Martin St. John Sutton

Antianginal effects of nitroglycerin patches

Nitroglycerin (NTG) patches provide potentially therapeutic NTG blood levels for 24 hours, but their effects on exercise tolerance (ExT) in patients with angina have not been well characterized. Therefore, blinded, randomized trials were performed of the acute effects of both low-dose and maximal-tolerated-dose NTG patches and placebo on ExT in 14 patients with coronary artery disease and typical exertional angina. The bicycle exercise protocol of the National Institutes of Health was used and sublingual NTG administered as a positive control. In 7 subjects, low-dose patches produced no statistically significant effect on ExT at 4, 8 or 24 hours after administration. Comparable doses of sublingual and oral isosorbide dinitrate, NTG ointment and transmucosal NTG in previous studies have produced effects similar to those of conventional doses of sublingual NTG. Maximally tolerated doses of 2 types of NTG patches were then tested. The first (n = 8, mean NTG dose delivered 25 mg) produced increases in ExT of 82 and 72 seconds at 4 and 8 hours, respectively (both p less than 0.01), but was ineffective at 24 hours. The second patch type (n = 5, mean NTG dose delivered 22 mg) was also ineffective at 24 hours. Furthermore, even at maximal doses, peak effects on ExT were about half of those of sublingual NTG. Thus, NTG patches, even at maximal doses, appear to have smaller therapeutic effects than other long-acting nitrates and are ineffective at 24 hours. These results suggest rapid attenuation of NTG effect during prolonged maintenance of constant blood levels.

Early postoperative changes in left ventricular chamber size, architecture, and function in aortic stenosis and aortic regurgitation and their relation to intraoperative changes in afterload: a prospective two-dimensional echocardiographic study.

We prospectively studied 16 patients with isolated aortic stenosis and eight with isolated aortic regurgitation undergoing aortic valve replacement, using two-dimensional echocardiography preoperatively, intraoperatively, and 41 +/- 7 days postoperatively to calculate the intraoperative change in afterload, quantify the postoperative changes in left ventricular chamber size, architecture, load and function, determine whether the postoperative left ventricular remodeling correlated with the intraoperative change in afterload in aortic stenosis and aortic regurgitation, and assess whether preoperative afterload excess precluded postoperative improvement in left ventricular function. Preoperative left ventricular mass, end-systolic meridional and circumferential wall stresses, ejection fraction, and stress-shortening relations in patients with aortic stenosis and aortic regurgitation were similar. However, our patients with aortic regurgitation had severe systolic dysfunction, with ejection fraction less than 55% in all but one patient, compared with only 10 of 16 patients with aortic stenosis. Left ventricular end-diastolic volume, mass/volume ratio, and chamber shape were significantly different in patients with aortic stenosis and aortic regurgitation (174 +/- 64 vs 294 +/- 140 ml, p less than .01; 1.81 +/- 0.63 vs 1.14 +/- 0.18, p less than .01; and 0.59 +/- 0.09 vs 0.69 +/- 0.09, p less than .05, respectively). Intraoperative end-systolic meridional and circumferential stresses fell significantly in patients with aortic stenosis but remained unchanged in those with aortic regurgitation. The changes in left ventricular volume and ejection fraction during early postoperative remodeling (6 weeks) correlated with the intraoperative change in afterload in patients with aortic stenosis. In contrast, there was no intraoperative change in afterload in patients with aortic regurgitation and no significant changes in left ventricular volume, architecture, or function at 6 weeks or at 6 months. The differences in left ventricular remodeling and changes in function between patients with aortic stenosis and aortic regurgitation in the early postoperative period most probably relates to the major difference in intraoperative reduction in afterload, although a contributory role may have been played by the preoperative left ventricular dysfunction in those with aortic regurgitation that was underestimated by measurement of ejection fraction.

Patterns of Structural and Functional Remodeling of the Left Ventricle in Chronic Heart Failure

Patients with heart failure show a wide variety of alterations in left ventricular (LV) volume, mass, and function. The purpose of this study was to define the common patterns of LV structural and functional remodeling and consider their clinical implications in patients with chronic heart failure. Two-dimensional echocardiograms obtained during the screening phase of a study involving patients (n = 315) with chronic heart failure were used to calculate LV volume, mass, geometry, and ejection fraction (EF). Inclusion required the diagnosis of heart failure in symptomatic patients on medical therapy. Measures of LV size or function were not used as inclusion or exclusion criteria. Plots of EF against LV end-diastolic volume (EDV) showing an inverse curvilinear relation allowed a description of 4 remodeling patterns. Pattern A (n = 66) was defined as normal EDV (<91 ml/m(2)) and normal EF (> or =50%); 65% of these patients showed LV hypertrophy or concentric remodeling. Pattern B (n = 65) was defined as normal EDV and depressed EF; hypertrophy or concentric remodeling was present in 63%. Pattern C (n = 175) was defined as increased EDV and depressed EF; eccentric hypertrophy was present in 94%. Pattern D (n = 9) was defined as increased EDV and normal EF; eccentric hypertrophy was present in 88%. In conclusion, these patterns of remodeling encompass a wide spectrum of geometric changes with different clinical and pathophysiologic features and possibly different management strategies.

CONGENITAL SINUS OF VALSALVA ANEURYSM : A MULTIPLANE TRANSESOPHAGEAL ECHOCARDIOGRAPHIC EXPERIENCE

Sinus of Valsalva aneurysm is a rare congenital anomaly which, if overlooked, may be associated with increased mortality and morbidity. Multiplane transesophageal echocardiography proved useful in identifying a variety of associated structural heart disease. This study sought to assess the accuracy of the surgical result on the basis of the multiplane transesophageal echocardiography findings and to describe patient demographics and clinical outcome in an Oriental patient cohort. From July 1984 to December 1995, clinical, catheterization, echocardiographic, and surgical results were retrospectively studied in 23 patients with documented sinus of Valsalva aneurysm. Compared with previous reports of Oriental patients, our patient cohort was older (p < 0.025), had more associated aortic, mitral, and tricuspid regurgitation (p < 0.01), but had fewer coexistent ventricular septal defects (p < 0.01), and had more associated coronary artery disease (9%). Multiplane transesophageal echocardiography precisely showed three undiagnosed and/or ambiguous transthoracic echocardiographic studies, and the preoperative transesophageal echocardiography TEE findings were confirmed intraoperatively in the last eight consecutive patients. We concluded that multiplane transesophageal echocardiography provides conclusive information and is the current technique of choice for diagnosis and clinical management of patients with sinus of Valsalva aneurysm; although the natural history of sinus of Valsalva aneurysm remains uncertain, it is likely that the incidence of unruptured sinus of Valsalva aneurysm is considerably higher in the elderly than has been previously reported.

Contribution of afterload, hypertrophy and geometry to left ventricular ejection fraction in aortic valve stenosis, pure aortic regurgitation and idiopathic dilated cardiomyopathy

To investigate the relation of left ventricular (LV) afterload, hypertrophy, geometry and systolic pump function, 17 normal persons, 24 patients with aortic stenosis (AS), 20 with aortic regurgitation (AR) and 15 with idiopathic dilated cardiomyopathy (DC) were studied. Two-dimensional echograms were used to assess end-systolic meridional and circumferential stresses and their ratio, LV mass, relative wall thickness (h/R ratio) and the ratio of LV minor axis to length, used as an index of shape. Independently obtained ejection fraction (EF) was used to determine which patients had normal (EF greater than or equal to 55%) and which had depressed (EF less than 55%) pump function. Patients with AS and low EF had similar LV mass (228 vs 215 g) but larger LV cavity (5.6 vs 4.5 cm), lower h/R ratio (0.53 vs 0.73, p less than 0.01), and therefore higher circumferential stress (336 vs 268 kdyne/cm2, p less than 0.05). Compared with normal persons, patients with DC had a lower h/R ratio (0.28 vs 0.38, p less than 0.01), higher circumferential stress (362 vs 215 kdyne/cm2, p less than 0.01) and more uniform stress distribution (meridional to circumferential stress ratio 0.57 vs 0.39, p less than 0.01), implying that meridional stress overestimates effective afterload. Afterload excess and LV shape change may be important to pump function in patients with AS or DC. In contrast, in those with AR, no significant shape differences were noted, although LV mass was higher in those with low EF (279 vs 211 g, p less than 0.05). Depressed pump function may result from impaired myocardial performance in AR without afterload excess.

Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is a fundamental component of cardiac adaptation to disorders which alter left ventricular pressure, volume or contractility on a chronic basis. In pressure and volume overload, the LVH response is, initially, quantitatively matched to the increase in hemodynamic load, so that each unit of myocardium performs under normal mechanical loading conditions [1]. As a result, cardiac compensation can be maintained without reliance on either preload reserve or increased contractility. This phase of compensated hypertrophy in turn permits the long asymptomatic phases observed in subjects with aortic stenosis, hypertensive heart disease, aortic regurgitation and mitral regurgitation. When decompensation occurs, it can be due in part to failure of compensatory hypertrophy to keep up with the hemodynamic burden, as well as to depression of contractile state [2]. Furthermore, successful therapeutic interventions, such as aortic valve replacement for aortic stenosis or aortic regurgitation, are often characterized by reversal of LVH and failure of such reversal may be a poor prognostic sign [3].

Importance of blood pressure control in left ventricular mass regression

Blood pressure (BP) reduction to 140/90 mm Hg or lower using renin-angiotensin-system blockers reportedly provides the greatest left ventricular (LV) mass regression; β-blockers have less effect. This study examined whether combination antihypertensive therapy would provide greater benefit. With a double-blind, parallel-group design, the effects of 3 different combinations, carvedilol controlled-release (CR)/lisinopril, atenolol/lisinopril, and lisinopril, on left ventricular mass index (LVMI) were assessed by MRI after 12 months. Patients were treated to achieve guideline-recommended BP (<140 mm Hg/<90 mm Hg; diabetes: <130 mm Hg/<80 mm Hg). Sample size was calculated to achieve 90% power to detect a 5 g/m(2) difference in mean change from baseline in LVMI between the carvedilol CR/lisinopril group and each of the other treatment groups. Of 287 patients randomized, more than 50% were titrated to maximum dosage; 73% reached targeted BP. At month 12 (last observation carried forward ≥ month 9) for 195 evaluable subjects, mean BP was similar in all groups (carvedilol CR/lisinopril: 128.8/77.9; atenolol/lisinopril: 128.7/76.5; lisinopril: 126.3/80.3 mm Hg). Compared with baseline, mean LVMI decreased to a similar extent in all groups (carvedilol CR/lisinopril: -6.3; atenolol/lisinopril: -6.7; lisinopril: -7.9 g/m(2)). Achievement of targeted BP control is more important than treatment regimen in achieving LV mass reduction.

Improvement in Clinical Outcomes With Biventricular Versus Right Ventricular Pacing : The BLOCK HF Study

BACKGROUNDnSustained right ventricular (RV) apical pacing may lead to deterioration in ventricular function and an increased risk of heart failure, especially in patients with pre-existing systolic dysfunction. The BLOCK HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) trial demonstrated that biventricular-paced patients had a reduced incidence of a composite endpoint of death, heart failure-related urgent care, and adverse left ventricular remodeling.nnnOBJECTIVESnIn a pre-specified analysis, this study examined clinical outcomes, including clinical composite score, quality of life (QOL), and change in New York Heart Association (NYHA) functional classification.nnnMETHODSnThe BLOCK HF trial randomized patients with atrioventricular block, NYHA symptom class I to III heart failure, and left ventricular ejection fractionxa0≤50% to biventricular or RV pacing. NYHA functional classification, QOL, and clinical composite score were assessed at 6, 12, 18, and 24 months. Bayesian statistical methods were used, with the pre-specified metric of benefit being a posterior probabilityxa0≥0.95.nnnRESULTSnPatients with biventricular pacing showed greater improvement in NYHA functional class at 12 months, with 19% improved, 61% unchanged, and 17% worsened, compared with 12%/62%/23% in the RV arm. QOL was improved through 12 months. At 6 months, clinical composite score was improved/unchanged/worsened in 53%/24%/24% in the biventricular arm compared with 39%/33%/28% in the RV arm. This improvement in clinical composite score was sustained through 24 months.nnnCONCLUSIONSnFor patients with atrioventricular block and systolic dysfunction, biventricular pacing not only reduces the risk of mortality/morbidity, but also leads to better clinical outcomes, including improved QOL and heart failure status, compared with RV pacing. (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block [BLOCK HF]; NCT00267098).

Unreliability of Hemodynamic Indexes of Left Ventricular Size during Cardiac Surgery

Pulmonary artery diastolic (PADP) and wedge pressures (PAWP) and left ventricular end-diastolic pressure (LVEDP) are commonly used to estimate left ventricular (LV) preload. To assess the ability of hemodynamic indexes of preload to estimate anatomical preload, or LV volume, we studied 45 patients during a coronary (18 patients) or aortic valve (27 patients) procedure and compared epicardial two-dimensional echocardiographic LV cavity area with simultaneous measurements of PADP, PAWP, and high-fidelity LVEDP. Pulmonary artery diastolic pressure, PAWP, and their percent change after bypass did not correlate with absolute values (before or after bypass) or percent change in LVEDP. Percent change in LV area correlated weakly with percent change in PADP (r = .34, p less than .03) but not with changes in PAWP or LVEDP. Changes were opposite in direction in 45% (PADP), 50% (PAWP), and 67% (LVEDP) of patients. In conclusion, both PADP and PAWP were poor guides to LVEDP and neither reflected changes in LV size. Thus, hemodynamic indexes of preload should be used with caution during cardiac operations.

Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota

Although several studies have reported on valve abnormalities among users of fenfluramine or dexfenfluramine, detailed information on these subjects has not been provided, limiting the ability to understand who may be at risk for valve abnormalities and to generate hypotheses about the etiology and pathogenesis of these abnormalities. This study was a detailed medical record review of 18 previously reported users of fenfluramine and phentermine, all with valve abnormalities on echocardiogram and 2 with surgical pathology. Both clinical characteristics and medication use were recorded by trained abstracters using a standardized data collection form. Two subjects (11%) had other possible etiologies of valve disease: a history of rheumatic fever and prescribed ergotamine. Three subjects (17%) had a history of migraine headaches and 4 (22%) had murmurs noted before using fenfluramine. Use of medications that may affect serotonin receptors was common: ergotamine (1 subject, 5%), selective serotonin reuptake inhibitors (6, 33%), sumatriptan (2, 11%), and mirtazapine (1, 5%). Prior medication and nonmedication allergies were recorded in 6 (33%) and 3 (17%) subjects, respectively. All subjects had symptoms possibly due to fenfluramine or phentermine side effects. This study raises the hypotheses that valvular heart disease among fenfluramine users may be less common than previously estimated, that serotonin excess may play a role in valve pathology, and that a patients response to anorexigens and other medications may serve as a marker for increased risk. Further study is needed to test these hypotheses.