Shelley M. Shapiro

Primary Pulmonary Hypertension: Improved Long-Term Effects and Survival With Continuous Intravenous Epoprostenol Infusion

OBJECTIVES This study sought to determine the long-term effects of continuous infusion of epoprostenol (epo) therapy on survival and pulmonary artery pressure in patients with primary pulmonary hypertension (PPH). BACKGROUND PPH is a progressive disease for which there are few effective therapies. METHODS Patients with PPH and New York Heart Association functional class III or IV symptoms of congestive heart failure underwent right heart catheterization and Doppler-echocardiography to measure the maximal systolic pressure gradient between the right ventricle and right atrium (delta P) and cardiac output (CO). Doppler-echocardiography and catheterization data were compared. Patients were followed up long term with Doppler-echocardiography. RESULTS Of 69 patients who went on to receive epo, 18 were followed up for > 330 days (range 330 to 700). During long-term follow-up, there was a significant reduction in delta P, which decreased from 84.1 +/- 24.1 to 62.7 +/- 18.2 (mean +/- SD, p < 0.01). A Kaplan-Meier plot of survival of our study patients demonstrated improved survival compared with that of historical control subjects. The 1-, 2- and 3-year survival rates for our patients were 80% (n = 36), 76% (n = 22) and 49% (n = 6) compared with 10- (88%, n = 31), 20- (56%, n = 27) and 30-month (47%, n = 17) survival rates in historical control subjects. CONCLUSIONS Patients receiving continuous infusion of epo for treatment of PPH experience a decrease in pulmonary artery pressure. Long-term follow-up of this single-center patient group demonstrated improved long-term survival during epo therapy compared with that in historical control subjects and confirms predicted improved outcomes based on shorter follow-up periods.

Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study): A Randomized Controlled Trial

BACKGROUND Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. METHODS A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. RESULTS Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). CONCLUSIONS The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Original ResearchPulmonary Vascular DiseaseFeaturedOral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study): A Randomized Controlled Trial

BACKGROUND Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. METHODS A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. RESULTS Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). CONCLUSIONS The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Acetylsalicylic Acid Reduces Vegetation Bacterial Density, Hematogenous Bacterial Dissemination, and Frequency of Embolic Events in Experimental Staphylococcus aureus Endocarditis Through Antiplatelet and Antibacterial Effects

BACKGROUND Platelets are integral to cardiac vegetations that evolve in infectious endocarditis. It has been postulated that the antiplatelet aggregation effect of aspirin (ASA) might diminish vegetation evolution and embolic rates. METHODS AND RESULTS Rabbits with Staphylococcus aureus endocarditis were given either no ASA (controls) or ASA at 4, 8, or 12 mg. kg-1. d-1 IV for 3 days beginning 1 day after infection. Vegetation weights and serial echocardiographic vegetation size, vegetation and kidney bacterial densities, and extent of renal embolization were evaluated. In addition, the effect of ASA on early S aureus adherence to sterile vegetations was assessed. In vitro, bacterial adherence to platelets, fibrin matrices, or fibrin-platelet matrices was quantified with either platelets exposed to ASA or S aureus preexposed to salicylic acid (SAL). ASA at 8 mg. kg-1. d-1 (but not at 4 or 12 mg. kg-1. d-1) was associated with substantial decreases in vegetation weight (P<0.05), echocardiographic vegetation growth (P<0.001), vegetation (P<0.05) and renal bacterial densities and renal embolic lesions (P<0.05) versus controls. Diminished aggregation resulted when platelets were preexposed to ASA or when S aureus was preexposed to SAL (P<0.05). S aureus adherence to sterile vegetations (P<0.05) or to platelets in suspension (P<0.05), fibrin matrices (P<0.05), or fibrin-platelet matrices (P<0.05) was significantly reduced when bacteria were preexposed to SAL. CONCLUSIONS ASA reduces several principal indicators of severity and metastatic events in experimental S aureus endocarditis. These benefits involve ASA effects on both the platelet and the microbe.

Pulmonic Valve Endocarditis as an Underdiagnosed Disease: Role of Transesophageal Echocardiography

Pulmonic valve endocarditis is a rare clinical entity. In spite of an increase in the frequency of right-sided endocarditis, primarily it is the tricuspid valve that is involved. Two-dimensional transthoracic echocardiography has improved our ability to diagnose infective endocarditis but has not identified many cases of pulmonic valve endocarditis. With the use of transesophageal echocardiography, three recent cases of pulmonic valve endocarditis were diagnosed by our laboratory. Each of these patients had clinical evidence of right-sided endocarditis, yet routine transthoracic echocardiograms failed to identify any pulmonic valve abnormalities. The true incidence of pulmonic valve endocarditis may be higher than previously reported, and the transesophageal echocardiogram is the preferred method for identifying and evaluating pulmonic valve endocarditis in adults.

Long-term prognosis of patients with a normal exercise echocardiogram and clinical suspicion of myocardial ischemia

This study confirms that patients with significant risk factors for coronary artery disease and chest pain syndromes, who have normal, symptom-limited exercise echocardiograms, have a very low long-term risk for major cardiac events.

Use of Transesophageal Echocardiography During Thrombolysis with Tissue Plasminogen Activator of a Thrombosed Prosthetic Mitral Valve

Inadequate anticoagulation in patients with mechanical prosthetic heart valves can result in a significant incidence of thromboembolic complications. An even more life-threatening complication is massive thrombosis of the valve itself. Thrombolytic therapy was given to a moribund 22-year-old woman with intractable heart failure caused by a thrombosed St. Jude prosthetic mitral valve (St. Jude Medical, Inc., St. Paul, Minn.). Although this form of therapy has been used before, this is the first report of a case in which transesophageal echocardiography was performed during thrombolytic therapy to continually record successful thrombolysis of the clotted prosthetic valve. Serial imaging during thrombolysis displayed progressive dissolution of the thrombus and progressive improvement in valve function. Transesophageal echocardiography is helpful in the diagnosis of prosthetic valve thrombosis and has the ability to monitor continually the effect of treatment with thrombolysis. Although thrombolytic therapy with recombinant tissue plasminogen activator is effective in treating prosthetic valve thrombosis, it carries a high risk for serious thromboembolic complications and thus should be reserved for critically ill patients who are too sick to undergo immediate surgery.

Influence of cardiac motion on Doppler measurements using in vitro and in vivo models

OBJECTIVES Using both in vitro and in vivo techniques, we investigated the extent to which cardiac motion alters Doppler-measured blood flow velocity and thus potentially can alter the calculation of valve areas or pressure gradients. BACKGROUND Blood flow velocity measured by Doppler ultrasound represents the net motion of the blood relative to the transducer. It is widely assumed that the measured velocity represents the actual flow. It has been demonstrated that cardiac motion generates regularly occurring low velocity Doppler signals that are commonly treated as artifact. METHODS We used an in vitro model that allowed us to measure and independently control the flow of a liquid through a chamber and the motion of the chamber relative to the Doppler beam. A cornstarch-water slurry was driven by a pulsatile pump through tubing to simulate the blood flow within the heart, and the tubing was cyclically moved by a piston to simulate the heart motion. We also measured cardiac motion using M-mode and two-dimensional echocardiography and compared the results with the Doppler signal derived from cardiac motion in subjects without cardiac disease. RESULTS In the in vitro model, alteration in the motion of the tubing resulted in apparent changes in the measured maximal velocity of the fluid. The Doppler spectrum of the combined motion of the tubing and the fluid was the algebraic sum of their Doppler signals. In human subjects, the maximal slope of the M-mode tracing of the aortic annular motion and the peak Doppler signal due to cardiac motion were compared and were highly correlated. CONCLUSIONS Cardiac motion alters the Doppler signal derived from blood flow. This effect can be demonstrated in vitro and in vivo.

Dyspnea lusoria: compression of the pulmonary artery by a Kommerell’s diverticulum

We report a rare case of Kommerells diverticulum presenting as dyspnea on exertion. After careful physical examination, selective imaging tests demonstrated a significant flow abnormality in the left pulmonary artery caused by an aneurysm of the descending aorta in the area of the ligamentum arteriosum.

Estimation of regional end-systolic wall stress during exercise in coronary artery disease

Estimating left ventricular wall stress has recognized applications, but formulae for global stress cannot be applied to ischemic ventricles. A mathematic method for estimating regional stress in infarcted ventricles has been described. The hypothesis tested was that exercise-induced ischemia increases end-systolic wall stress. Subcostal four-chamber echocardiograms were recorded at rest and during peak symptom-limited exercise in 19 controls and 41 patients with chest pain undergoing coronary arteriography. Centerline regional wall motion and regional end-systolic wall stress were measured at rest and at peak exercise. The normal controls had increased wall motion with exercise, but wall stress remained low. All 32 of the patients with coronary artery disease (> or = 50% diameter narrowing) had wall motion abnormalities with exercise, but the sensitivity of identifying right coronary artery obstructions was poor. Patients with coronary disease had higher regional stress at peak exercise than did the controls. The sensitivity of identifying lesions in all three coronary arteries (0.95 to 1.0) was better than that for wall motion (p < 0.04). The specificity of wall stress needs to be tested in a larger population. Exercise-induced ischemia causes increased regional end-systolic wall stress that reflects its distribution in patients with coronary artery disease. These changes can be measured non-invasively during exercise echocardiography.