Park W. Willis

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

OBJECTIVESnThe aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH).nnnBACKGROUNDnPrimary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized.nnnMETHODSnEchocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone.nnnRESULTSnDuring the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis.nnnCONCLUSIONSnPericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Effects of Long-term Infusion of Prostacyclin (Epoprostenol) on Echocardiographic Measures of Right Ventricular Structure and Function in Primary Pulmonary Hypertension

Background Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy. Methods and Results The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricul...

Apoptosis as a Possible Cause of Gradual Development of Complete Heart Block and Fatal Arrhythmias Associated With Absence of the AV Node, Sinus Node, and Internodal Pathways

BACKGROUNDnGradually progressive development of complete heart block in young people often is associated with cardiac arrhythmia and sudden death, but the pathogenesis remains unexplained.nnnMETHODS AND RESULTSnA young woman with complete heart block died suddenly. Her mother had serological but no clinical evidence of antiphospholipid syndrome. Five brothers of another family had arrhythmia and heart block. Three died suddenly; the other two have automatic defibrillators and are alive. The hearts from the young woman and two of the three brothers who died were available for our histological examination of their cardiac conduction systems. In two of the three hearts, the AV node was absent; in the third heart, only fragments of the AV node remained. In all three hearts, the sinus node was nearly destroyed by a noninflammatory degeneration with no abnormal fibrosis or infiltrate. In each heart, the interatrial and internodal pathways were similarly involved, and in the young woman, there were no myocardial cells in which these pathways normally exist.nnnCONCLUSIONSnIn these three subjects with progressive development of complete heart block and various arrhythmias, all of whom died suddenly, the histological abnormalities of their cardiac conduction systems are best interpreted as resulting from apoptosis. Programmed cell death is a logical explanation for the pathogenesis of this puzzling clinical picture.

The Bitter End The Ubiquitin-Proteasome System and Cardiac Dysfunction

Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process. Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.

Racial differences in left ventricular structure in healthy young adults

Racial differences in cardiac structure and function were evaluated in 62 black and 71 white healthy young adults. Left ventricular (LV) mass index, relative wall thickness, fractional shortening, resting cardiac index and resting systemic vascular resistance index were estimated using M-mode echocardiography. Pulsed Doppler interrogation of transmitral flow was used to characterize LV filling. Average daytime blood pressure (BP) was determined by ambulatory monitoring during a typical work or school day. Ambulatory daytime BP averaged 127 +/- 12/80 +/- 7 mm Hg in black subjects, and 127 +/- 9/80 +/- 6 mm Hg in white subjects (p = not significant). The 2 groups were also similar in resting BP, age and gender composition. Relative wall thickness was significantly greater in black than in white subjects (0.37 +/- 0.06 vs 0.34 +/- 0.05; p less than 0.01). This difference was found in both men and women. Black subjects also had a higher resting systemic vascular resistance index (2,110 +/- 570 vs 1,920 +/- 500 dynes.s.cm-5.m2; p less than 0.05) and lower resting cardiac index (3.14 +/- 0.84 vs 3.46 +/- 0.85 L/min/m2; p less than 0.05). There were no significant differences between black and white subjects in LV mass index, fractional shortening and normalized peak filling velocity. These results suggest that racial differences in LV structure and systemic hemodynamics exist even in patients without sustained hypertension. In our study population, the greater relative wall thickness in black subjects was not accompanied by significant differences in LV systolic function or diastolic filling.

Frequency and Severity of Tricuspid Regurgitation Determined by Doppler Echocardiography in Primary Pulmonary Hypertension

W previously described a high prevalence of functional tricuspid regurgitation (TR) in patients with severely symptomatic primary pulmonary hypertension (PPH).1 We report the relations of TR to right ventricular (RV) size and geometry, tricuspid annulus diameter, tricuspid leaflet displacement, hemodynamics, and exercise capacity in these patients. • • • The study group consisted of 78 patients enrolled in a multicenter trial of epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, North Carolina) for the treatment of severe PPH.2 The study consisted of 56 women and 32 men (mean age 40 15 years). Most (74%) had New York Heart Association class III symptoms; their average mean pulmonary arterial pressure was 60 12 mm Hg. All participants met the criteria for PPH as defined by the National Institutes of Health Patient Registry,3 and all had New York Heart Association class III or class IV symptoms. The study was approved by the institutional review committee of each participating center, and informed consent was acquired from each patient before enrollment. Baseline echocardiograms of all participants were obtained using a defined imaging protocol and recorded on videotape. All studies were analyzed using an off-line quantification system by a single observer from the core echocardiographic laboratory. Measurements were obtained on 3 representative beats, and the results averaged. Details of the imaging and quantification protocols, including reproducibility data, have been described previously.1 The severity of TR was determined from 2-dimensional and Doppler color flow images in the apical 4-chamber view. Frame-by-frame analysis of each cardiac cycle was used to identify the maximum area of the Doppler color flow jet. The outline of the regurgitant signal, including aliased signals and contiguous velocities moving in the same direction, was traced and the area determined by computerized planimetry. The area of the right atrium was similarly measured on the same frame. The severity of TR was quantified as the ratio of the Doppler regurgitant jet area to the right atrial (RA) area (the TR/RA ratio). Previous investigators have demonstrated that this ratio is correlated closely with the severity of TR measured by a double thermodilution technique.4 Severe TR was defined as a TR/RA ratio 0.34, a ratio that corresponds to severe TR as judged by thermodilution4 or intraoperative digital palpation.5 TR was considered moderate if the TR/RA ratio was 0.20 and 0.34, and mild if the TR/RA ratio was 0.20. The tricuspid valve was examined in the apical 4-chamber view for thickening or doming, and for abnormal closure. The apical displacement of the tricuspid leaflets, an index of abnormal closure due to chordal tension, was measured as the distance from the coaptation point to the plane of the tricuspid annulus at the time of maximal systolic closure. Loss of coaptation was defined as a visible separation of the septal and anterior leaflets throughout systole. The following echocardiographic measures of RV structure were obtained in the apical 4-chamber view at end-diastole and at end-systole. (1) The tricuspid annulus diameter was measured from the point of attachment of the septal leaflet to the attachment of the anterior leaflet. This diameter was corrected for differences in body size by dividing by height. (2) The RV remodeling index was calculated as the ratio of RV short and long axes; the short axis was defined as the distance between the septal and free wall endocardial surfaces of the right ventricle at the midventricular level. The long axis was measured from the endocardial surface at the tip of the RV apex to the midpoint of the annular plane. (3) RV area was measured by planimetry, tracing the endocardial edge of the right ventricle and the plane of the tricuspid valve, and corrected for height. From the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; University of Washington, Seattle, Washington; Maine Medical Center, Portland, Maine; Washington University, St. Louis, Missouri; Rhode Island Hospitals, Providence, Rhode Island; Louisiana State Medical Center, New Orleans, Louisiana; Cato Research Ltd., Durham, North Carolina; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina; GlaxoSmithKline, Research Triangle Park, North Carolina; and United Therapeutics Inc., Chapel Hill, North Carolina. This study was supported by Burroughs Wellcome Co., Research Triangle Park, North Carolina. Dr. Hinderliter’s address is: Division of Cardiology, University of North Carolina, CB 7075, Chapel Hill, North Carolina, 27599. E-mail: hinderli@med.unc.edu. Manuscript received July 29, 2002; revised manuscript received and accepted December 20, 2002.

Ethnic differences in forearm vasodilator capacity

Previous studies have demonstrated significant ethnic differences in left ventricular structure in both normotensive and hypertensive subjects. To determine if these differences in ventricular geometry are associated with differences in vascular structure, we measured the minimum forearm vascular resistance in 30 healthy young African-American adults and in 30 whites matched for age, gender, and blood pressure. Average daytime blood pressure was determined by ambulatory monitoring during a typical work day. Minimum forearm vascular resistance was measured by plethysmography after 10 minutes of forearm ischemia. Indexed left ventricular mass and relative wall thickness were measured by 2-dimensional-directed M-mode echocardiography. The mean (+/-SD) ambulatory pressure was 126 +/- 11/79 +/- 8 mm Hg in African-Americans and 126 +/- 11/79 +/- 7 mm Hg in whites. The 2 groups were similar in body mass index and in family history of hypertension. African-Americans had a higher minimum forearm vascular resistance than did whites (2.39 +/- 0.75 vs 2.03 +/- 0.55 mm Hg, p <0.05). There was a trend toward a greater left ventricular relative wall thickness in African-Americans (0.38 +/- 0.07 vs 0.35 +/- 0.06, p=0.09). These results suggest that early vascular remodeling is present in African-Americans who do not have established hypertension, and that this ethnic difference in vascular structure is associated with a difference in ventricular geometry.

Patients with borderline elevated blood pressure have enhanced left ventricular contractility

Recent analyses of midwall left ventricular mechanics have demonstrated that patients with established hypertension and ventricular hypertrophy have depressed myocardial contractility. In this study, myocardial performance was assessed in subjects with borderline blood pressure elevations by relating the velocity of circumferential midwall fiber shortening to end-systolic stress in young men and women who were classified as normotensive (n = 92) or as having marginally elevated blood pressure (n = 43) based on daytime ambulatory systolic blood pressure. On average, velocity of midwall fiber shortening in those with higher blood pressure was 8% greater than predicted from results of normotensive controls. These results suggest that young patients with borderline blood pressure elevations have enhanced left ventricular contractility.

Blood pressure responses to stress: Relation to left ventricular structure and function

The relations of resting blood pressure, blood pressure during standardized stressors, and workplace blood pressure to left ventricular structure and diastoKc filling were evaluated in 133 healthy young adults (mean age = 30 + 7 years) without hypertension. Each subject underwent the following. (a) measurement of basal blood pressure at the end of 15 minutes of rest; (b) measurement of blood pressure during a competitive reaction time task (a laboratory stressor which elicits a beta-adrenergically mediated increase in cardiac output); (c) measurement of blood pressure during a forehead compressor test, which results primarily in an increase in total peripheral resistance due to alpha-adrenergic stimulation; and (d) ambulatory blood pressure monitoring during a typical workday. Left ventricular structure (indexed left ventricular mass and relative wall thickness) and diastolic filling (peak filling velocity) were evaluated by echocardiography.All four measures of systolic blood pressure were significantly correlated with indexed left ventricular mass. The best predictor of indexed left ventricular mass was the systolic blood pressure during the compressor test (r = 0.32, p < O. 001), and this relation was significant after correcting for resting systolic blood pressure (p < 0.05). Relative wall thickness was most closely related to the average ambulatory workplace systolic pressure (r = 0.23, p < 0.01), and this relation was also independent of resting systolic blood pressure (p < 0.05). Peak filling velocity was inversely related to the systolic pressure in response to each stressor, but the correlations with stress-induced pressures were not significant after correcting for resting levels of blood pressure.These results demonstrate an association of structural characteristics of the left ventricle with blood pressure responses to stress.

Evolution of regional left ventricular wall motion abnormalities in acute Q and non-Q wave myocardial infarction.

The evolution of segmental wall motion in Q and non-Q wave acute myocardial infarction was studied in detail in 15 patients without known prior ischemic events. Serial two-dimensional echocardiographic studies were performed beginning early after the onset of chest pain and continuing until 10 to 14 days after admission. An area of apparent infarction was identified on each initial study based on later correlation of ECG and echocardiographic findings. Wall motion of infarct-and noninfarct-related areas was graded in a semiquantitative fashion based on the scoring of a visual analysis. Sequential image data demonstrated significant spontaneous improvement in wall motion of the infarct area in non-Q but not in Q wave events. Patients with non-Q wave infarction and improvement in regional function were at high risk for recurrent infarction within 6 months. Improvement in wall motion inside or outside the area of infarction in Q wave events was related to future risk. We concluded that in patients with initial acute myocardial infarction, failure to develop Q waves correlated with return of function in the apparent area of infarction. Improvement in regional wall motion after the initial study suggested risk for future ischemic events in both ECG types of myocardial infarction. Serial echocardiographic imaging may be a means to identify patients at risk for infarct extension in both non-Q and Q wave events.