[Show abstract][Hide abstract] ABSTRACT: The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD).
Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3±54.1?meters in the treated group as compared to no improvement in the control group (0.4±185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up.
These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 02/2011; 6(7):805-12. DOI:10.4244/EIJV6I7A139 · 3.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several methods are available for delivering stem cells to the heart. Recent studies have highlighted the advantages of injecting the cells directly into the myocardium in order to increase myocardial retention of cells. A particular focus has been on percutaneous transendocardial injection, facilitated by electromechanical mapping.The NOGA XP Cardiac Navigation System has a multicomponent catheter that is designed to guide and deliver transendocardial injections via a transfemoral approach, without a guidewire. However, this method may not be feasible in some patients who have peripheral vascular disease. Herein, we describe the case of a 68-year-old man whose tortuous, sharply angled iliac arteries precluded a femoral approach to transendocardial injection. To overcome the anatomic and mechanical challenges, we used a brachial approach. We believe that this is the 1st report of using the brachial route for transendocardial injection, and that it can be a viable alternative to the transfemoral approach in selected patients.
Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 01/2011; 38(2):179-82. · 0.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stem cell therapy has emerged as a novel therapeutic treatment alternative for early and end stage LV dysfunction. The rapid translation into clinical trials has left many questions unanswered. Moreover, results of randomized trials in the setting of acute myocardial infarction are controversial, emphasizing a need for further basic and translational research to improve understanding of cell functionality. This review attempts to summarize some of the functional issues related to cell therapy and also evaluate the current status of stem cell clinical trials. Although results to date have shown modest improvement in left ventricular function, the progress should follow a coordinated, multidisciplinary, and well designed path to address issues of cell homing, cell retention, and also look at outcomes beyond physiological parameters.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention (PCI). Two hundred fifty-five consecutive patients presenting with ST-segment elevation myocardial infarctions who underwent primary PCI were enrolled. Patients were divided into 2 groups on the basis of the loading dose of clopidogrel received before the procedure (600 vs 300 mg). Procedural angiographic end points and 1-year major adverse cardiac events were compared between the 2 groups. Major adverse cardiac events were defined as death, nonfatal myocardial infarction, and target vessel revascularization. There were no significant differences in baseline clinical and angiographic features between the 2 groups: 157 (62%) in the clopidogrel 600 mg group and 98 (38%) in the 300 mg group. Patients receiving 600-mg loading dose of clopidogrel showed a significantly lower incidence of post-PCI myocardial blush grade 0 or 1 (odds ratio 0.64, 95% confidence interval 0.43 to 0.96, p = 0.03) and significantly less common no-reflow phenomenon (odds ratio 0.38, 95% confidence interval 0.15 to 0.98, p = 0.04) compared to those in the 300-mg group. Propensity-adjusted Cox analysis showed significantly higher survival free of major adverse cardiac events in patients receiving 600-mg loading dose of clopidogrel compared to those receiving the lower dose (hazard ratio 0.57, 95% confidence interval 0.33 to 0.98, p = 0.04). In conclusion, a 600-mg loading dose of clopidogrel is associated with improvements in procedural angiographic end points and 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction who undergo primary PCI compared to a 300-mg dose.
The American journal of cardiology 11/2010; 106(9):1208-11. DOI:10.1016/j.amjcard.2010.06.044 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With favorable regenerative and immunotolerant profiles, patient-derived human mesenchymal stem cells (hMSCs) are increasingly considered in cell therapy. Derived from bone marrow (BM) and standardized with culture in fetal bovine serum (FBS), translation of hMSC-based approaches is impeded by protracted expansion times, risk of xenogenic response, and exposure to zoonoses. Here, human platelet lysate adherent to good manufacturing practices (GMP-hPL) provided a nonzoonotic adjuvant that enhanced the capacity of BM-hMSC to proliferate. The nurturing benefit of GMP-hPL was generalized to hMSC from adipose tissue evaluated as an alternative to bone marrow. Long-term culture in GMP-hPL maintained the multipotency of hMSC, while protecting against clonal chromosomal instability detected in the FBS milieu. Proteomic dissection identified TGF-β, VEGF, PDGF, FGF, and EGF as highly ranked effectors of hPL activity, revealing a paradigm of healing that underlies platelet lysate adjuvancy. Thus, GMP-adherent human platelet lysate accelerates hMSC proliferation with no chromosomal aberrancy, through an innate repair paradigm.
[Show abstract][Hide abstract] ABSTRACT: To date, cardiac resynchronization therapy remains the only treatment that enhances systolic function while improving long-term outcome and survival. Here, we review the molecular alterations associated with dyssynchronous heart failure and their reversibility induced by cardiac resynchronization therapy. We focus upon the molecular portrait of dyssynchronous heart failure and how cardiac resynchronization therapy influences electrophysiologic, metabolic and adrenergic pathways.
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction.
Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome.
hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta(1), bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points.
Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity.
Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.
Journal of the American College of Cardiology 08/2010; 56(9):721-34. DOI:10.1016/j.jacc.2010.03.066 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study sought to define the additional effective radiation dose, procedural time, and contrast medium needed to obtain fractional flow reserve (FFR) measurements after a diagnostic coronary angiogram.
The FFR measurements performed at the end of a diagnostic angiogram allow the obtaining of functional information that complements the anatomic findings.
In 200 patients (mean age 66 +/- 10 years) undergoing diagnostic coronary angiography, FFR was measured in at least 1 intermediate coronary artery stenosis. Hyperemia was achieved by intracoronary (n = 180) or intravenous (n = 20) adenosine. The radiation dose (mSv), procedural time (min), and contrast medium (ml) needed for diagnostic angiography and FFR were recorded.
A total of 296 stenoses (1.5 +/- 0.7 stenoses per patient) were assessed. The additional mean radiation dose, procedural time, and contrast medium needed to obtain FFR expressed as a percentage of the entire procedure were 30 +/- 16% (median 4 mSv, range 2.4 to 6.7 mSv), 26 +/- 13% (median 9 min, range 7 to 13 min), and 31 +/- 16% (median 50 ml, range 30 to 90 ml), respectively. The radiation dose and contrast medium during FFR were similar after intravenous and intracoronary adenosine, though the procedural time was slightly longer with intravenous adenosine (median 11 min, range 10 to 17 min, p = 0.04) than with intracoronary adenosine (median 9 min, range 7 to 13 min). When FFR was measured in 3 or more lesions, radiation dose, procedural time, and contrast medium increased.
The additional radiation dose, procedural time, and contrast medium to obtain FFR measurement are low as compared to other cardiovascular imaging modalities. Therefore, the combination of diagnostic angiography and FFR measurements is warranted to provide simultaneously anatomic and functional information in patients with coronary artery disease.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of thrombus aspiration in a real-world all-comer patient population with STEMI undergoing primary PCI.
Catheter thrombus aspiration in primary PCI was beneficial in randomized clinical trials.
We enrolled 313 STEMI patients presenting with TIMI Flow Grade 0 or 1 in the infarct related artery at baseline angiogram undergoing primary PCI. PATIENTS were divided in two groups based on whether thrombus aspiration was attempted. This decision was left at operator's discretion. Procedural and long-term clinical outcomes were compared between the two groups.
Baseline characteristics were similar between groups: 194 (62%) received thrombus aspiration and 119 underwent conventional PCI. Thrombus aspiration was associated with significantly lower post-PCI TIMI Frame Count values (19 +/- 15 vs. 25 +/- 17; P = 0.002) and higher TIMI Flow Grade 3 (92% vs. 73%; P < 0.001). Postprocedural myocardial perfusion assessed by myocardial blush grade (MBG) was significantly increased in the thrombus aspiration group (MBG 3: 44% vs. 21%; P < 0.001). No significant difference was found between the two groups in clinical outcome at 30 days. At one year, patients treated with thrombus aspiration showed significantly higher overall survival (HR 0.41, 95% CI 0.20-0.81; log-rank P = 0.010) and MACE-free survival (HR 0.49, 95% CI 0.28-0.85; log-rank P = 0.011).
In real-world all-comer STEMI patients with occluded infarct-related artery, thrombus aspiration prior to PCI improves coronary flow, myocardial perfusion, and long-term clinical outcome as compared with PCI in the absence of thrombus aspiration.
[Show abstract][Hide abstract] ABSTRACT: Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs.
Echocardiography, levels of neurohormones and conductance catheter measurements of left ventricular pressure-volume relationships were obtained in 17 beagle dogs 2 months after a coronary artery ligation, and in 6 controls.
Healed myocardial infarction was associated with preserved echocardiographic left ventricular ejection fraction (0.57 +/- 0.01, mean +/- SEM) and altered Doppler mitral indices of diastolic function. NT-proBNP was increased, aldosterone was decreased, and norepinephrine was unchanged. Invasive measurements showed a markedly decreased end-systolic elastance (2.1 +/- 0.2 vs 6.1 +/- 0.8, mmHg/ml, p < 0.001) and end-systolic elastance to effective arterial elastance ratio (0.6 +/- 0.1 vs 1.4 +/- 0.2, p < 0.001), with altered active relaxation (dP/dtmin -1992 +/- 71 vs -2821 +/- 305, mmHg/s, p < 0.01) but preserved left ventricular capacitance (70 +/- 6 vs 61 +/- 3, ml at 20 mmHg, p = NS) and stiffness constant. Among echocardiographic variables, the wall motion score index was the most reliable indicator of cardiac contractility while E', E/A and E'/A' were correlated to dP/dtmin.
In the canine model of healed myocardial infarction induced by coronary ligation, heart failure is essentially characterized by an altered contractility with left ventricular-arterial uncoupling despite vascular compensation rather than by abnormal diastolic function.
[Show abstract][Hide abstract] ABSTRACT: The initial evaluation of chest pain in the emergency department is based on the patient's clinical history, changes in the ECG and necrosis biomarkers. Although management of patients with ST-elevation myocardial infarction or non-ST-elevation myocardial infarction with positive markers of myocardial damage is well defined, exclusion of coronary artery disease or myocardial ischemia in the remaining patients is more challenging. This group represents the majority of patients admitted for chest pain syndromes and that have a substantial risk of an adverse outcome. Given that troponin, as a marker of myocardial damage, detects terminal events in the cascade of acute coronary syndrome, there is a need to search for biomarkers that are able to identify patients at high risk, allowing rapid, bedside stratification. Data suggest that clinical events are prone to occur more frequently in patients with coronary artery stenosis associated with myocardial ischemia. Accordingly, identification of systemic biomarkers of ischemia could facilitate identification of high-risk patients with a high burden of coronary atherosclerosis and plaque rupture. We describe six biomarkers that have been linked to myocardial ischemia. Until now, these biomarkers of ischemia are relevant in order to exclude ischemic heart disease (high negative predictive value) but still lack specificity. Future prospective studies should be performed in larger and more diverse sets of patients presenting with ischemia, and in a complementary fashion in order to provide valuable tools for clinical decision making.
Biomarkers in Medicine 06/2010; 4(3):375-83. DOI:10.2217/bmm.10.59 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to diagnose heart failure with preserved ejection fraction (HFPEF) in outpatients with unexplained chronic dyspnea and to elucidate its underlying mechanisms in this population using invasive pressure-volume loop analysis.
The diagnosis of HFPEF in stable outpatients with unexplained dyspnea is difficult.
Thirty patients (age 67 +/- 8.6 years, 27% males) with preserved left ventricular (LV) ejection fraction (>50%) and unexplained chronic New York Heart Association functional class II to III dyspnea underwent heart catheterization. Patients with significant coronary artery stenosis (>50%) were excluded. Pressure-volume loops were assessed using a conductance catheter at rest, hand-grip exercise, leg lifting, and nitroprusside and dobutamine infusion.
Twenty (66%) patients showed LV end-diastolic pressure >16 mm Hg (HFPEF), whereas the remaining 10 patients served as controls. Patients with HFPEF had significantly higher end-diastolic stiffness (0.205 +/- 0.074 vs. 0.102 +/- 0.017, p < 0.001) at rest, and their end-diastolic pressure-volume relationship showed a consistent upward and leftward shift during all hemodynamic interventions compared with controls. Regarding the underlying mechanism of HFPEF, 14 (70%) patients had markedly increased end-diastolic stiffness, which was considered a sufficient single pathology to induce increased LV end-diastolic pressure. Four (20%) patients showed a concomitant presence of moderately increased stiffness and severe LV dyssynchrony, and the remaining 2 (10%) patients, with normal stiffness, showed significant exercise-induced mitral regurgitation at hand-grip exercise. If the invasive pressure measurements were absent, only 5 (25%) of the outpatients with HFPEF fulfilled the European Society of Cardiology definition of HFPEF.
A significant proportion of stable outpatients with unexplained chronic dyspnea may have HFPEF. In the patients whom we studied, increased LV stiffness, dyssynchrony, and dynamic mitral regurgitation were the major mechanisms underlying development of HFPEF.
Journal of the American College of Cardiology 04/2010; 55(16):1701-10. DOI:10.1016/j.jacc.2009.11.076 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mature, biologically active 32-amino acid long B-type natriuretic peptide (BNP(1-32)), is cleaved by corin from the BNP prohormone. Recent data demonstrated that BNP(1-32) might be an ideal substrate for the endogenous aminopeptidase, dipeptidyl-peptidase (DPP) IV. DPP IV removes the two amino-terminal amino acids (Ser and Pro) from BNP(1-32) to produce BNP(3-32), which has been detected in plasma of patients with heart failure. In a canine model, intravenous BNP(3-32) infusion resulted in less natriuresis, diuresis and vasodilation compared to intravenous infusion of BNP(1-32). The clinical relevance of these observations may be important for patients with high plasma BNP concentrations, which can be measured by commercially available immunoassays. Further studies are needed to explore whether DPP IV inhibitors increase the bioavailability of BNP(1-32), delay the progression of heart failure and increase the efficacy of exogenously administered BNP(1-32) in decompensated heart failure.
Biomarkers in Medicine 04/2010; 4(2):315-20. DOI:10.2217/bmm.10.5 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The influence of atherosclerosis and its risk factors on coronary microvascular function remain unclear as current methods of assessing microvascular function do not specifically test the microcirculation in isolation. We examined the influence of epicardial vessel atherosclerosis on coronary microvascular function using the index of myocardial resistance (IMR).
IMR (a measure of microvascular function) and fractional flow reserve (FFR, a measure of the epicardial compartment) were measured in 143 coronary arteries (116 patients). Fifteen patients (22 arteries, mean age 48+/-16 years) had no clinical evidence of atherosclerosis (control group). One hundred and one patients (121 arteries, mean age 63+/-11 years) had established atherosclerosis and multiple cardiovascular risk factors (atheroma group). Mean IMR in the control group (19+/-5, range 8-28) was significantly lower than in the atheroma group (25+/-13, range 6-75) (P<0.01). However, there was large overlap between IMR in both groups, with 69% of IMR values in patients with atheroma being within the control range. Mean FFR was also higher in the control group (0.96+/-0.02, range 0.93-1.00) than in the atheroma group (0.85+/-0.14, range 0.19-1.00) (P<0.01). There was no correlation between IMR and FFR (r=0.09; P=0.24), even when results in the control (r=0.02; P=0.92) and atheroma (r=0.15; P=0.10) groups were analysed in isolation. Using stepwise multiple regression analysis presence/absence of atheroma (ss=0.42; P=0.02) was the only independent determinant of IMR.
Mean IMR is higher in patients with epicardial atherosclerosis. However, there is a large overlap between IMR in patients with and without epicardial atherosclerosis.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 04/2010; 5(8):939-45. DOI:10.4244/EIJV5I8A158 · 3.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the correlation between myocardial ischemia detected by myocardial perfusion imaging (MPI) with single-photon emission computed tomography with intracoronary pressure-derived fractional flow reserve (FFR) in patients with multivessel coronary disease at angiography.
Myocardial perfusion imaging can underestimate the number of ischemic territories in patients with multivessel disease. However, there are limited data comparing MPI and FFR, a highly accurate functional index of myocardial ischemia, in multivessel coronary disease.
Sixty-seven patients (201 vascular territories) with angiographic 2- or 3-vessel coronary disease were prospectively scheduled to undergo within 2 weeks MPI (rest/stress adenosine) and FFR in each vessel.
In 42% of patients, MPI and FFR detected identical ischemic territories (mean number of territories 0.9 +/- 0.8 for both; p = 1.00). In the remaining 36% MPI underestimated (mean number of territories; MPI: 0.46 +/- 0.6, FFR: 2.0 +/- 0.6; p < 0.001) and in 22% overestimated (mean number of territories; MPI: 1.9 +/- 0.8, FFR: 0.5 +/- 0.8; p < 0.001) the number of ischemic territories in comparison with FFR. There was poor concordance between the ability of the 2 methods to detect myocardial ischemia on both a per-patient (kappa = 0.14 [95% confidence interval: -0.10 to 0.39]) and per-vessel (kappa = 0.28 [95% confidence interval: 0.15 to 0.42]) basis.
Myocardial perfusion imaging with single-photon emission computed tomography has poor concordance with FFR and tends to underestimate or overestimate the functional importance of coronary stenosis seen at angiography in comparison with FFR in patients with multivessel disease. These findings might have important consequences in using MPI to determine the optimal revascularization strategy in patients with multivessel coronary disease.
[Show abstract][Hide abstract] ABSTRACT: The field of myocardial regeneration (angiogenesis and myogenesis) might prove to play an important role in the future management of cardiovascular disease. Stem cells are currently undergoing testing in Phase I and Phase II clinical trials. Methods of delivery will affect the outcome of such therapies, perhaps significantly. This document provides suggested guidance in 4 methods of delivery: endocardial, intracoronary, coronary sinus, and epicardial. (J Am Coll Cardiol Inty 2010;3:265-75) (C) 2010 by the American College of Cardiology Foundation
[Show abstract][Hide abstract] ABSTRACT: Platelet reactivity is greater in patients with stable angina and with more extensive peripheral vascular atherosclerosis. We sought to evaluate whether impaired peripheral microcirculatory endothelial function might correlate with platelet reactivity after clopidogrel and therefore predispose to an unfavorable outcome after percutaneous coronary intervention (PCI). In 52 consecutive patients with stable angina undergoing elective PCI, endothelial function was assessed by (1) endothelial peripheral arterial tonometry (measuring the "Endoscore"); (2) the von Willebrandt factor antigen level and ristocetin co-factor activity. Basal platelet reactivity was assessed by soluble P-selectin. Patients then received a 600-mg clopidogrel loading dose > or = 12 hours before PCI. A blood sample was withdrawn 12 hours later, but before PCI, to assess platelet reactivity using the P2Y12 reaction unit and percentage of P2Y12 inhibition with the point-of-care VerifyNow P2Y12 assay. Troponin T was assessed 24 hours after PCI. The Endoscore inversely correlated with von Willebrandt factor antigen activity (r = -0.52, p = 0.0001) and soluble P-selectin concentration (r = -0.36, p = 0.021), suggesting greater platelet reactivity with increased impaired endothelial function. After clopidogrel, the Endoscore correlated directly with the percentage of P2Y12 inhibition (r = 0.36, p = 0.009) and inversely with the P2Y12 reaction unit (r = -0.41, p = 0.002), suggesting greater residual platelet reactivity with more impaired endothelial function. The average Endoscore was significantly lower in patients with troponin T elevation (troponin positive group 0.267 + or - 0.091) than in patients without troponin T elevation (troponin negative group 0.508 + or - 0.041, p = 0.015 vs troponin positive). In conclusion, an impaired endothelial response before clopidogrel was associated with greater platelet reactivity after clopidogrel. This link might explain the unfavorable PCI outcomes in patients with more severe endothelial impairment.
The American journal of cardiology 02/2010; 105(3):333-8. DOI:10.1016/j.amjcard.2009.09.033 · 3.28 Impact Factor