Ravi Marfatia

Matrix Metalloproteinase Activation Predicts Amelioration of Remodeling After Dietary Modification in Injured Arteries

Objective—To establish and validate early noninvasive imaging of matrix metalloproteinase (MMP) activation for monitoring the progression of vascular remodeling and response to dietary modification. Methods and Results—Apolipoprotein E−/− mice that were fed a high-fat diet underwent left common carotid artery wire injury. One week after surgery, a group of animals were withdrawn from the high-fat diet. The other group of animals continued that diet throughout the study. Micro single-photon emission computed tomographic (microSPECT)/CT imaging with RP805 (a 99mTc-labeled tracer targeting activated MMPs) was repeatedly performed at 2 and 4 weeks after surgery. Histological analysis at 4 weeks showed significant left carotid neointima formation, monocyte/macrophage infiltration, and upregulation of several MMPs, which were ameliorated by withdrawal from the high-fat diet. In vivo microSPECT/CT images visualized significant RP805 uptake, reflecting MMP activation, in the injured carotid arteries. MMP activation was reduced as early as 1 week after withdrawal from the high-fat diet and significantly correlated with neointimal area at 4 weeks after surgery. Conclusion—MMP activation predicts the progression of vascular remodeling and can track the effect of dietary modification after vascular injury.

Integrin-Targeted Imaging of Inflammation in Vascular Remodeling

Objective—Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express &agr;v&bgr;3 integrin. We used an &agr;v integrin-specific tracer, 99mTc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation. Methods and Results—The binding of a fluorescent homologue of NC100692 to &agr;v&bgr;3 on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl2. NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl2-exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant difference in normalized &agr;v, &bgr;3, or &bgr;5 mRNA expression between right and left carotid arteries. Finally, NC100692 uptake strongly correlated with macrophage marker expression in carotid arteries. Conclusion—NC100692 imaging can detect vessel wall inflammation in vivo. If further validated, &agr;v-targeted imaging may provide a noninvasive approach for identifying patients who are at high risk for vascular events and tracking the effect of antiinflammatory treatments.

INtensive versus standard ambulatory blood pressure lowering to prevent functional DeclINe in the ElderlY (INFINITY).

Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages ≥75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of ≤130 mm Hg or standard to achieve a goal 24-hour systolic BP of ≤145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease.

Effects of Telmisartan with Hydrochlorothiazide versus Valsartan with Hydrochlorothiazide in Patients with Moderate-to-Severe Hypertension

Combination therapy is recommended for patients with blood pressure (BP) significantly above goal by recent consensus guidelines around the globe. The use of angiotensin II receptor blockers (ARBs) alone or in combination with a thiazide diuretic is a preferred treatment strategy due to both efficacy and safety considerations. However, there are few data known about the benefits of ARB-diuretic combination therapy in patients with moderate-to-severe hypertension. We performed a subanalysis from two large clinical trials that compared the antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg, both combined with hydrochlorothiazide (HCTZ) 25 mg in a subpopulation of 725 patients with moderate-to-severe hypertension (systolic BP SBP ≥ 160 mm Hg). Treatment with telmisartan-HCTZ induced significantly greater reductions in BP (−31.1/−18.3 mm Hg) than valsartan-HCTZ (−28.4/−16.3 mm Hg; SBP P = 0.0265, diastolic BP P = 0.0041). More patients receiving the telmisartan combination achieved a BP goal < 140/90 mm Hg than those receiving valsartan-HCTZ. There were similar safety and tolerability data for the two active treatment groups. These findings support the use of longer-acting ARBs combined with higher doses of thiazide diuretic to improve BP control in patients with moderate-to-severe hypertension.

Effect of Adjuvant Chemotherapy on Left Ventricular Remodeling in Women with Newly Diagnosed Primary Breast Cancer: A Pilot Prospective Longitudinal Cardiac Magnetic Resonance Imaging Study

Purpose: The aim of this study was to assess the left ventricular (LV) remodeling response to chemotherapy in low–cardiac-risk women with newly diagnosed nonmetastatic breast cancer. Cardiotoxic effects of chemotherapy are an increasing concern. To effectively interpret cardiac imaging studies performed for screening purposes in patients undergoing cancer therapy it is necessary to understand the normal changes in structure and function that may occur. Methods: Twenty women without preexisting cardiovascular disease, of a mean age of 50 years, newly diagnosed with nonmetastatic breast cancer and treated with anthracycline or trastuzumab, were prospectively enrolled and evaluated at four time points (at baseline, during chemotherapy, 2 weeks after chemotherapy, and 6 months after chemotherapy) using cardiac magnetic resonance imaging, blood samples, and a clinical questionnaire. Results: Over a 6-month period, the left ventricular ejection fraction (%) decreased (64.15±5.30 to 60.41±5.77, P<0.002) and the LV end-diastolic (mm) and end-systolic (mm) volumes increased (124.73±20.25 to 132.21±19.33, P<0.04 and 45.16±11.88 to 52.57±11.65, P<0.00, respectively). The LV mass (g) did not change (73.06±11.51 to 69.21±15.3, P=0.08), but the LV mass to LVEDV ratio (g/mm) decreased (0.594±0.098 to 0.530±0.124, P<0.04). Conclusions: In low–cardiac-risk women with nonmetastatic breast cancer, the increased LV volume and a mildly decreased left ventricular ejection fraction during and after chemotherapy do not seem to be associated with laboratory or clinical evidence of increased risk for heart failure.

Applications of Molecular Small-Animal Imaging in Cardiology

Cardiovascular disease (CVD) is a leading cause of death in both industrialized and developing countries, claiming more than 800,000 lives in the US and millions more in the rest of the world in recent years. Despite recent reduction in age-specific CVD mortality rate, increasing longevity, urbanization and industrialization has led to a rapid increase in the prevalence of CVD in both developed and developing nations. With surging health care costs the focus is shifting from treatment to prevention of disease as well as developing cost effective diagnostic and prognostic strategies. Conventional imaging modalities such as coronary angiography, echocardiography, myocardial perfusion imaging, computed tomography (CT) and magnetic resonance imaging (MRI), have been historically used to define structure and function as well as to monitor response to therapy, relying on the contrast provided by heterogeneity of anatomy, physiology and metabolism. As such, they provide valuable anatomical and physiological information about vasculature (e.g., extent of the disease, location, presence of calcification) and the myocardium (e.g., ejection fraction, wall thickening, dilatation, viability and cardiac output). However, traditional imaging modalities have limited use in detecting molecular and cellular events that determine the course of disease and its response to therapeutic interventions. Emerging molecular imaging modalities utilizing probes targeted at relevant molecular and cellular events can advance research on pathophysiology, allow early detection of disease, assist in the design of novel therapies, facilitate monitoring disease activity and response to therapy, and provide prognostic information.

Abstract P3-15-11: Chemotherapy-related fatigue in low cardiac risk breast cancer patients: A sign of cardiotoxicity?

BACKGROUND: Fatigue in breast cancer patients receiving chemotherapy is a common occurrence and is related to multiple factors. Limited studies exist regarding fatigue as an early symptom of cardiotoxicity. HYPOTHESIS: Fatigue will occur in a majority of early stage breast cancer patients receiving adjuvant chemotherapy despite normal systolic function by echocardiogram and cardiac magnetic resonance imaging (CMR). METHODS: We prospectively enrolled 20 patients with stage I-IIb breast cancer undergoing adjuvant anthracycline or trastuzumab based chemotherapy. Mean age 49 ± 12 years. Seventeen patients completed all 4 time points. CMR, echocardiography and cardiac biomarkers were obtained at 4 different time-points: baseline, during chemotherapy and then 2 weeks and 6 months after completion of chemotherapy. A heart failure questionnaire was completed at each time point with physical examination. Statistics were analyzed by a linear mixed model. RESULTS: Symptoms of fatigue increased during chemotherapy but did not reach statistical significance (table 1). CMR detected significant increases in LV end-diastolic and end-systolic volumes and a significant decrease LV ejection fraction (table2). Biomarkers of cardiac injury troponin I, c-reactive protein, and brain natriuretic peptide did not change significantly. CONCLUSION: Transient fatigue occurred in a majority of patients during chemotherapy but was not clinically significant. However, transient increases in volumetric size did reach statistical significance and paralleled fatigue symptoms. These changes may indicate early cardiotoxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-11.

Intramural hematoma of the aorta as a presenting sign of accelerated hypertension.

Funding: National Institutes of Health #R01 AG022092-06 (Dr hite). Conflict of Interest: None. Authorship: All authors had full access to the data and played a role in writing the manuscript. Requests for reprints should be addressed to William B. White, MD, Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3940. E-mail address: wwhite@nso1.uchc.edu

Treating Pain and Inflammation in Hypertension

In recent years, there has been a substantial evaluation of the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors, including in patients with and without hypertension. In this chapter, the focus is on the effects of both NSAIDs and COX-2 inhibitors on blood pressure. Clinical trials and observational studies reviewing the relationships among NSAIDs, blood pressure, and blood pressure destabilization are discussed. The results of clinical trial for NSAIDs and COX-2 inhibitors have shown varying levels of destabilization of blood pressure control in treated hypertensive patients as well as variable incident rates in the development of arrhythmias, congestive heart failure, myocardial infarction, and stroke. Nonselective and COX-2-selective NSAIDs can be used with caution in selected arthritis patients with hypertension and very stable CV disorders (excluding congestive heart failure and moderate-to-severe kidney dysfunction) when the individual clinical benefit of anti-inflammatory therapy outweighs the CV and gastrointestinal risk. Consensus from various specialty groups suggests using NSAIDs at the lowest doses and for the shortest periods of time for the relief of pain and inflammation when patients are older and are at an increased risk for gastrointestinal or cardiovascular risk.

OT1-02-12: Early Detection of Cardiotoxicity by Advanced Cardiac Imaging and a Novel Biomarker in Breast Cancer Patients Undergoing Chemotherapy.

Background The survival rate of breast cancer patients has increased due to improvements in cancer treatment. However, many survivors develop irreversible or reversible cardiotoxicity associated with anthracycline or trastuzumab therapy, respectively. To detect cardiac damage, the currently accepted method is to measure left ventricular ejection fraction (LVEF) by echocardiography, which lacks the sensitivity to predict early cardiac dysfunction. Early identification of cardiotoxicity is essential to cancer survivors, as development of cardiomyopathy carries a worse outcome independent of cancer prognosis. Currently, there are no accepted guidelines for the early detection of myocardial injury. The use of cardiac biomarkers and more sensitive echocardiographic techniques have expanded options for monitoring, but have yet to reach a consensus. Hence, our study will evaluate the potential predictive value of novel cardiac biomarkers and advanced echocardiographic and cardiac magnetic resonance imaging (CMR) techniques to detect subclinical myocardial damage. Our findings may be applicable for monitoring new antineoplastic agents during food and drug administration (FDA) clinical trials. Trial Design Prospective cohort study with internal control of 20 patients newly diagnosed with breast cancer. The trial will assess endpoints at baseline, 2 weeks after initiation of therapy, and 2 weeks and 6 months after chemotherapy completion. 1. Primary Endpoint a. Decline in left ventricular ejection fraction assessed by CMR and 3D-echo not detected by conventional methods b. Presence of either myocardial fibrosis or edema detected by CMR c. Changes in myocardial deformation detected by echo or CMR strain d. Increase in cardiac biomarkers (Serum caspase-3 p17 peptide, Troponin I, B-type natriuretic peptide) and possible correlation with imaging parameters 2. Secondary Endpoint a. Development New York Heart Association class 1 to 4 symptoms b. Decrease in LVEF of ≥5% to ≤50% with or without symptoms Eligibility Criteria Inclusion Criteria: 1. Newly diagnosed stage I, II, or III breast cancer 2. Age between 18 and 75 years old. 3. Treatment with trastuzumab or anthracycline-based chemotherapy Exclusion Criteria: 1. History of cardiovascular disease 2. Pacemaker 3. History of mediastinal radiotherapy 4. Creatinine clearance 5. Serum bilirubin >2.0 mg/dl, ALT and AST > 100 U/1) 6. Hypertension, uncontrolled >140/90 7. LVEF 8. Claustrophobia Specific Aims 1. Detect early myocardial injury. 2. Evaluate early predictors of left ventricular dysfunction. 3. Evaluate timing of monitoring during or post treatment Statistical Method This is a pilot study and 20 patients are required to reach statistical significance with 85% power. All values will be analyzed as mean±SD or n (%). Categorical indicators will be analyzed using nonparametric statistics such as Cochran9s Q. Changes in imaging and biomarker parameters will be assessed using analysis of variance, while correlation between the two will be assessed using mixed models appropriate for binary outcome. Significance will be accepted at p ≤0.05 for all tests. Present accrual and target accrual Nine subjects are enrolled with a goal of 20. Contact for people interested in trial: 1. Dr. Erick Avelar, eavelar@uchc.edu 2. Dr. Susan Tannenbaum, stannenbaum@uchc.edu Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-12.