Carey Kimmelstiel

Randomized, Controlled Evaluation of Short- and Long-Term Benefits of Heart Failure Disease Management Within a Diverse Provider Network The SPAN-CHF Trial

Background—Several trials support the usefulness of disease management (DM) for improving clinical outcomes in heart failure (HF). Most of these studies are limited by small sample size; absence of concurrent, randomized controls; limited follow-up; restriction to urban academic centers; and low baseline use of effective medications. Methods and Results—We performed a prospective, randomized assessment of the effectiveness of HF DM delivered for 90 days across a diverse provider network in a heterogeneous population of 200 patients with high baseline use of approved HF pharmacotherapy. During a 90-day follow-up, patients randomized to DM experienced fewer hospitalizations for HF [primary end point, 0.55±0.15 per patient-year alive versus 1.14±0.22 per patient-year alive in control subjects; relative risk (RR), 0.48, P=0.027]. Intervention patients experienced reductions in hospital days related to a primary diagnosis of HF (4.3±0.4 versus 7.8±0.6 days hospitalized per patient-year; RR, 0.54; P<0.001), cardiovascular hospitalizations (0.81±0.19 versus 1.43±0.24 per patient-year alive; RR, 0.57; P=0.043), and days in hospital per patient-year alive for cardiovascular cause (RR, 0.64; P<0.001). Intervention patients showed a trend toward reduced all-cause hospitalizations and total hospital days. On long-term (mean, 283 days) follow-up, there was substantial attrition of the 3-month gain in outcomes, with sustained significant reduction only in days in hospital for cardiac cause. Conclusions—In a population with high background use of standard HF therapy, a DM intervention, uniformly delivered across varied clinical sites, produced significant short-term improvement in HF-related clinical outcomes. Longer-term benefit likely requires more active chronic intervention, even among patients who appear clinically stable.

Role of Percutaneous Septal Ablation in Hypertrophic Obstructive Cardiomyopathy

Case Presentation : A 58-year-old diabetic man was referred for severe progressive exertional dyspnea consistent with New York Heart Association (NYHA) functional class III. Six years earlier, he underwent coronary artery bypass grafting, complicated by a sternal wound infection. Physical examination was notable for a bifid carotid pulse and loud apical systolic ejection murmur. Echocardiography documented hyperdynamic left ventricular (LV) systolic function and asymmetric hypertrophy confined to the basal ventricular septum (measuring 20 mm in thickness) consistent with hypertrophic cardiomyopathy (HCM). Continuous wave Doppler estimated a 65 mm Hg subaortic gradient due to dynamic systolic anterior motion of the mitral valve with septal contact. Coronary angiography showed patent bypass grafts. Medical management with β-blockers and verapamil was ineffective in controlling symptoms. Catheter-based intervention was considered for this patient to reduce outflow obstruction and symptoms. HCM is a relatively common genetic disease with important clinical consequences, including sudden death in the young and disability due to heart failure at any age.1,2 It is estimated that progression to NYHA functional classes III/IV associated with obstruction to LV outflow occurs in about 10% of HCM patients who are limited largely by exertional dyspnea, chest pain, fatigue, and occasionally orthopnea or nocturnal dyspnea.1,2 Long-term consequences of HCM attributable to outflow obstruction have been emphasized, particularly progression of disabling symptoms and death related to heart failure.2 The traditional first line of therapy to improve quality of life in HCM patients with symptoms and outflow obstruction has been administration of negative inotropic agents, including β-blockers, verapamil, and disopyramide.1,2 Although symptoms can be controlled by drug treatment, a small minority of patients may become disabled and refractory to maximum medical management, and consequently eligible for major therapeutic interventions that target relief of obstruction and mitral regurgitation.1 Historically, this strategy has been confined …

Implications of the mechanical (PCI) vs thrombolytic controversy for ST segment elevation myocardial infarction on the organization of emergency medical services: the Boston EMS experience.

With the many advances in rapid reperfusion therapy for management of acute ST segment elevation myocardial infarction (STEMI), there is a need to revisit the current plan for prehospital triage (point of entry). Until recently in Boston, and nationwide, there has been a policy that patients with suspected acute MI were brought to the nearest hospital. Then, if ST segment elevation was present, patients were treated with either thrombolytic therapy or primary percutaneous coronary intervention (PCI). Recent data, however, have shown that with advances in interventional devices, techniques and institutional experience, primary PCI is associated with improved outcomes compared with thrombolytic therapy for all patients with STEMI when provided at expert centers with high institutional volumes, with experienced interventional cardiologists as the operators, and with relatively short time to treatment. We describe the rationale for and the implementation of the Boston EMS STEMI Triage Plan and Treatment Registry. Many of the issues that prompted the implementation of the Boston STEMI plan are relevant to all EMS systems. Among these issues are the accuracy of prehospital identification of STEMI patients, the availability of mechanical reperfusion therapy, the appropriate triage of patients with complicated myocardial infarction or shock, as well as the local consensus regarding strength of the evidence favoring mechanical reperfusion. This article describes the history of the Boston EMS STEMI Triage Plan and Treatment Registry and suggests the need for other EMS systems to develop a systematic approach to patients with STEMI.

Heart Failure in Women

Observational and other studies suggest gender-related differences in the incidence and prognosis of heart failure. Women appear to live longer after the diagnosis of heart failure when compared with men. After myocardial infarction, women seem more likely than men to exhibit clinical heart failure. Diabetes appears to promote heart failure to a greater extent in women than in men. Review of data from clinical and epidemiologic studies suggests that men and women may differ in their myocardial adaptation to a variety of cardiac insults. Future investigation is necessary to better define gender-related differences and possible sex-specific therapies for those diseases resulting in heart failure.

Bivalirudin Is a Dual Inhibitor of Thrombin and Collagen-Dependent Platelet Activation in Patients Undergoing Percutaneous Coronary Intervention

Background— Bivalirudin, a direct thrombin inhibitor, is a widely used adjunctive therapy in patients undergoing percutaneous intervention (PCI). Thrombin is a highly potent agonist of platelets and activates the protease-activated receptors, PAR1 and PAR4, but it is not known whether bivalirudin exerts antiplatelet effects in PCI patients. We tested the hypothesis that bivalirudin acts as an antiplatelet agent in PCI patients by preventing activation of PARs on the platelet surface. Methods and Results— The effect of bivalirudin on platelet function and systemic thrombin levels was assessed in patients undergoing elective PCI. Mean plasma levels of bivalirudin were 2.7±0.5 &mgr;mol/L during PCI, which correlated with marked inhibition of thrombin-induced platelet aggregation and significantly inhibited cleavage of PAR1. Unexpectedly, bivalirudin also significantly inhibited collagen-platelet aggregation during PCI. Collagen induced a conversion of the platelet surface to a procoagulant state in a thrombin-dependent manner that was blocked by bivalirudin. Consistent with this result, bivalirudin reduced systemic thrombin levels by >50% during PCI. Termination of the bivalirudin infusion resulted in rapid clearance of the drug with a half-life of 29.3 minutes. Conclusions— Bivalirudin effectively suppresses thrombin-dependent platelet activation via inhibition of PAR1 cleavage and inhibits collagen-induced platelet procoagulant activity as well as systemic thrombin levels in patients undergoing PCI.

Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study

We investigated the prevalence of migraine in patients with patent foramen ovale (PFO), and the effect of PFO closure on migraine symptoms and medications.

Statin use is associated with enhanced collateralization of severely diseased coronary arteries

BACKGROUND The presence of coronary collateral vessels has been associated with improved clinical outcome in patients with coronary artery disease. Animal experiments have shown that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) can promote angiogenesis in ischemic tissues in a cholesterol-independent manner. We hypothesized that statin therapy is associated with increased coronary collateral formation in patients with severe coronary artery disease. METHODS AND RESULTS Patients undergoing clinically indicated coronary angiography at the Tufts-New England Medical Center from September 2000 to April 2001 who had at least 1 major coronary artery occlusion, or a stenosis of > or =95% with Thrombolysis In Myocardial Infarction (TIMI) trial grade < or =1 anterograde flow on their angiograms, were included. Fifty-one patients were taking statins before admission, and 43 patients were not. Their angiograms were reviewed and coronary collaterals were graded from 0 to 3 according to the Cohen-Rentrop method. The statin-treated group had a significantly higher mean collateral score compared with the patients not taking statins (2.05 vs 1.52, P =.005). Multivariate analysis supported the significance of the effect of statin therapy on the collateral score. There was no relation between collateral score and low-density lipoprotein levels (r = -0.06, P =.64). The statin-treated group also had a significantly higher left ventricular ejection fraction compared to the patients not taking statins (51% vs 44%, P <.05). CONCLUSIONS Statin therapy is associated with enhanced coronary collateral formation in patients with severely diseased coronary arteries.

Suppression of Arterial Thrombosis without Affecting Hemostatic Parameters with A Cell-Penetrating PAR1 Pepducin

Background— Thrombin-dependent platelet activation is heightened in the setting of percutaneous coronary intervention and may cause arterial thrombosis with consequent myocardial necrosis. Given the high incidence of adverse effects in patients with acute coronary syndromes, there remains an unmet need for the development of new therapeutics that target platelet activation without unduly affecting hemostasis. The thrombin receptor, PAR1, has recently emerged as a promising new target for therapeutic intervention in patients with acute coronary syndromes. Methods and Results— We report the development of a first-in-class intracellular PAR1 inhibitor with optimized pharmacokinetic properties for use during percutaneous coronary intervention in patients with acute coronary syndromes. PZ-128 is a cell-penetrating pepducin inhibitor of PAR1 that targets the receptor–G-protein interface on the inside surface of platelets. The structure of PZ-128 closely resembles the predicted off-state of the corresponding juxtamembrane region of the third intracellular loop of PAR1. The onset of action of PZ-128 was rapid and suppressed PAR1 aggregation and arterial thrombosis in guinea pigs and baboons and strongly synergized with oral clopidogrel. There was full recovery of platelet function by 24 hours. Importantly, PZ-128 had no effect on bleeding or coagulation parameters in primates or in blood from patients undergoing percutaneous coronary intervention. Conclusions— Based on the efficacy data in nonhuman primates with no noted adverse effects on hemostasis, we anticipate that the rapid onset of platelet inhibition and reversible properties of PZ-128 are well suited to the acute interventional setting of percutaneous coronary intervention and may provide an alternative to long-acting small-molecule inhibitors of PAR1.

Congestive Heart Failure in Women: Focus on Heart Failure due to Coronary Artery Disease and Diabetes

Congestive heart failure (CHF) is an important clinical syndrome. Evidence from several observational studies suggests sex-related differences in the incidence and prognosis of CHF, particularly in the setting of coronary artery disease. Women appear to be more prone than men to develop heart failure late after myocardial infarction as well as in the peri-infarction period. Additionally, diabetes mellitus appears to promote heart failure to a greater extent in women than in men.

The pulmonary artery pulsatility index identifies severe right ventricular dysfunction in acute inferior myocardial infarction.

Background: Right ventricular dysfunction (RVD) is a major cause of morbidity and mortality in the setting of acute inferior wall myocardial infarction (IWMI), and early detection may improve clinical outcomes. We defined a novel hemodynamic index, the pulmonary artery pulsatility index (PAPi), and explored whether the PAPi correlates with severe RVD in acute IWMI.