Otavio Coelho-Filho

Effect of Cardiac Stem Cells on Left-Ventricular Remodeling in a Canine Model of Chronic Myocardial Infarction

Background— Regenerative medicine, including cell therapy, is a promising strategy for recovery of the damaged myocardium. C-kit–positive cardiac stem cells (CSCs) have been shown to improve myocardial function after ischemic injury in animal models and in early clinical experience. We used a chronic large animal model of myocardial infarction with substantial reductions in left-ventricular (LV) ejection fraction and adverse remodeling to examine the effect of late autologous CSC intramyocardial injection on long-term cardiac structure and function. Methods and Results— Thoracotomy and ligation of the proximal left anterior descending artery, additional diagonal branches, and atrial biopsy for CSC culture were performed in canines. Baseline cardiac MRI was performed at 6 weeks postinfarct followed by repeat thoracotomy for randomization to intramyocardial injection of CSCs (n=13) or vehicle alone (n=6). At 30 weeks postmyocardial infarction, repeat MRI was performed. Data were analyzed using nonparametric tests (Wilcoxon signed-rank and rank-sum tests). In control animals, LV end-systolic volume and end-diastolic volume increased from 6 to 30 weeks (median and interquartile range, 51.3 mL [43.3–57.4] to 76.1 mL [72.0–82.4]; P=0.03 and 78.5 mL [69.7–86.1] to 99.2 mL [97.1–100.4]; P=0.03). Left-ventricular ejection fraction declined further (35.2% [27.9–38.7] to 26.4% [22.0–31.0]; P=0.12). In the cell-treated animals, this late adverse LV remodeling was attenuated (LV end-systolic volume, 42.6 mL [38.5–50.5] to 56.1 mL [50.3–63.0]; P=0.01 versus control). There was a nonsignificant attenuation in the increase in LV end-diastolic volume (64.8 mL [60.7–71.3] to 83.5 mL [74.7–90.8]; P=0.14 versus control) and LV ejection fraction change over time differed (30.5% [28.4–33.4] to 32.9% [28.6–36.9]; P=0.04 versus control). Conclusions— Intramyocardial injection of autologous CSCs in a late phase model of chronic infarction resulted in less increase in LV end-systolic volume and preservation of LV ejection fraction.

Stress Cardiac Magnetic Resonance Imaging Provides Effective Cardiac Risk Reclassification in Patients With Known or Suspected Stable Coronary Artery Disease

Background— A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. Methods and Results— In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17; P<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81–0.86; P=0.04; adjusted hazard ratio=7.37; P<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063–0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81–1.39). Conclusions— Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01821924.

Myocardial Tissue Remodeling in Adolescent Obesity

Background Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function.

Vasodilator stress perfusion CMR imaging is feasible and prognostic in obese patients.

OBJECTIVESnThis study sought to determine feasibility and prognostic performance ofxa0stress cardiac magnetic resonance (CMR) in obese patients (body mass index [BMI] ≥30 kg/m(2)).nnnBACKGROUNDnCurrent stress imaging methods remain limited in obese patients. Given the impact of the obesity epidemic on cardiovascular disease, alternative methods to effectively risk stratify obese patients are needed.nnnMETHODSnConsecutive patients with a BMI ≥30 kg/m(2) referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes.nnnRESULTSnOf 285 obese patients, 272 (95%) completed the CMR protocol, and among these, 255xa0(94%) achieved diagnostic imaging quality. Mean BMI was 35.4 ± 4.8 kg/m(2), with a maximum weight of 200 kg. Reasons for failure to complete CMR included claustrophobia (nxa0= 4), intolerance to stress agent (nxa0= 4), poor gating (nxa0= 4), and declining participation (nxa0= 1). Sedation was required in 19 patientsxa0(7%; 2 patients with intravenous sedation). Sixteen patients required scanning by a 70-cm-bore system (6%). Patients without inducible ischemia or LGE experienced a substantially lowerxa0annual rate of MACE (0.3% vs. 6.3% for those with ischemia and 6.7% for those with ischemia and LGE). Median follow-up of the cohort was 2.1 years. In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, inducible ischemia (hazard ratio 7.5; 95% confidence interval: 2.0 to 28.0; pxa0=xa00.002) remained independently associated with MACE. When patients with early coronary revascularization (within 90 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE.nnnCONCLUSIONSnStress CMR is feasible and effective in prognosticating obese patients, with a veryxa0low negative event rate in patients without ischemia or infarction.

Cardiac magnetic resonance imaging in clinical practice

Resumo Objective: To evaluate and describe indications, mainly diagnoses and cardiac magnetic resonance imaging findings observed in clinical practice. Materials and Methods: Retrospective and descriptive study of cardiac magnetic resonance performed at a private hospital and clinic in the city of Niterói, RJ, Brazil, in the period from May 2007 to April 2011. Results: The sample included a total of 1000 studies performed in patients with a mean age of 53.7 ± 16.2 years and predominance for male gender (57.2%). The majority of indications were related to assessment of myocardial perfusion at rest and under pharmacological stress (507/1000; 51%), with positive results in 36.2% of them. Suspected myocarditis was the second most frequent indication (140/ 1000; 14%), with positive results in 63.4% of cases. These two indications were followed by study of arrhythmias (116/1000; 12%), myocardial viability (69/1000; 7%) and evaluation of cardiomyopathies (47/1000; 5%). In a subanalysis, it was possible to identify that most patients were assessed on an outpatient basis (58.42%). Conclusion: Cardiac magnetic resonance has been routinely performed in clinical practice, either on an outpatient or emergency/ inpatient basis, and myocardial ischemia represented the main indication, followed by investigation of myocarditis, arrhythmogenic right ventricular dysplasia and myocardial viability.Barranhas AD, Santos AASMD, Coelho-Filho OR, Marchiori E, Rochitte CE, Nacif MS. Cardiac magnetic resonance imaging in clinical practice. RadiolBras. 2014 Jan/Fev;47(1):1–8.AbstractResumoObjective: To evaluate and describe indications, mainly diagnoses and cardiac magnetic resonance imaging findings observed in clinicalpractice.Materials and Methods: Retrospective and descriptive study of cardiac magnetic resonance performed at a private hospital and clinic inthe city of Niteroi, RJ, Brazil, in the period from May 2007 to April 2011.Results: The sample included a total of 1000 studies performed in patients with a mean age of 53.7 ± 16.2 years and predominancefor male gender (57.2%). The majority of indications were related to assessment of myocardial perfusion at rest and under pharm acologicalstress (507/1000; 51%), with positive results in 36.2% of them. Suspected myocarditis was the second most frequent indication ( 140/1000; 14%), with positive results in 63.4% of cases. These two indications were followed by study of arrhythmias (116/1000; 12% ),myocardial viability (69/1000; 7%) and evaluation of cardiomyopathies (47/1000; 5%). In a subanalysis, it was possible to ident ify thatmost patients were assessed on an outpatient basis (58.42%).Conclusion: Cardiac magnetic resonance has been routinely performed in clinical practice, either on an outpatient or emergency/inpatient basis, and myocardial ischemia represented the main indication, followed by investigation of myocarditis, arrhythmoge nic rightventricular dysplasia and myocardial viability.Keywords: Cardiac magnetic resonance; Health profile; Evidence-based medicine; Diagnostic methods – policies.Objetivo: Avaliar e descrever as indicacoes, os principais diagnosticos e os achados de imagem de ressonâncias magneticas cardiacasrealizadas na pratica clinica.Materiais e Metodos: Estudo descritivo e retrospectivo dos exames de ressonância magnetica cardiaca realizados em um hospital euma clinica particulares do municipio de Niteroi, RJ, no periodo de maio de 2007 a abril de 2011.Resultados: Um total de 1000 exames foi incluido, com pacientes apresentando media de idade de 53,7 ± 16,2 anos e predominiono sexo masculino (57,2%). A maioria das indicacoes foi para pesquisa de isquemia miocardica com estresse farmacologico (507/1000; 51%), que teve resultado positivo em 36,2% das avaliacoes. A pesquisa de miocardite (140/1000; 14%) foi a segundaindicacao mais frequente, com resultados positivos em 63,4% dos casos. Estas duas principais indicacoes foram seguidas de avali acaode arritmias (116/1000; 12%), viabilidade miocardica (69/1000; 7%) e cardiomiopatias diversas (47/1000, 5%). Em uma subanalise,foi possivel identificar que a grande maioria dos exames foi realizada pela via ambulatorial (58,42%).Conclusao: A ressonância magnetica cardiaca esta sendo realizada de rotina na pratica clinica, tanto via ambulatorial ou pela viaemergencial/intra-hospitalar, e a pesquisa de isquemia miocardica foi a principal indicacao, seguida de miocardite, displasia a rritmoge-nica do ventriculo direito e viabilidade miocardica.Unitermos: Ressonância magnetica cardiaca; Perfil de saude; Medicina baseada em evidencias; Exames medicos – politicas.

Imaging methods for detection of chemotherapy-associated cardiotoxicity and dysfunction.

Survival in cancer has improved, shifting some of the focus of care to minimizing the long term complications of cancer therapy. Cardiovascular disease is a leading long-term cause of morbidity and mortality in patients who survive cancer. In the review we will focus on imaging techniques that are used to detect the cardiovascular consequences of chemotherapy. We will differentiate cardiotoxicity and cardiac injury from cardiac dysfunction and cardiomyopathy. We will discuss the current clinical measures that are used to monitor patients, the limitations of each technique, and then detail research into novel methods for tracking and detecting the cardiac toxicity and cardiac dysfunction that may occur as a result of chemotherapy.

Myocardial tissue remodeling after orthotopic heart transplantation: a pilot cardiac magnetic resonance study

After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47u2009±u20097xa0years, 30u2009% female, median follow-up post-OHT 6xa0months) and 30 age-matched healthy volunteers (mean age 50.5u2009±u200915xa0years; LVEF 63.5u2009±u20097u2009%). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3u2009±u200911u2009%) with higher LV mass relative to age-matched healthy volunteers (114u2009±u200927 vs. 85.8u2009±u200918xa0g; pu2009<u20090.001). There was no late gadolinium enhancement in either group. Both myocardial extracellular volume fraction (ECV) and intracellular lifetime of water (τic), a measure of cardiomyocyte hypertrophy, were higher in patients post-OHT (ECV: 0.39u2009±u20090.06 vs. 0.28u2009±u20090.03, pu2009<u20090.0001; τic: 0.12u2009±u20090.08 vs. 0.08u2009±u20090.03, pu2009<u20090.001). ECV was associated with LV mass (ru2009=u20090.74, pu2009<u20090.001). In follow-up, OHT recipients with normal biopsies by pathology (ISHLT grade 0R) in the first year post-OHT exhibited a lower ECV relative to patients with any rejection ≥2R (0.35u2009±u20090.02 for 0R vs. 0.45u2009±u20090, pu2009<u20090.001). Higher ECV but not LVEF was significantly associated with a reduced rejection-free survival. After OHT, markers of tissue remodeling by CMR (ECV and τic) are elevated and associated with myocardial hypertrophy. Interstitial myocardial remodeling (by ECV) is associated with cellular rejection. Further research on the impact of graft preservation and early immunosuppression on tissue-level remodeling of the allograft is necessary to delineate the clinical implications of these findings.

Characterization of both myocardial extracellular volume expansion and myocyte hypertrophy by CMR in heart transplantation recipients without active rejection: implications for early cardiac remodeling

Background Left ventricular hypertrophy (LVH) after heart transplant (HTx) is multifactorial, associations include hypertension, chronic immune injury and the intrinsic effects of immunosuppression. Its consequences are significant and potentially provide an explanation for the development of diastolic dysfunction and exercise intolerance, as well as the limited life expectancy after HTx. Both expansion of myocardial extracellular volume (ECV) and myocyte hypertrophy (MH) coexist in this setting. Cardiac biopsies have limitations and may be non-representative to assess global myocardial remodeling. The goal of this pilot study was to characterize both ECV and MH by CMR in cohort of HTx recipients without active rejection. Methods T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water (τic), a cell size-dependent parameter, and extracellular volume fraction, a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Results Nineteen HTx recipients (mean age 50±0, 6 female, BSA 1,70±0,16m 2 , median follow-up after HTx 11±13 months) without acute rejection and 20 age matched health volunteers (mean age 51±14) underwent CMR (1.5T) includingmeasurement of LV function, T2, T1 mapping pre- and post-gadolinium and LGE, and a echocardiogram for measurement of diastolic function. HTx recipients demonstrated normal LVEF (68±11%) with a significant increased in LVMass in comparison with age-matched volunteers (LVMass 114±19g vs. 80±5g; p<0.05). Both groups (HTx and controls) did not show LGE or abnormal signal intensity in T2 images. ECV was substantially higher in HTx patients (0,43 ±0,14) compared with volunteers (0.29±0.03, p<0.0001). Both ECV, a marker of interstitial fibrosis, and τic ,a new validated maker of myocyte hypertrophy, were significantly associated with LV mass (r=0.72 and r=0.68 respectively , both p<0.05). ECV and τic also demonstrated a strong association with E wave deceleration time (EDT) by TTE (r=0.77 and 0.74 respectively, both p<0.05). ECV maintained the positive association with EDT indexed to E wave. (r=0.66, p<0.01). by ROC curve analysis, the ECV was able to predict diastolic dysfunction using EDT by ETT with AUC 0.97 (ECV cut value 0.37, Sens 100%, Spec 86%, p<0.01).

Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease

OBJECTIVESnThe goal of this study was to demonstrate that cardiac magnetic resonance could reveal anthracycline-induced early tissue remodeling and its relation to cardiac dysfunction and left ventricular (LV) atrophy.nnnBACKGROUNDnSerum biomarkers of cardiac dysfunction, although elevated after chemotherapy, lack specificity for the mechanism of myocardial tissue alterations.nnnMETHODSnA total of 27 women with breast cancer (mean age 51.8 ± 8.9 years, mean body mass index 26.9 ± 3.6 kg/m2), underwent cardiac magnetic resonance before and up to 3 times after anthracycline therapy. Cardiac magnetic resonance variables were LV ejection fraction, normalized T2-weighted signal intensity for myocardial edema, extracellular volume (ECV), LV cardiomyocyte mass, intracellular water lifetime (τic; a marker of cardiomyocyte size), and late gadolinium enhancement.nnnRESULTSnAt baseline, patients had a relatively low (10-year) Framingham cardiovascular event risk (median 5%), normal LV ejection fractions (mean 69.4 ± 3.6%), and normal LV mass index (51.4 ± 8.0 g/m2), a mean ECV of 0.32 ± 0.038, mean τic of 169 ± 69 ms, and no late gadolinium enhancement. At 351 to 700 days after anthracycline therapy (240 mg/m2), mean LVxa0ejection fraction had declined by 12% to 58 ± 6% (pxa0< 0.001) and mean LV mass index by 19 g/m2 to 36 ± 6 g/m2 (pxa0<xa00.001), and mean ECV had increased by 0.037 to 0.36 ± 0.04 (pxa0= 0.004), while mean τic had decreased by 62 ms to 119xa0± 54 ms (pxa0= 0.004). Myocardial edema peaked at about 146 to 231 days (pxa0< 0.001). LV mass index was associated with τic (βxa0= 4.1 ± 1.5 g/m2 per 100-ms increase in τic, pxa0= 0.007) but not with ECV. Cardiac troponin T (mean 4.6 ± 1.4 pg/ml atxa0baseline) increased significantly after anthracycline treatment (pxa0< 0.001). Total LV cardiomyocyte mass, estimated as: (1xa0-xa0ECV)xa0× LV mass, declined more rapidly after anthracycline therapy, with peak cardiac troponin T >10 pg/ml. There was no evidence for any significant interaction between 10-year cardiovascular event risk and the effect of anthracycline therapy.nnnCONCLUSIONSnA decrease in LV mass after anthracycline therapy may result from cardiomyocyte atrophy, demonstrating that mechanisms other than interstitial fibrosis and edema can raise ECV. The loss of LV cardiomyocyte mass increased with the degree of cardiomyocyte injury, assessed by peak cardiac troponin T after anthracycline treatment. (Doxorubicin-Associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients; NCT03000036).

A Simpler and Shorter Neuromuscular Electrical Stimulation Protocol Improves Functional Status and Modulates Inflammatory Profile in Patients with End-Stage Congestive Heart Failure

Background: Neuromuscular electrical stimulation (NMES) using a stimulation wave for 5 days/week over 8 weeks has been used as a treatment option for congestive heart failure (CHF) patients who are unable to tolerate aerobic exercise. Objective: We assessed the impact of a shorter NMES protocol using a Russian stimulation wave on the functional status, quality of life (QoL) and inflammatory profile of end-stage CHF patients. Methods: Twenty-eight patients with end-stage CHF (53 ± 11 years) were randomized to the NMES or control group. Treatment was an NMES training program with Russian stimulation wave, applied for 50 minutes to both quadriceps femoral muscles twice weekly over seven weeks. The stimulation intensity was chosen to elicit muscle contractions in the NMES group and current input up to sensory threshold in the control group. Distance in the 6-minute walk test (6MWD) and QoL score by the Minnesota Living with Heart Failure Questionnaire were evaluated before, immediately after and one month after NMES protocol completion. Peripheral leukocytes were obtained to measure the gene expression levels of inflammatory cytokines. Results: The NMES group showed increases in the 6MWD (324 ± 117 vs. 445 ± 100 m; p = 0.02) and QoL score (64 ± 22 vs. 45 ± 17; p < 0.01) immediately but not 1 month after protocol completion, as well as increased gene expression levels of IL-1β, IL-6 and IL-8 after protocol completion. Conclusion: Using a shorter and fewer sessions NMES protocol improved the QoL score and functional class of severe CHF patients, and modulated the gene expression levels of some cytokines. This protocol might be a good alternative for patients with severe CHF and limitations in protocol adherence. (Int J Cardiovasc Sci. 2017;30(6)484-495)Mailing Address: Maria Carolina Basso Sacilotto Avenida Arlindo Joaquim de Lemos, 865, Apto: 32. Postal Code: 13100450, Vila Lemos, Campinas, SP – Brazil E-mail: mariacarolinasacilotto@gmail.com; orlandopetrucci@gmail.com A Simpler and Shorter Neuromuscular Electrical Stimulation Protocol Improves Functional Status and Modulates Inflammatory Profile in Patients with End-Stage Congestive Heart Failure Maria Carolina Basso Sacilotto, Carlos Fernando Ramos Lavagnoli, Lindemberg Mota Silveira-Filho, Karlos Alexandre de Souza Vilarinho, Elaine Soraya Barbosa de Oliveira, Daniela Diógenes de Carvalho, Pedro Paulo Martins de Oliveira, Otávio Rizzi Coelho-Filho, Orlando Petrucci Junior