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1.  Atrial Fibrillation in Hypertrophic Cardiomyopathy: Prevalence, Clinical Correlations, and Mortality in a Large High‐Risk Population 
Background
Atrial fibrillation (AF) is a common sequela of hypertrophic cardiomyopathy (HCM), but evidence on its prevalence, risk factors, and effect on mortality is sparse. We sought to evaluate the prevalence of AF, identify clinical and echocardiographic correlates, and assess its effect on mortality in a large high‐risk HCM population.
Methods and Results
We identified HCM patients who underwent evaluation at our institution from 1975 to 2012. AF was defined by known history (either chronic or paroxysmal), electrocardiogram, or Holter monitoring at index visit. We examined clinical and echocardiographic variables in association with AF. The effect of AF on overall and cause‐specific mortality was evaluated with multivariate Cox proportional hazards models. Of 3673 patients with HCM, 650 (18%) had AF. Patients with AF were older and more symptomatic (P<0.001). AF was less common among patients with obstructive HCM phenotype and was associated with larger left atria, higher E/e’ ratios, and worse cardiopulmonary exercise tolerance (all P values<0.001). During median (interquartile range) follow‐up of 4.1 (0.2 to 10) years, 1069 (29%) patients died. Patients with AF had worse survival compared to those without AF (P<0.001). In multivariate analysis adjusted for established risk factors of mortality in HCM, the hazard ratio (95% confidence interval) for the effect of AF on overall mortality was 1.48 (1.27 to 1.71). AF did not have an effect on sudden or nonsudden cardiac death.
Conclusions
In this large referral HCM population, approximately 1 in 5 patients had AF. AF was a strong predictor of mortality, even after adjustment for established risk factors.
doi:10.1161/JAHA.114.001002
PMCID: PMC4309084  PMID: 24965028
atrial fibrillation; hypertrophic cardiomyopathy; mortality
2.  Atrial fibrillation in myocardial infarction patients: impact on healthcare utilization 
American heart journal  2013;166(4):10.1016/j.ahj.2013.07.013.
Background
Atrial fibrillation (AF) often complicates myocardial infarction (MI). While AF adversely impacts survival in MI patients, the impact of AF on healthcare utilization has not been studied.
Methods
The risk of hospitalizations, emergency department (ED) visits, and outpatient visits associated with prior, early-onset (<30 days post-MI) and late-onset (≥30 days post-MI) AF was assessed among incident MI patients from the Olmsted County, MN community.
Results
Of 1502 MI patients, 237 had prior AF, 163 developed new-onset AF, 113 developed late-onset AF, and 989 had no AF. Over a mean follow-up of 3.9 years, 3661 hospitalizations, 5559 ED visits, and 80,240 outpatient visits occurred. After adjustment, compared to patients without AF, those with prior and early-onset AF exhibited a 1.6-fold and 1.4-fold increased risk of hospitalization, respectively. In contrast, late-onset AF carried a 2.2-fold increased risk of hospitalization. The hazard ratios were 1.4, 1.2, and 1.8 for ED visits and 1.5, 1.2, and 1.7 for outpatient visits for prior, early-onset, and late-onset AF. Additional adjustment for time-dependent recurrent MI and heart failure attenuated the results slightly for hospitalizations and ED visits; however, patients with late-onset AF still exhibited more than a 50% increased risk for both utilization measures.
Conclusions
In MI patients, the risk of hospitalizations, ED visits, and outpatient visits differed by the timing of AF onset, with the greatest risk conferred by late-onset AF. AF imparts an adverse prognosis after MI underscoring the importance of its management in MI patients.
doi:10.1016/j.ahj.2013.07.013
PMCID: PMC3811034  PMID: 24093857
3.  Clinical and Angiographic Risk Stratification and Differential Impact on Treatment Outcomes in the BARI 2D Trial 
Circulation  2012;126(17):2115-2124.
Background
The BARI 2D trial assigned patients with type 2 diabetes to prompt coronary revascularization (REV) plus intensive medical therapy versus intensive medical therapy (MED) alone and reported no significant difference in mortality. Among patients selected for CABG, REV was associated with a significant reduction in death/MI/stroke compared with MED. We hypothesized that clinical and angiographic risk stratification would impact the effectiveness of the treatments overall and within revascularization strata.
Methods and Results
An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham risk score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups.
No overall MED versus REV outcome differences were seen in any risk stratum. The five-year risk of death/MI/stroke was 36.8% for MED compared with 24.8% for REV among the 381 CABG-selected patients in the highest angiographic risk tertile (p=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% MED versus 27.1% REV, p=0.010; Hazard Ratio=2.10, p=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the CABG stratum nor any subgroups within the PCI stratum.
Conclusions
Among patients with diabetes and stable ischemic heart disease, a strategy of prompt CABG significantly reduces the rate of death/MI/stroke in those with extensive coronary artery disease or impaired left ventricular function.
Clinical Trial Registration: ClinicalTrials.gov NCT00006305
doi:10.1161/CIRCULATIONAHA.112.092973
PMCID: PMC4104411  PMID: 23008442
Diabetes mellitus; coronary revascularization; coronary artery disease
4.  Use of Evidence-Based Primary and Secondary Cardiac Prevention Therapy Among Outpatients with Atrial Fibrillation 
The American journal of medicine  2013;126(7):625-32.e1.
Background
Patients with atrial fibrillation often have cardiovascular risk factors or known comorbid disease, yet the use of evidence-based primary and secondary prevention cardiac therapy among atrial fibrillation outpatients is unknown.
Methods
Using baseline data collected between June 2010 and August 2011 from 174 sites participating in ORBIT-AF, a US national registry of patients with atrial fibrillation coordinated from Durham, NC, USA, we examined professional guideline -recommended evidence-based therapy use for cardiovascular comorbid conditions and risk factors. Multivariable logistic regression was used to identify factors associated with receipt of all indicated evidence-based therapy.
Results
Among 10096 enrolled patients, 93.5% were eligible for one or more evidence-based therapy. Among those eligible, 46.6% received all indicated therapies: 62.3% received an antiplatelet agent, 72.3% received a β-blocker, 59.5% received an angiotensin converting enzyme or angiotensin receptor blocker, 15.3% received an aldosterone antagonist, 65.7% received a statin, and 58.8% received implantable cardioverter-defibrillator. A minority of patients with coronary artery disease, diabetes mellitus, heart failure, and peripheral vascular disease received all indicated therapies (25.1%, 43.2%, 42.5%, and 43.4%, respectively). A total of 52.4% of patients had controlled hypertension and 74.6% of patients with hyperlipidemia received a statin. Factors associated with non-receipt of all indicated therapies included frailty, comorbid illness, geographic region, and antiarrhythmic drug therapy.
Conclusions
The majority of eligible atrial fibrillation outpatients did not receive all guideline-recommended therapies for cardiovascular comorbid conditions and risk factors. This represents a potential opportunity to improve atrial fibrillation patients’ quality of care and outcomes.
doi:10.1016/j.amjmed.2013.01.037
PMCID: PMC4037289  PMID: 23787195
atrial fibrillation; evidence-based medicine; registry
5.  Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial 
Purpose
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
Patients and Methods
Patients with HER2-positive operable early breast cancer were randomized to 1 of 3 treatment arms: doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or paclitaxel plus trastuzumab then trastuzumab alone (Arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18–21 months post-registration.
Results
A total of 1944 patients completed AC with a satisfactory LVEF and proceeded to post-AC therapy. Post-AC cardiac events (congestive heart failure [CHF] or cardiac death [CD]) were: Arm A, n=3 (2 CHF, 1 CD); Arm B, n=19 (18 CHF, 1 CD); Arm C, n=19 (all CHF); 3-year cumulative incidence was 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event after AC in Arms B and C were older age (P<.003), prior/current antihypertensive agents (P=.005), and lower registration LVEF (P=.033). Incidence of asymptomatic LVEF decreases requiring trastuzumab to be held was 8–10%; LVEF recovered and trastuzumab was restarted in approximately 50% of these patients.
Conclusion
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus control arm but by <4%. Older age, lower registration LVEF, and antihypertensive medications increase the risk of cardiac dysfunction in patients receiving trastuzumab following AC.
doi:10.1200/JCO.2007.13.5467
PMCID: PMC4048960  PMID: 18250349
HER2; trastuzumab; adjuvant; breast cancer; doxorubicin; cyclophosphamide; paclitaxel; cardiac safety
6.  Syncope While Driving: Clinical Characteristics, Causes, and Prognosis 
Circulation  2009;120(11):928-934.
Background
The risk of syncope occurring while driving has obvious implications for personal and public safety. We aimed to define the clinical characteristics, causes, and prognosis of syncope while driving.
Methods and Results
In this case-control study of consecutive patients evaluated for syncope from 1996 through 1998 at an academic medical center, we documented causes, clinical characteristics, and recurrence of syncope while driving. Of 3,877 patients identified, 381 (9.8%) had syncope while driving (“driving group”). Compared with the 3,496 patients (90.2%) who did not have syncope while driving, the driving group was younger (P=.01) and had higher percentages of males (P<.001) and patients with history of any cardiovascular disease (P=.01) and stroke (P=.02). Syncope while driving was commonly caused by neurally mediated syncope (37.3%) and cardiac arrhythmias (11.8%). Long-term survival in the driving group was comparable to that of an age- and sex-matched cohort from the Minnesota population (P=.15). Among the driving group, syncope recurred in 72 patients, 35 of whom (48.6%) had recurrence more than 6 months after the initial evaluation. Recurrences during driving occurred in 10 patients in the driving group, 7 of which (70%) occurred more than 12 months after the initial evaluation.
Conclusions
In our study, neurally mediated syncope was the most common type of syncope while driving. The causes of syncope, the late recurrences of syncope (during ≥6 months of follow-up), and the overall low incidence of recurrent syncope while driving provide useful information to supplement current recommendations on driving for these patients.
doi:10.1161/CIRCULATIONAHA.108.827626
PMCID: PMC3918881  PMID: 19720940
prognosis; survival; syncope
7.  Relationship between sex, shape, and substrate in hypertrophic cardiomyopathy 
American heart journal  2008;155(6):1128-1134.
Background
Hypertrophic cardiomyopathy (HCM) is a disease characterized by substantial genetic, morphologic, and prognostic heterogeneity. Recently, sex-related differences in HCM were reported, with women being older at diagnosis and exhibiting greater left ventricular outflow tract obstruction than men. We sought to evaluate the influence of sex on the HCM phenotype in a large cohort of unrelated patients with genetically and morphologically classified HCM.
Methods
Comprehensive genotyping of 13 HCM-susceptibility genes encoding myofilament and Z-disc proteins of the cardiac sarcomere was performed previously on 382 unrelated patients with HCM. Blinded to the genotype, the septal morphology was graded as reverse-curvature, sigmoidal, apical, or neutral-contour HCM by echocardiography.
Results
Overall, women (a) were significantly older at diagnosis (45.1 ± 20 vs 35.8 ± 17 years, P < .001), (b) had greater left ventricular outflow tract obstruction (53.5 ± 45 vs 41.7 ± 42 mm Hg, P = .009), (c) were more likely to have concomitant hypertension (19% vs 11%, P = .02), and (d) had a higher rate of surgical myectomy (49% vs 36%, P = .01) than men. Interestingly, these sex-based differences were apparent only among patients with sigmoidal HCM (P < .001).
Conclusions
In this largest cohort of comprehensively genotyped and morphologically classified patients with clinically diagnosed HCM, we observed that the striking sex-related differences in the clinical phenotype are confined largely to the subset of mutation-negative sigmoidal HCM. Whereas mutations within the sarcomere appear to dominate the disease process, in their absence, sex has a significant modifying effect, specifically noted in cases of sigmoidal HCM.
doi:10.1016/j.ahj.2008.01.005
PMCID: PMC3912560  PMID: 18513529
8.  Chronic Coronary Artery Disease: Diagnosis and Management 
Mayo Clinic Proceedings  2009;84(12):1130-1146.
Coronary artery disease (CAD) is the single most common cause of death in the developed world, responsible for about 1 in every 5 deaths. The morbidity, mortality, and socioeconomic importance of this disease make timely accurate diagnosis and cost-effective management of CAD of the utmost importance. This comprehensive review of the literature highlights key elements in the diagnosis, risk stratification, and management strategies of patients with chronic CAD. Relevant articles were identified by searching the PubMed database for the following terms: chronic coronary artery disease or stable angina. Novel imaging modalities, pharmacological treatment, and invasive (percutaneous and surgical) interventions have revolutionized the current treatment of patients with chronic CAD. Medical treatment remains the cornerstone of management, but revascularization continues to play an important role. In the current economic climate and with health care reform very much on the horizon, the issue of appropriate use of revascularization is important, and the indications for revascularization, in addition to the relative benefits and risks of a percutaneous vs a surgical approach, are discussed.
doi:10.4065/mcp.2009.0391
PMCID: PMC2787400  PMID: 19955250
9.  Prevalence, Hemodynamics, and Cytokine Profile of Effusive-Constrictive Pericarditis in Patients with Tuberculous Pericardial Effusion 
PLoS ONE  2013;8(10):e77532.
Background
Effusive constrictive pericarditis (ECP) is visceral constriction in conjunction with compressive pericardial effusion. The prevalence of proven tuberculous ECP is unknown. Whilst ECP is distinguished from effusive disease on hemodynamic grounds, it is unknown whether effusive-constrictive physiology has a distinct cytokine profile. We conducted a prospective study of prevalence and cytokine profile of effusive-constrictive disease in patients with tuberculous pericardial effusion.
Methods
From July 2006 through July 2009, the prevalence of ECP and serum and pericardial levels of inflammatory cytokines were determined in adults with tuberculous pericardial effusion. The diagnosis of ECP was made by combined pericardiocentesis and cardiac catheterization.
Results
Of 91 patients evaluated, 68 had tuberculous pericarditis. The 36/68 patients (52.9%; 95% confidence interval [CI]: 41.2-65.4) with ECP were younger (29 versus 37 years, P=0.02), had a higher pre-pericardiocentesis right atrial pressure (17.0 versus 10.0 mmHg, P<0.0001), serum concentration of interleukin-10 (IL-10) (38.5 versus 0.2 pg/ml, P<0.001) and transforming growth factor-beta (121.5 versus 29.1 pg/ml, P=0.02), pericardial concentration of IL-10 (84.7 versus 20.4 pg/ml, P=0.006) and interferon-gamma (2,568.0 versus 906.6 pg/ml, P=0.03) than effusive non-constrictive cases. In multivariable regression analysis, right atrial pressure > 15 mmHg (odds ratio [OR] = 48, 95%CI: 8.7-265; P<0.0001) and IL-10 > 200 pg/ml (OR=10, 95%CI: 1.1, 93; P=0.04) were independently associated with ECP.
Conclusion
Effusive-constrictive disease occurs in half of cases of tuberculous pericardial effusion, and is characterized by greater elevation in the pre-pericardiocentesis right atrial pressure and pericardial and serum IL-10 levels compared to patients with effusive non-constrictive tuberculous pericarditis.
doi:10.1371/journal.pone.0077532
PMCID: PMC3796485  PMID: 24155965
10.  Cardiac Cell Repair Therapy: A Clinical Perspective 
Mayo Clinic Proceedings  2009;84(10):876-892.
From bone marrow transplants 5 decades ago to the most recent stem cell—derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the “broken” heart.
PMCID: PMC2755807  PMID: 19797777
11.  Changing Trends of Hospital Utilization in Patients After their First Episode of Atrial Fibrillation 
The American journal of cardiology  2008;102(5):568-572.
A marked increase in hospitalization for patients with AF has previously been noted. Whether this increase was related to a change in the prevalence of AF, or change in the pattern of practice with respect to the management of AF remains unclear. To determine the trends in hospital utilization after first atrial fibrillation (AF) in a community-based setting, Olmsted County, Minnesota residents diagnosed with first AF during 1980-2000 were identified and followed until 2004. The primary outcome of interest was hospital admission for cardiovascular reasons. Of a total of 4,498 subjects (73±14 years old, 51% men), 2,503 (56%) were admitted to the hospital for cardiovascular causes for at least once during a mean follow-up of 5.5±5.0 years. The risk of first hospitalization was greatest during the first year of AF [cumulative incidence 31%, 95% confidence interval (CI) 30-32%]. First hospitalization was strongly related to age (P<0.0001), but not with sex (P=0.38). During 1980-2000, the age-and sex-adjusted rate of first hospitalization increased, on average, by 2.5% a year (95% CI 1.8-3.2%, P<0.0001), even after multivariable adjustment for comorbidities. When we excluded all hospital admissions for the purposes of AF management, the increase in hospitalization was only 0.8% per year (95% CI 0.05-1.6%, P=0.04), which was no longer significant after multivariable adjustment for comorbidities (P=0.25). In conclusion, the marked increase in hospitalization after first AF diagnosis during 1980-2000 appeared to be largely driven by the changing practice pattern in AF management.
doi:10.1016/j.amjcard.2008.04.025
PMCID: PMC3743254  PMID: 18721513
atrial fibrillation; hospitalization; epidemiology
12.  Provider Specialty and Atrial Fibrillation Treatment Strategies in United States Community Practice: Findings From the ORBIT‐AF Registry 
Background
The prevalence of atrial fibrillation (AF) continues to increase; however, there are limited data describing the division of care among practitioners in the community and whether care differs depending on provider specialty.
Methods and Results
Using the Outcomes Registry for Better Informed Treatment of AF (ORBIT‐AF) Registry, we described patient characteristics and AF management strategies in ambulatory clinic practice settings, including electrophysiology (EP), general cardiology, and primary care. A total of 10 097 patients were included; of these, 1544 (15.3%) were cared for by an EP provider, 6584 (65.2%) by a cardiology provider, and 1969 (19.5%) by an internal medicine/primary care provider. Compared with those patients who were cared for by cardiologists or internal medicine/primary care providers, patients cared for by EP providers were younger (median age, 73 years [interquartile range, IQR, 64, 80 years, Q1, Q3] versus 75 years [IQR, 67, 82 years] for cardiology and versus 76 years [IQR, 68, 82 years] for primary care). Compared with cardiology and internal medicine/primary care providers, EP providers used rhythm control (versus rate control) management more often (44.2% versus 29.7% and 28.8%, respectively, P<0.0001; adjusted odds ratio [OR] EP versus cardiology, 1.66 [95% confidence interval, CI, 1.05 to 2.61]; adjusted OR for internal medicine/primary care versus cardiology, 0.91 [95% CI, 0.65 to 1.26]). Use of oral anticoagulant therapy was high across all providers, although it was higher for cardiology and EP providers (overall, 76.1%; P=0.02 for difference between groups).
Conclusions
Our data demonstrate important differences between provider specialties, the demographics of the AF patient population treated, and treatment strategies—particularly for rhythm control and anticoagulation therapy.
doi:10.1161/JAHA.113.000110
PMCID: PMC3828776  PMID: 23868192
antithrombotic therapy; atrial fibrillation; ORBIT‐AF; outpatient; provider; specialty
13.  Factors Associated with 30-Day Readmission Rates after Percutaneous Coronary Intervention 
Archives of internal medicine  2011;172(2):112-117.
Context
Thirty day readmission rates have become a publicly reported quality performance measure for congestive heart failure (CHF), acute myocardial infarction (AMI), and percutaneous coronary intervention (PCI). However, little is known regarding the factors associated with 30-day readmission after PCI.
Objective
To assess the demographic, clinical, and procedural factors associated with 30-day readmission rates after PCI.
Design, Setting, and Patients
We identified 15,498 PCI hospitalizations (elective or for acute coronary syndromes) from January 1998 through June 2008 at Saint Marys Hospital, Rochester, MN. All were included in this analysis. Multivariable logistic regression models were employed to estimate the adjusted association between demographic, clinical, and procedural variables and 30-day readmission. The association between 30-day readmission and 1-year mortality was estimated using Cox proportional hazards models with readmission as a time dependent covariate and by using landmark analysis.
Main Outcome Measure(s)
All-cause 30-day readmission to any hospital following PCI and 1-year mortality.
Results
Overall, 9.4% of PCIs (n=1,459) were readmitted and 0.68% (n=106) of PCIs resulted in death within 30-days after discharge. After multivariable analysis, female sex, Medicare insurance, less than a high school education, unstable angina, cerebrovascular accident/transient ischemic attack (CVA/TIA), moderate/severe renal disease, chronic obstructive pulmonary disease (COPD), peptic ulcer disease, metastatic cancer, and a length of stay >3 days were associated with an increased risk of 30-day readmission after PCI. Thirty-day readmission after PCI was associated with a higher risk of 1-year mortality (adjusted HR=1.38; 95% CI: 1.08–1.75; p=0.009).
Conclusions
Nearly 1 in 10 patients undergoing PCI were readmitted within 30-days. Thirty-day readmission after PCI was associated with a higher risk of 1-year mortality.
doi:10.1001/archinternmed.2011.569
PMCID: PMC3688066  PMID: 22123752
14.  Atorvastatin Enhance Efficacy of Mesenchymal Stem Cells Treatment for Swine Myocardial Infarction via Activation of Nitric Oxide Synthase 
PLoS ONE  2013;8(5):e65702.
Background
In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury.
Methods and Results
42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both “perfusion” defined by Single-Photon Emission Computed Tomography (−6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and “metabolism” defined by Positron Emission Tomography (−3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA.
Conclusions
Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.
doi:10.1371/journal.pone.0065702
PMCID: PMC3669282  PMID: 23741509
15.  Hypotheses, rationale, design, and methods for prognostic evaluation of cardiac biomarker elevation after percutaneous and surgical revascularization in the absence of manifest myocardial infarction. A comparative analysis of biomarkers and cardiac magnetic resonance. The MASS-V Trial 
Background
Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis.
Methods/Design
The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR.
Discussion
The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass.
doi:10.1186/1471-2261-12-65
PMCID: PMC3468382  PMID: 22898311
Cardiopulmonary bypass; Necrosis markers; Myocardial infarction; PCI; CABG
16.  Rhythm Control Strategies and the Role of Antiarrhythmic Drugs in the Management of Atrial Fibrillation: Focus on Clinical Outcomes 
Atrial fibrillation (AF) is a common disorder that significantly impacts the lives of affected patients. The restoration of sinus rhythm may prevent AF progression and reduce the occurrence of negative sequelae; however, available antiarrhythmic drugs (AADs) have largely failed to demonstrate significant benefit relative to rate control with respect to morbidity and mortality outcomes. The review commentary will address current knowledge regarding the pathologic mechanisms of AF, current trials that investigate rate and rhythm strategies, and future therapies that may change treatment approaches based on preliminary evidence suggesting a more favorable safety profile. The observed outcomes are likely a reflection of the limited efficacy plus poor safety and tolerability of available AADS. However, data from patients who attained and maintained sinus rhythm in a number of clinical studies demonstrate that the achievement of normal sinus rhythm can indeed reduce AF-associated morbidity and mortality. Furthermore, the results of trials designed to assess specific morbidity and mortality outcomes such as cardiovascular death hospitalization suggest that the development of safer AF therapies, whether pharmacologic or nonpharmacologic, can potentially improve clinical outcomes.
doi:10.1007/s11606-010-1574-8
PMCID: PMC3077493  PMID: 21108047
atrial fibrillation; drugs; ablation; stroke; heart failure; outcomes
17.  Ethnic Differences in Cardiovascular Risks and Mortality in Atherothrombotic Disease: Insights From the REduction of Atherothrombosis for Continued Health (REACH) Registry 
Mayo Clinic Proceedings  2011;86(10):960-967.
OBJECTIVE: To determine whether ethnic-specific differences in the prevalence of cardiovascular risk factors and outcomes exist worldwide among individuals with stable arterial disease.
PATIENTS AND METHODS: From December 1, 2003, to June 30, 2004, the prospective, observational REduction of Atherothrombosis for Continued Health (REACH) Registry enrolled 49,602 out-patients with coronary artery disease, cerebrovascular disease, and/or peripheral arterial disease from 7 predefined ethnic/racial groups: white, Hispanic, East Asian, South Asian, Other Asian, black, and Other (comprising any race distinct from those specified). The baseline demographic and risk factor profiles, medication use, and 2-year cardiovascular outcomes were assessed among these groups.
RESULTS: The prevalence of traditional atherothrombotic risk factors varied significantly among the ethnic/racial groups. The use of medical therapies to reduce risk was comparable among all groups. At 2-year follow-up, the rate of cardiovascular death was significantly higher in blacks (6.1%) compared with all other ethnic/racial groups (3.9%; P=.01). Cardiovascular death rates were significantly lower in all 3 Asian ethnic/racial groups (overall, 2.1%) compared with the other groups (4.5%; P<.001).
CONCLUSION: The REACH Registry, a large international study of individuals with atherothrombotic disease, documents the important ethnic-specific differences in cardiovascular risk factors and variations in cardiovascular mortality that currently exist worldwide.
doi:10.4065/mcp.2011.0010
PMCID: PMC3184025  PMID: 21964173
18.  Histologic characterization of hypertrophic cardiomyopathy with and without myofilament mutations 
American Heart Journal  2009;158(5):799-805.
Background
Between 30% and 60% of clinical cases of hypertrophic cardiomyopathy (HC) can be attributed to mutations in the genes encoding cardiac myofilament proteins. Interestingly, it appears that the likelihood of an underlying myofilament mutation can be predicted by echocardiographic assessment of left ventricular morphology. However, it is not known whether genotypically characterized HC exists as a separate entity with discrete phenotypic morphology and histology or to what extent recognized polymorphisms of the renin-angiotensin-aldosterone system (RAAS) influence this relationship. The presence of cardiac myofilament and mutations and RAAS polymorphisms will have a strong association with the severity of histologic features of HC and characteristic septal shape.
Methods
We conducted a retrospective review of histology specimens, obtained at septal myectomy among 181 patients with medically refractory symptomatic HC. All patients underwent comprehensive genetic analysis for mutations in 8 myofilament-encoding genes; a subset was genotyped for 6 known RAAS-polymorphisms. Patients underwent comprehensive echocardiography by an expert blinded to genotype and microscopic status.
Results
Microscopically, severity of myocyte hypertrophy appears to be associated with the presence of recognized HC cardiac myofilament mutations (P = .03). Other histologic features characteristic of HC were not consistently associated with myofilament mutation status. A higher burden of pro-LVH RAAS polymorphisms also appeared to predict only myocyte hypertrophy (P = .01). The presence of RAAS polymorphisms was not associated with the development of a specific septal morphology (P = .6).
Conclusion
Myofilament-positive HC does not appear to represent a distinct clinical phenotypic entity as evidenced by specific histologic characteristics and septal shape.
doi:10.1016/j.ahj.2009.09.006
PMCID: PMC3281581  PMID: 19853701
19.  Predictors of Heart Failure in Patients with Stable Coronary Artery Disease: A PEACE Study 
Circulation. Heart failure  2009;2(3):209-216.
Background
Heart failure (HF) is a disease commonly associated with coronary artery disease (CAD). Most risk models for HF development have focused on acute myocardial infarction (MI) patients. The prevention of events with angiotensin-converting enzyme inhibition (PEACE) population enabled the development of a risk model to predict HF in patients with stable CAD and preserved ejection fraction.
Methods and Results
In the 8290 PEACE patients without pre-existing HF, new-onset HF hospitalizations and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if p<0.05. A risk score was developed and converted to an integer-based scoring system. Among the PEACE population (age 64±8, female 18%, prior MI 55%), there were 268 cases of fatal and non-fatal HF. Twelve characteristics were associated with increased risk of HF along with several baseline medications, including older age, history of hypertension, and diabetes. Randomization to trandolapril independently reduced risk of HF. There was no interaction between trandolapril treatment and other risk factors for HF. The risk score (range 0–21) demonstrated excellent discriminatory power (c-statistic 0.80). Risk of HF ranged from 1.75% in patients with a risk score of 0 to 33% in patients with risk score≥16.
Conclusion
Among patients with stable CAD and preserved EF, traditional and newer factors were independently associated with increased risk of HF. Trandolopril decreased the risk of HF in these patients with preserved EF.
doi:10.1161/CIRCHEARTFAILURE.108.820696
PMCID: PMC3009573  PMID: 19808342
heart failure; coronary artery disease; ACE-inhibitors; predictors
20.  A Sensitive Cardiac Troponin T Assay in Stable Coronary Artery Disease 
The New England journal of medicine  2009;361(26):2538-2547.
BACKGROUND
In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown.
METHODS
We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years.
RESULTS
With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 μg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 μg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P = 0.11).
CONCLUSIONS
After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.
doi:10.1056/NEJMoa0805299
PMCID: PMC2997684  PMID: 19940289
21.  Hypotheses, rationale, design, and methods for prognostic evaluation in type 2 diabetic patients with angiographically normal coronary arteries. The MASS IV-DM Trial 
Background
The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of São Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus.
Methods/Design
The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage.
Discussion
The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro-thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM.
doi:10.1186/1471-2261-10-47
PMCID: PMC2956708  PMID: 20920271
22.  Expression Patterns of Cardiac Myofilament Proteins – Genomic and Protein Analysis of Surgical Myectomy Tissue from Patients with Obstructive Hypertrophic Cardiomyopathy 
Circulation. Heart failure  2009;2(4):325-333.
Background
Mutations in myofilament proteins, most commonly MYBPC3-encoded myosin binding protein C and MYH7-encoded β-myosin heavy chain, can cause hypertrophic cardiomyopathy (HCM). Despite significant advances in structure-function relationships pertaining to the cardiac sarcomere, there is limited knowledge of how a mutation leads to clinical HCM. We therefore set out to study expression and localization of myofilament proteins in left ventricular tissue of patients with HCM.
Methods and Results
Frozen surgical myectomy specimens from 47 patients with HCM were examined and genotyped for mutations involving 8 myofilament-encoding genes. Myofilament protein levels were quantified by western blot with localization graded from immunohistochemical staining of tissue sections. Overall, 25/47 (53%) patients had myofilament-HCM including 12 with MYBPC3-HCM and 9 with MYH7-HCM. Compared to healthy heart tissue, levels of myofilament proteins were increased in patients manifesting a mutation in either gene. Patients with a frameshift mutation predicted to truncate MYBPC3 exhibited marked disturbances in protein localization as compared to missense mutations in either MYBPC3 or MYH7.
Conclusions
In this first expression study in human HCM tissue, increased myofilament protein levels in patients with either MYBPC3 or MYH7-mediated HCM suggest a poison peptide mechanism. Specifically, the mechanism of dysfunction may vary according to the genetic subgroup suggested by a distinctly abnormal distribution of myofilament proteins in patients manifesting a truncation mutation in MYBPC3.
doi:10.1161/CIRCHEARTFAILURE.108.789735
PMCID: PMC2765062  PMID: 19808356
Cardiomyopathy; Hypertrophy; Genetics; Protein
23.  Long-term Risk of Atrial Fibrillation with Symptomatic Gastroesophageal Reflux Disease and Esophagitis 
The American journal of cardiology  2008;102(9):1207-1211.
Mechanisms underlying the triggers and maintenance of atrial fibrillation(AF) are not fully understood. One potential unproven mechanism is that gastroesophageal reflux disease(GERD) where acid reflux induces local and systemic inflammation may increase in triggered activity in the myocardium and pulmonary veins and increase AF risk. A self-report questionnaire was mailed to a random sample of 5288 Olmsted County residents aged 25-74 years to assess the presence and frequency of GERD from 1988-1994. Long-term risk of AF over a period of 11.4 ± 5.0 years was determined through review of clinical evaluations and the electrocardiogram database in those without prior AF. The average age was 53±17 years and 2571(49%) were male. Of these patients, 741 developed AF[cumulative probability of AF was 20%(95% CI 17-22%) at 18 years]. Age[HR 1.09(95% CI 1.08-1.10),p<0.001], male gender[HR 1.81(95% CI 1.53-2.14),p<0.001], hypertension[HR 1.36(95% CI 1.14-1.61),p=0.0006), and heart failure[HR 1.74(95% CI 1.16-2.60),p=0.007) were independently associated with the risk of AF. The presence of any GERD was not associated with risk of AF[HR 0.81(95% CI 0.68-0.96),p=0.014] after adjustment for other risk factors. Frequency of GERD did not significantly impact risk of AF, although patients with more frequent GERD had a slightly higher AF risk. Esophagitis increased risk of AF [HR = 1.94(95% CI 1.35-2.78),p<0.001], but the association did not persist when accounting for other risk factors(p=0.72). In conclusion, in this large population-based study of patients surveyed for GERD, we did not find an association with presence or frequency of symptoms and AF. Patients with esophagitis were more likely to develop AF, although this association requires further study.
doi:10.1016/j.amjcard.2008.06.048
PMCID: PMC2895499  PMID: 18940293
24.  Outcomes of a System-Wide Protocol for Elective and Nonelective Coronary Angioplasty at Sites Without On-site Surgery: The Mayo Clinic Experience 
Mayo Clinic Proceedings  2009;84(6):501-508.
OBJECTIVE: To compare outcomes of percutaneous coronary interventions (PCIs) at 2 community hospitals without on-site surgery (Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital) with a center with on-site surgery (Saint Marys Hospital).
PATIENTS AND METHODS: Using a matched case-control design, we studied 1842 elective and 667 nonelective PCI procedures (myocardial infarction [MI]/cardiogenic shock) performed from January 1, 1999, through December 31, 2007. The quality assurance protocol included operator volume and training, application of a risk-adjustment model, transport protocol, and database participation. We compared in-hospital mortality and/or emergent coronary artery bypass surgery after PCI at Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital, which do not have on-site surgery, with Saint Marys Hospital, a medical center with the capability to perform coronary artery bypass grafting on site.
RESULTS: Of 22 baseline variables, significant imbalances between matched groups were present in only 3 (hyperlipidemia, history of MI, American College of Cardiology/American Heart Association B2/C type lesion) in the elective group and 2 (Canadian Cardiovascular Society class III/IV angina, multivessel disease) in the nonelective group. The primary end point occurred in 0.3%, 0.1%, and 0.6% of patients undergoing elective PCI (P=.07) and 3.3%, 3.3%, and 3.7% of patients undergoing nonelective PCI (P=.65) at Immanuel St. Joseph's Hospital, Franciscan Skemp Healthcare, and Saint Marys Hospital, respectively. The in-hospital mortality rate at Immanuel St. Joseph's Hospital and Franciscan Skemp Healthcare was comparable to that at Saint Marys Hospital for both elective (0.3%, 0.1%, 0.4%; P=.24) and nonelective PCI (2.6%, 2.4%, 3.1%; P=.49). No patient undergoing elective PCI required transfer for emergency cardiac surgery. Of the 21 transfers, 20 (95%) were in the setting of MI and cardiogenic shock or left main/3-vessel disease; 18 patients (86%) survived to discharge.
CONCLUSION: Optimal outcomes with PCI have been observed at community hospitals without on-site cardiac surgical programs with application of a prospective, standardized quality assurance protocol.
In-hospital mortality and/or emergent coronary artery bypass surgery after percutaneous coronary intervention at 2 community hospitals that do not have on-site surgery was compared with a center that has the capability to perform cardiac surgery on site. Outcomes were optimal in the hospitals without on-site surgery with application of a prospective, standardized quality assurance protocol.
PMCID: PMC2688623  PMID: 19483166
25.  Genotype—phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin ☆ 
Background
TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte’s stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.
Methods
DNA was obtained from 389 patients with HCM (215 male, left ventricular wall thickness of 21.6 ± 6 mm) and analyzed for mutations involving all translated exons of CSRP3 and TCAP and targeted HCM-associated exons (2, 3, 4, and 14) of TTN using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. Clinical data were extracted from patient records and maintained independent of the genotype.
Results
Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected. Seven patients were also found to have a concomitant myofilament mutation. Seven patients with a MLP-mutation were found to harbor the DCM-associated, functionally characterized W4R mutation. W4R-MLP was also noted in a single white control subject. Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM.
Conclusions
Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation.
doi:10.1016/j.ymgme.2005.10.008
PMCID: PMC2756511  PMID: 16352453
Genetics; Genes; Hypertrophy; Cardiomyopathy; Z-disc; Muscle LIM protein; Telethonin; TCAP; Titin

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