. This study sought to evaluate the role and incremental value of atropine in a large patient group undergoing dobutamine stress echocardiography.Background. The use of atropine to potentiate dobutamine stress is not standard practice. Although the utility of atropine has been described, data on its incremental value remain limited and do not exist for a routine clinical practice setting.Methods. Dobutamine stress echocardiography was perfomed in 1,171 patients with use of a standard protocol. Atropine (maximal dose 2.0 mg) was given to 299 patients (26%) who did not attain target heart rate. Coronary angiography was performed in 183 patients (46 received atropine), 148 of whom were found to have significant coronary artery disease (≥ 70% diameter stenosis in a major epicardial vessel, ≥50% stenosis for left main coronary artery disease). All tests were reviewed independently by experienced observers.Results. There were no major adverse events. Patients receiving atropine had a lower rest heart rate (65 vs. 74 beats/min, p < 0.0001) and more often received beta-adrenergic blocking agents (49% vs. 14%, p < 0.0001). Of 444 patients in whom stress-induced ischemia developed, 70 (16%) required atropine before ischemia became evident. Sensitivity for detection of significant coronary artery disease was 90% with dobutamine alone and 95% after the addition of atropine. In 66 patients with normal wall motion at rest, test sensitivity was 65% before and 84% after atropine was given. Atropine use did not compromise test specificity. New diagnostic information was obtained in 20 (50%) of 40 patients with angiographic coronary artery disease given atropine. Proportionately more patients with single-vessel disease required atropine before an ischemic response was observed; this effect appeared related to the higher ischemic threshold in these patients.Conclusions. Augmentation of heart rate had a modest influence on the overall diagnostic sensitivity of dobutamine stress echocardiography in our study cohort. However, it was particularly helpful in patients receiving beta-blockers and those with milder coronary disease. Despite the use of ≥1 mg of atropine in some patients, this incremental value was not achieved at the expense of safety.
Journal of the American College of Cardiology 10/1996; · 14.16 Impact Factor
