Relationship of cardiac magnetic resonance imaging and myocardial biopsy in the evaluation of nonischemic cardiomyopathy.

This study was performed to determine the relative role of cardiac magnetic resonance (CMR) imaging and endomyocardial biopsy (EMB) in the evaluation of cardiomyopathy. Sixty-six patients with a clinical diagnosis of nonischemic dilated cardiomyopathy or restrictive cardiomyopathy underwent both EMB and CMR imaging as part of their diagnostic evaluation. The authors retrospectively reviewed the results of these two methods to determine their diagnostic impact and congruency. CMR imaging provided data on cardiac anatomy, left ventricular volumes, mass, and function in 85% of the patients, uncovered fibrosis in 31%, myocardial ischemia in 7%, and fibrofatty infiltration in two patients. EMB provided the histologic findings of cardiomyocyte hypertrophy in 77% of patients and substantial interstitial fibrosis in 59%. Six patients had EMB-proven amyloid heart disease, which was detected by CMR imaging in two. CMR imaging showed patterns of late gadolinium enhancement supportive of infiltrative disease or inflammation in 6 patients with EMB-proven definite (n=3) or borderline (n=3) myocarditis, but failed to do so in two other patients with borderline and two with resolving myocarditis. At the present time, CMR imaging and EMB remain complementary procedures in the evaluation of cardiomyopathic conditions.

Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

BACKGROUND: Interfering with angiogenesis is an effective, widely used approach to cancer therapy, but antiangiogenic therapies have been associated with important systemic cardiovascular toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction. As the use of vascular endothelial growth factor signaling pathway (VSP) inhibitors broadens to include older patients and those with existing cardiovascular disease, the adverse effects are likely to be more frequent, and cardiologists will increasingly be enlisted to help oncologists manage patients who develop adverse cardiovascular effects. METHODS: The Cardiovascular Toxicities Panel of the National Cancer Institute reviewed the published literature and abstracts from major meetings, shared experience gained during clinical development of VSP inhibitors, and contributed extensive clinical experience in evaluating and treating patients with cancer with cardiovascular disease. This report was edited and approved by the National Cancer Institute Investigational Drug Steering Committee. It presents the panel's expert opinion on the current clinical use and future investigation for safer, more expansive use of these drugs. RESULTS AND CONCLUSIONS: The panel recommends that physicians (1) conduct and document a formal risk assessment for existing cardiovascular disease and potential cardiovascular complications before VSP inhibitor treatment recognizing that preexisting hypertension and cardiovascular disease are common in patients with cancer, (2) actively monitor for blood pressure elevations and cardiac toxicity with more frequent assessments during the first treatment cycle, and (3) aggressively manage blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications of VSP inhibitor therapy.

Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors.

Hypertension is a mechanism-based toxic effect of drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP). Substantial evidence exists for managing hypertension as a chronic condition, but there are few prospectively collected data on managing acute hypertension caused by VSP inhibitors. The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate this problem, to make recommendations to the Cancer Therapy Evaluation Program on further study, and to structure an approach for safe management by treating physicians. The panel reviewed: the published literature on blood pressure (BP), hypertension, and specific VSP inhibitors; abstracts from major meetings; shared experience with the development of VSP inhibitors; and established principles of hypertension care. The panel generated a consensus report including the recommendations on clinical concerns summarized here. To support the greatest possible number of patients to receive VSP inhibitors safely and effectively, the panel had four recommendations: 1) conduct and document a formal risk assessment for potential cardiovascular complications, 2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy, 3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment, and 4) manage BP with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors). Proper agent selection, dosing, and scheduling of follow-up should enable maintaining VSP inhibition while avoiding the complications associated with excessive or prolonged elevation in BP.

Latent development of occlusive coronary atherosclerosis as a cause of decompensation of non-ischemic dilated cardiomyopathy.

Four patients with chronically well-compensated, non-ischemic dilated cardiomyopathy (NIDC) presented with occlusive atherosclerotic coronary artery disease as the cause of subacute decompensation (FC III-IV heart failure) 8-13 years following the diagnosis of NIDC. In addition to the atherogenic condition of heart failure, 3 of the patients acquired major atherosclerotic risk factors (dyslipidemia, diabetes mellitus) during the interval between the diagnoses of NIDC and problematic atherosclerotic coronary disease. For each patient, dyspnea on exertion was the primary symptom during the subacute decompensation. Only 1 patient noted precordial chest pain in the form of atypical angina during some of the dyspneic events. The diagnosis of occlusive coronary artery disease was made by coronary angiography, followed by angioplasty-stent deployment in 3 patients and coronary artery bypass surgery in 1; all improved to their baseline FC I-II status following these coronary interventions. As survival of patients with NIDC increases, occlusive coronary artery disease may enter an otherwise stable clinical course to provoke unanticipated decompensation (principally dyspnea), and can do so without causing angina pectoris as a heralding symptom.

Serum response factor neutralizes Pur alpha- and Pur beta-mediated repression of the fetal vascular smooth muscle alpha-actin gene in stressed adult cardiomyocytes.

Mouse hearts subjected to repeated transplant surgery and ischemia-reperfusion injury develop substantial interstitial and perivascular fibrosis that was spatially associated with dysfunctional activation of fetal smooth muscle alpha-actin (SM alpha A) gene expression in graft ventricular cardiomyocytes. Compared with cardiac fibroblasts in which nuclear levels of the Sp1 and Smad 2/3 transcriptional-activating proteins increased markedly after transplant injury, the most abundant SM alpha A gene-activating protein in cardiomyocyte nuclei was serum response factor (SRF). Additionally, cardiac intercalated discs in heart grafts contained substantial deposits of Pur alpha, an mRNA-binding protein and known negative modulator of SRF-activated SM alpha A gene transcription. Activation of fetal SM alpha A gene expression in perfusion-isolated adult cardiomyocytes was linked to elevated binding of a novel protein complex consisting of SRF and Pur alpha to a purine-rich DNA element in the SM alpha A promoter called SPUR, previously shown to be required for induction of SM alpha A gene transcription in injury-activated myofibroblasts. Increased SRF binding to SPUR DNA plus one of two nearby CArG box consensus elements was observed in SM alpha A-positive cardiomyocytes in parallel with enhanced Pur alpha:SPUR protein:protein interaction. The data suggest that de novo activation of the normally silent SM alpha A gene in reprogrammed adult cardiomyocytes is linked to elevated interaction of SRF with fetal-specific CArG and injury-activated SPUR elements in the SM alpha A promoter as well as the appearance of novel Pur alpha protein complexes in both the nuclear and cytosolic compartments of these cells.

A heart failure specialist's perspective on cardiac surgery for heart failure.

Aside from cardiac transplantation, ventricular assist devices, and the total artificial heart, cardiac surgery now also plays a major role in the overall management of the heart failure patient. For patients with heart failure, cardiac surgery has steadily moved from being a predominant rescue procedure (eg, aneursymectomy, rupture repair, transplantation) to surgical interventions that can prevent or delay the progression of cardiac dysfunction and failure; these operations now include coronary artery bypass surgery, ventricular restoration, and valvular repair/replacement. This article discusses the role and impact of these specific surgical interventions in the setting of ventricular dysfunction and heart failure.

Dobutamine-induced eosinophilia.

A man with dilated cardiomyopathy presented with decompensated heart failure and marked eosinophilia. After extensive clinical and laboratory evaluation for hypereosinophilic syndrome, including a myocardial biopsy, it was determined by means of rechallenge (second dobutamine infusion) that the patient was afflicted with dobutamine-induced eosinophilia. This report is important because of the high utilization rate of this drug in a sick population. Simply discontinuing it or switching to another agent can avert the high cost and risk of the evaluation for hypereosinophilic syndrome in this compromised group of patients.

Metastatic melanoma of the left ventricle: cardiac imaging in the diagnosis and surgical approach.

A mass lesion occupying the left ventricle was noted on a screening CT scan in a 42-year-old man with a history of malignant melanoma. Subsequent echocardiography and cardiac MR imaging provided further hemodynamic and anatomic characterization of the lesion. These studies were also essential in guiding the proper surgical approach to allow extensive resection of the large mass without disrupting cardiac structures and function. The unique clinical aspects of this case are the unusual location for a lone cardiac metastasis of melanoma and the asymptomatic presentation despite the large size of the tumor and its apparent obstruction of ventricular outflow. The clinical and imaging features of this patient's threatening cardiac lesion are presented.

Dilated Cardiomyopathy.

The management of patients with dilated cardiomyopathy (DCM) heart failure starts with the determination of the underlying diagnosis, definition of the hemodynamic character (eg, systolic, diastolic, valvular, right- and left-sided heart dysfunction), recognition of complicating factors (eg, atrial fibrillation, renal dysfunction), and consideration for any surgically remedial lesions (eg, severe valvular regurgitation, high-grade coronary artery occlusive disease). Angiotensin-converting enzyme inhibitors, beta-blocking agents, digoxin, and judicious diuretic administration make up the therapeutic plan for patients with symptomatic DCM heart failure. Angiotensin-converting enzymes are indicated for patients with DCM who have mild or no detectable symptoms; whether this subgroup would benefit from long-term beta-blockade remains to be established. Spirolactone also has been shown to be effective in patients with more advanced stages of heart failure. Biventricular pacing (cardiac resynchronization therapy) recently has been approved for use in patients with DCM and a left ventricular or intraventricular conduction defect and a QRS duration of longer than 140 msec. More intense pharmacotherapy, mechanical devices, and transplantation are directed at patients with severely symptomatic end-stage DCM. The effectiveness of any heart failure treatment plan is very much dependent on nonpharmacologic approaches, including dietary measures, exercise conditioning, and similar considerations, all of which are best delivered by dedicated heart failure programs.