Carl J Pepine

Dallas Zoo, Dallas, Texas, United States

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Publications (752)5821.45 Total impact

  • Carl J Pepine
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    ABSTRACT: Among angina patients undergoing coronary angiography to further evaluate suspected ischemic heart disease (IHD), "normal" or "non-obstructive" coronary artery disease (CAD) is found in 30% of men and 40-60% of women and appears to be increasing.(1) It is becoming very clear that such patients do not have benign outcomes as documented in larger and larger prospective cohorts.(2-5) Also important are accumulating data indicating that patient-reported outcomes and societal implications rival those observed with obstructive CAD.(6, 7.)
    Circulation 02/2015; · 14.95 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia.
    American Heart Journal. 01/2015;
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    ABSTRACT: Women are more likely than men to develop resistant hypertension, which is associated with excess risk of major adverse outcomes; however, the impact of resistant hypertension in women with ischemia has not been explicitly studied. In this Women's Ischemia Syndrome Evaluation (WISE) analysis, we assessed long-term adverse outcomes associated with apparent treatment-resistant hypertension (aTRH) among women with suspected myocardial ischemia referred for coronary angiography. Women (n=927) were grouped according to baseline blood pressure (BP): normotensive (no hypertension history, BP <140/90 mm Hg, no antihypertensive drugs); controlled (BP <140/90 mm Hg and a hypertension diagnosis or on 1 to 3 drugs); uncontrolled (BP ≥140/90 mm Hg on ≤2 drugs); or aTRH (BP ≥140/90 mm Hg on 3 drugs or anyone on ≥4 drugs). Adverse outcomes (first occurrence of death [any cause], nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or angina) were collected over 10 years of follow-up. Apparent treatment-resistant hypertension prevalence was 10.4% among those with hypertension. Women with aTRH had a greater incidence of adverse outcomes, compared with normotensive women (adjusted hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.94 to 5.43), and women with controlled (HR, 1.77; 95% CI, 1.26 to 2.49) and uncontrolled (HR, 1.62; 95% CI, 1.15 to 2.27) hypertension; outcome differences were evident early in follow-up. Risk of all-cause death was greater in the aTRH group, compared to the normotensive women and women with controlled and uncontrolled hypertension. In this cohort of women with evidence of ischemia, aTRH was associated with a profoundly increased long-term risk of major adverse events, including death, that emerged early during follow-up.
    Journal of the American Heart Association 12/2014; 3(1):e000660.
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    ABSTRACT: Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, select patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size following STEMI. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac magnetic resonance imaging (cMRI). Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cMRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0%±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs (P=0.046) and in those with faster BMC growth rates in CFU-Hill and ECFC functional assays (P=0.033 and P=0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with STEMI and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these STEMI patients, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation.
    Circulation Research 11/2014; · 11.09 Impact Factor
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    ABSTRACT: The efficacy and safety of angiotensin receptor blockers (ARBs) in the older population is unclear.
    American Journal of Hypertension 11/2014; · 3.40 Impact Factor
  • John W. Petersen, Carl J. Pepine
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    ABSTRACT: Many patients with angina and signs of myocardial ischemia on stress testing have no significant obstructive epicardial coronary disease. There are many potential coronary and non-coronary mechanisms for ischemia without obstructive epicardial coronary disease, and prominent among these is coronary microvascular and/or endothelial dysfunction. Patients with coronary microvascular and/or endothelial dysfunction are often at increased risk of adverse cardiovascular events, including ischemic events and heart failure despite preserved ventricular systolic function. In this article, we will review the diagnosis and treatment of coronary microvascular and endothelial dysfunction, discuss their potential contribution to heart failure with preserved ejection fraction, and highlight recent advances in the evaluation of atherosclerotic morphology in these patients, many of whom have non-obstructive epicardial disease.
    Trends in Cardiovascular Medicine 11/2014; · 2.07 Impact Factor
  • Ki E. Park, Carl J. Pepine
    Trends in Cardiovascular Medicine 11/2014; · 2.07 Impact Factor
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    ABSTRACT: Stem/progenitor cell-based therapies offer novel treatment for many prevalent diseases. However, most physicians are not trained or introduced to cell therapy. We describe a model of a training program aimed at empowering physician-scientists with the knowledge and skills necessary for advancing the field of cardiovascular cell therapy. To date, five full-time scholars have completed this training program, obtained a full-time academic appointment in Cardiovascular Disease, and continue to actively contribute to the advancement of cell therapy applications. Another has returned to his parent institution to complete his PhD and several part-time scholars have continued in scholarly activities in other academic programs.
    Regenerative Medicine 11/2014; 9(6):793-797. · 3.87 Impact Factor
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    ABSTRACT: Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN.
    Journal of the American Heart Association 10/2014; 3(6).
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    ABSTRACT: Objective To evaluate the impact of aspirin in stable coronary artery disease. We hypothesized that aspirin’s benefit would be attenuated among individuals with stable coronary artery disease, but no prior ischemic event. Background Aspirin is recommended in stable coronary artery disease based on myocardial infarction and stroke studies. However, benefit among stable coronary artery disease patients who have not suffered an acute ischemic event is uncertain. Methods An observational study was conducted from the INternational VErapamil-SR/Trandolapril STudy cohort. Ambulatory patients ≥50 years of age with clinically stable coronary artery disease requiring antihypertensive drug therapy (n=22,576) were classified ‘ischemic’ if they had a history of unstable angina, myocardial infarction, transient ischemic attack, or stroke at the baseline visit. All others were classified ‘non-ischemic’. Aspirin use was updated at each clinic visit and considered as a time-varying covariate in a Cox regression model. The primary outcome was first occurrence of all-cause mortality, myocardial infarction, or stroke. Results At baseline, 56.7% of all participants used aspirin, which increased to 69.3% at study close out. Among the ‘non-ischemic’ group (n=13,091) aspirin was not associated with a reduction in risk (hazard ratio[HR]=1.11, 95% confidence interval [CI] 0.97–1.28; P=0.13); however, among the ‘ischemic’ group (n=9,485) aspirin was associated with a reduction in risk (HR=0.87, 95%CI 0.77–0.99; P=0.033). Conclusions In patients with stable coronary artery disease and hypertension, aspirin use was associated with reduced risk for adverse cardiovascular outcomes among those with prior ischemic events. Among patients with no prior ischemic events, aspirin use was not associated with a reduction in risk.
    The American Journal of Medicine 10/2014; 128(2). · 5.30 Impact Factor
  • David E Winchester, Carl J Pepine
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    ABSTRACT: Considerable progress has been made over the last few decades in the management of clinically stable coronary heart disease (SCHD), including improvements in interventions (e.g., percutaneous revascularization), pharmacological management, and risk factor control (e.g., smoking, diet, activity level, hypercholesterolemia, hypertension). Although β blockers have long been used for the treatment of SCHD, their efficacy was established in the era before widespread use of reperfusion interventions, modern medical therapy (e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers), or preventive treatments (e.g., aspirin, statins). On the basis of these older data, β blockers are assumed beneficial, and their use has been extrapolated beyond patients with heart failure and previous myocardial infarction, which provided the best evidence for efficacy. However, there are no randomized clinical trials demonstrating that β blockers decrease clinical events in patients with SCHD in the modern era. Furthermore, these agents are associated with weight gain, problems with glycemic control, fatigue, and bronchospasm, underscoring the fact that their use is not without risk. In conclusion, data are currently lacking to support the widespread use of β blockers for all SCHD patients, but contemporary data suggest that they be reserved for a well-defined high-risk group of patients with evidence of ongoing ischemia, left ventricular dysfunction, heart failure, and perhaps some arrhythmias.
    The American Journal of Cardiology 08/2014; · 3.43 Impact Factor
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    ABSTRACT: Background The 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those ≥60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD). Objectives This study sought to evaluate optimal BP in patients ≥60 years of age. Methods Patients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on-treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, ≥150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score–adjusted models. Results Among 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of ≥150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0.0001), and nonfatal stroke (0.86% vs 1.89% vs 2.86%; p<0.0001) compared with groups 2 and 3, respectively. In multiple propensity score–adjusted models, compared with the reference group of <140 mm Hg (group 1), the risk of cardiovascular mortality (adjusted hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.01 to 1.77; p = 0.04), total stroke (adjusted HR: 1.89; 95% CI: 1.26 to 2.82; p = 0.002) and nonfatal stroke (adjusted HR: 1.70; 95% CI: 1.06 to 2.72; p = 0.03) was increased in the group with BP of 140 to <150 mm Hg, whereas the risk of primary outcome, all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke was increased in the group with BP ≥150 mm Hg. Conclusions In hypertensive patients with CAD who are ≥60 years of age, achieving a BP target of 140 to <150 mm Hg as recommended by the JNC-8 panel was associated with less benefit than the previously recommended target of <140 mm Hg.
    Journal of the American College of Cardiology 08/2014; 64(8):784–793. · 15.34 Impact Factor
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    ABSTRACT: Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche following acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular dysfunction (LVD). Methods and Results: BM from 280 patients with IHD and LVD were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% vs. 2.3-2.7% in other cohorts; p < 0.05). BM-derived endothelial colonies were significantly decreased (p < 0.05). Increased BM CD11b(+) cells associated with worse left ventricular ejection fraction (LVEF) after AMI (p < 0.05). While increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% vs. +2.3%, p=0.03, for AMI patients; and +6.6% vs. -0.02%, p=0.021 for chronic IHD patients), decreased BM CD34(+) percentage in chronic IHD patients correlated with decrement in LVEF after cell therapy (-2.9% vs. +0.7%, p=0.0355). Conclusions: In this study we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34(+) cell nadir seven days after AMI, a negative correlation between CD11b percentage and post-infarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and/or reversal of co-morbid BM impairment.
    Circulation Research 08/2014; · 11.09 Impact Factor
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    ABSTRACT: A report from panel members appointed to the Eighth Joint National Committee titled "2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults" has garnered much attention due to its major change in recommendations for hypertension treatment for patients ≥60 years of age and for their treatment goal. In response, certain groups have opposed the decision to initiate pharmacologic treatment to lower blood pressure (BP) at systolic BP ≥150 mm Hg and treat to a goal systolic BP of <150 mm Hg in the general population age ≥60 years. This paper contains 3 sections-an introduction followed by the opinions of 2 writing groups-outlining objections to or support of maintaining this proposed strategy in certain at-risk populations, namely African Americans, women, and the elderly. Several authors argue for maintaining current targets, as opposed to adopting the new recommendations, to allow for optimal treatment for older women and African Americans, helping to close sex and race/ethnicity gaps in cardiovascular disease morbidity and mortality.
    Journal of the American College of Cardiology 07/2014; 64(4):394-402. · 15.34 Impact Factor
  • Journal of hypertension. 07/2014; 32(7):1547.
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    ABSTRACT: In order to identify patients at increased risk of cardiovascular outcomes, apparent treatment resistant hypertension (aTRH) is defined as having a blood pressure above goal despite the use of three or more antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. In light of growing scientific interest in the treatment of this group, a multi-stakeholder think-tank was convened to discuss the current state of knowledge, improve the care of these patients, and identify appropriate study populations for future observational and randomized trials in the field. Although recent epidemiologic studies in selected populations estimate the prevalence of aTRH is 10-15%, further large-scale observational studies will be needed to better elucidate risk factors. In order to spur the development of therapies for aTRH, the development of an “aTRH” label for pharmacologic and device therapies with a developmental pathway including treatment added to the use of existing therapies is favored. Although demonstration of adequate blood pressure lower should be sufficient to gain FDA approval for therapies targeting aTRH, assessment of improvement in quality of life and cardiovascular outcomes are also desirable and considered in CMS coverage decisions. Device trials under the aTRH label will need uniform and consistent processes for defining appropriate patient populations and post-approval registries assessing both long-term safety and duration of responses. Finally, patients with aTRH are likely to benefit from evaluation by a hypertension team in order to assure proper patient identification, diagnostic work-up and therapeutic management prior to consideration of advanced or novel therapies to lower BP.
    American Heart Journal 06/2014; · 4.56 Impact Factor
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    ABSTRACT: Endothelial dysfunction is highly prevalent and associated with adverse outcomes among patients without obstructive coronary artery disease (CAD). Angiotensin II inhibition may improve endothelial function, but with continued treatment, "aldosterone escape" may occur. Thus, it is unknown if adding aldosterone blockade further improves endothelial function.
    American Heart Journal 06/2014; 167(6):826-32. · 4.56 Impact Factor
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    ABSTRACT: To understand the role of bone marrow mononuclear cells in the treatment of acute myocardial infarction, this overview offers a retrospective examination of strengths and limitations of 3 contemporaneous trials with attention to critical design features and provides an analysis of the combined data set and implications for future directions in cell therapy for acute myocardial infarction.
    Circulation Research 05/2014; 114(10):1564-8. · 11.09 Impact Factor
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    ABSTRACT: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD. TFC was determined in a sample of women with no obstructive CAD enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC). A total of 298 women, with angiograms suitable for TFC analysis and long-term (6-10 year) follow up data, were included in this sub-study. Their age was 55±11 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC >35, 15% in women with a cTFC ≤35, P<0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality. In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.
    PLoS ONE 05/2014; 9(5):e96630. · 3.53 Impact Factor
  • John W Petersen, Carl J Pepine
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    ABSTRACT: Considerable evidence has accumulated to counter older concepts of a categorical definition of ischemic heart disease (IHD) as simply the presence or absence of a flow-limiting stenosis. Revised concepts increasingly recognize IHD as a continuous spectrum that is not limited to obstructive plaque seen by angiography in an epicardial coronary artery. Included in this spectrum are functional disorders of the large and smaller coronary blood vessels. These smaller vessels, collectively the coronary microcirculation, comprise most of the coronary blood vessels and control the volume and distribution of blood flow to myocardium.
    Circulation 04/2014; · 14.95 Impact Factor

Publication Stats

23k Citations
5,821.45 Total Impact Points


  • 2014
    • Dallas Zoo
      Dallas, Texas, United States
  • 1978–2014
    • University of Florida
      • • Division of Cardiovascular Medicine
      • • Department of Medicine
      Gainesville, Florida, United States
  • 2013
    • Rhode Island Hospital
      Providence, Rhode Island, United States
    • Vancouver General Hospital
      Vancouver, British Columbia, Canada
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2011–2013
    • Duke University Medical Center
      Durham, North Carolina, United States
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2010–2013
    • VA San Diego Healthcare System
      San Diego, California, United States
    • Mayo Clinic - Rochester
      • Department of Cardiovascular Diseases
      Rochester, Minnesota, United States
    • University of Missouri - Kansas City
      Kansas City, Missouri, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of Texas Health Science Center at Houston
      • Coordinating Center for Clinical Trials (CCCT)
      Houston, Texas, United States
  • 2012
    • Allegheny General Hospital
      • Department of Cardiology
      Pittsburgh, Pennsylvania, United States
    • Uniformed Services University of the Health Sciences
      • Department of Medical & Clinical Psychology
      Bethesda, MD, United States
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2010–2012
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2010–2011
    • Abbott Northwestern Hospital
      Minneapolis, Minnesota, United States
  • 1995–2011
    • American College of Cardiology
      Washington, Washington, D.C., United States
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1999–2010
    • Cedars-Sinai Medical Center
      • • Division of Cardiology
      • • Department of Medicine
      Los Angeles, CA, United States
  • 2009
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, IL, United States
    • National University (California)
      San Diego, California, United States
  • 2004–2009
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, California, United States
    • Rush University Medical Center
      Chicago, Illinois, United States
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2008
    • University of Barcelona
      Barcino, Catalonia, Spain
  • 2007
    • The University of Chicago Medical Center
      • Department of Medicine
      Chicago, Illinois, United States
    • Florida Institute of Technology
      Melbourne, Florida, United States
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
    • Beth Israel Medical Center
      • Department of Medicine
      New York City, New York, United States
  • 2006
    • St. Luke's Hospital
      Cedar Rapids, Iowa, United States
  • 2001–2006
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, PA, United States
  • 2005
    • Rush Medical College
      Chicago, Illinois, United States
    • World Institute for Scientific Exploration (WISE)
      Baltimore, Maryland, United States
    • Abbott Laboratories
      • Abbott Laboratories
      North Chicago, Illinois, United States
  • 2002
    • George Washington University
      • Division of Cardiology
      Washington, D. C., DC, United States
  • 2000
    • Furman University
      • Department of Health Sciences
      Greenville, SC, United States
  • 1995–2000
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, Alabama, United States
  • 1996–1999
    • University of Florida Health Science Center-Jacksonville
      Jacksonville, Florida, United States
    • Johns Hopkins Medicine
      • Division of Cardiology
      Baltimore, MD, United States
    • Baylor College of Medicine
      • Department of Medicine
      Houston, TX, United States
  • 1998
    • Brown University
      • Division of Cardiology
      Providence, RI, United States
    • East Tennessee State University
      • Division of Cardiology
      Johnson City, TN, United States
  • 1996–1998
    • Brigham and Women's Hospital
      • Center for Brain Mind Medicine
      Boston, MA, United States
  • 1994–1997
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1991
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • Thomas Jefferson University Hospitals
      • Division of Cardiology
      Philadelphia, Pennsylvania, United States
  • 1981–1984
    • Florida Hospital
      Florida, United States