Mortality and morbidity of aortic regurgitation in clinical practice. A long-term follow-up study.

BACKGROUND: The outcome of aortic regurgitation conservatively followed in clinical practice is poorly defined. METHODS AND RESULTS: Long-term outcome of 246 patients with severe or moderately severe aortic regurgitation diagnosed by color Doppler echocardiography was analyzed. With conservative management, mortality rate was higher than expected (at 10 years, 34+/-5%, P<0. 001) and morbidity was high (10-year rates of 47+/-6% for heart failure and 62+/-4% for aortic valve surgery). At 10 years, 75+/-3% of patients had died or had surgery and 83+/-3% had had cardiovascular events. In multivariate analysis, predictors of survival were age (P<0.001), functional class (P<0.001), comorbidity index (P=0.033), atrial fibrillation (P=0.002), and left ventricular end-systolic diameter corrected for body surface area (P=0.025). Ejection fraction was also an independent predictor of overall survival, including postoperative follow-up of surgically treated patients (P<0.001). High risk during conservative treatment, with mortality rate in excess of that expected, was noted among patients with severe, even transient, symptoms (24.6% yearly, P<0.001) but also in those with mild (class II) symptoms (6.3% yearly, P=0.02) and in asymptomatic patients with left ventricular ejection fraction <55% (5.8% yearly, P=0.03) or with end-systolic diameter normalized to body surface area >/=25 mm/m2 (7.8% yearly, P=0.004). Surgery performed during follow-up was independently associated with reduced cardiovascular mortality (adjusted hazard ratio, 0.54; P=0.048). CONCLUSIONS: Patients diagnosed with severe aortic regurgitation in clinical practice incur excess mortality and high morbidity, underscoring the serious prognosis of the disease. Surgery, which reduces cardiac mortality rates, should be considered promptly in high-risk patients.

Doppler index combining systolic and diastolic myocardial performance: clinical value in cardiac amyloidosis.

OBJECTIVES: This study was designed to determine the clinical value of a Doppler-derived index of combined systolic and diastolic myocardial performance in the assessment of cardiac amyloidosis. BACKGROUND: Cardiac amyloidosis is an infiltrative disease with diastolic and systolic dysfunction. Therefore, the index of myocardial performance combining systolic and diastolic time intervals could be a useful predictor of clinical outcome in cardiac amyloidosis. METHODS: The study included 45 patients with biopsy-proved amyloidosis and 45 age-matched normal subjects. All patients had typical echocardiographic features of amyloid cardiac involvement. A Doppler-derived index, defined as the sum of isovolumetric contraction time and isovolumetric relaxation time divided by ejection time, was measured from left ventricular outflow and mitral inflow Doppler velocity profiles recorded during routine echocardiography. The index as well as conventional systolic or diastolic echocardiographic/Doppler variables were related to subsequent outcome. RESULTS: The isovolumetric contraction and relaxation times were prolonged and ejection time was shortened (p < 0.001) in patients with amyloidosis compared with that in normal subjects, resulting in a marked increase of the index from normal values (p < 0.001). In the amyloid group the index was highest in patients with a low stroke index or with both shortened mitral deceleration time and lower ejection fraction. By univariate analysis, New York Heart Association functional class, the index, ejection fraction and mitral deceleration time were significant predictors of outcome. However, by multivariate stepwise regression analysis, functional class and the index were the only independent predictors of survival. CONCLUSIONS: The Doppler-derived index of combined systolic and diastolic myocardial performance correlates with global cardiac dysfunction and is a useful predictor of clinical outcome in patients with cardiac amyloidosis.

Echocardiographic assessment of left ventricular remodeling: are left ventricular diameters suitable tools?

OBJECTIVES: We sought to analyze the value of echocardiographic left ventricular (LV) diameters in assessing LV remodeling. BACKGROUND: LV diameters are easily measured and commonly used as a substitute for volumetric analysis to evaluate LV remodeling caused by ventricular overload or dysfunction. However, the impact of these measurements on outcome is disputed, suggesting that they may not adequately assess LV remodeling. METHODS: M-mode echocardiographically measured LV dimensions and the derived LV ejection fraction and end-systolic wall stress were compared with LV volumes and the derived LV ejection fraction and wall stress using the biplane Simpson rule. These measurements were made prospectively and simultaneously in 463 patients (289 men, 174 women; mean [+/-SD] age 62 +/- 15 years), including 46 normal subjects, 52 with aortic regurgitation, 253 with mitral regurgitation and 112 with LV dysfunction. RESULTS: The correlation between diameter and volume was good at end-systole (r = 0.91, p < 0.0001) and end-diastole (r = 0.86, p < 0.0001). However, the relation was exponential, and the 95% confidence interval increased with increasing diameter. The calculated LV ejection fraction and wall stress using LV diameter and volume correlated linearly with a limited range of error (r = 0.96, SEE = 5%, p < 0.0001 and r = 0.95, SEE = 20 g/cm2, p < 0.0001, respectively). CONCLUSIONS: For assessing LV remodeling, LV diameters measured by M-mode echocardiography allow acceptable estimation of LV ejection fraction and wall stress and correlate significantly with LV volumes but are hindered by a wide range of error for assessment of LV size, especially for enlarged ventricles, suggesting that measurement of LV volume should be the preferred method of echocardiographically assessing LV remodeling.

Long-term follow-up of patients with undiagnosed fever of unknown origin.

BACKGROUND: A casual diagnosis cannot be established in 10% to 25% of the patients who are studied for fever of unknown origin (FUO). The long-term clinical outcome of these patients cannot be inferred from the literature. This study describes the results of a 5-year follow-up of 61 patients studied for FUO and discharged from the hospital with no causal diagnosis being established. METHODS: Patients meeting the classic criteria for FUO who were studied in the 1980s and discharged from the hospital without a casual diagnosis were followed up for at least 5 years or until death. Follow-up was performed by review of the patients' medical records or by consulting the treating physician and occasionally the patients themselves. The final diagnosis, clinical course (resolution of the fever and required treatments), and morality rate were studied. RESULTS: Of a cohort of 199 patients with FUO, 61 individuals (30%) were discharged from the hospital without a final diagnosis being established. A definite diagnosis could be established in 12 cases, mostly (eight of 12) within 2 months after discharge. Thirty-one individuals became symptom free during hospitalization or shortly following discharge. Eighteen patients had persisting or recurring fever for several months or even years after discharge, but 10 of them were considered to be finally cured. Four patients were treated with corticosteroids and six patients required intermittent therapy with nonsteroidal anti-inflammatory agents. Six patients died, but the cause of death was considered to be related to the disease that caused FUO in only two cases. CONCLUSION: No single disease, particularly not tuberculosis, was found to be a cause of undiagnosed FUO. Most cases resolved spontaneously, and corticosteroids were seldom required. Most symptomatic patients could be treated with nonsteroidal anti-inflammatory drugs. The mortality rate in patients with undiagnosed FUO who were followed up for 5 years or more was only 3.2%.

Effect of losartan on degree of mitral regurgitation quantified by echocardiography.

The objective of this study was to determine the effect of oral losartan on the degree of mitral regurgitation (MR). The regurgitant volume and effective regurgitant orifice were quantified using 3 methods (flow convergence, quantitative Doppler, and quantitative 2-dimensional echocardiography) in 32 patients (26 men, mean age 67 +/- 14 years) with MR, both at baseline and 4 hours after losartan (50 mg orally). Twenty-eight patients were also reevaluated after 1 month of continued treatment with losartan (50 mg/day). With treatment, systolic blood pressure decreased from 143 +/- 16 to 130 +/- 18 mm Hg and left ventricular end-systolic wall stress from 173 +/- 46 to 156 +/- 44 g/cm2 (both p < 0.001). With treatment, regurgitant volume decreased (from 77 +/- 28 to 64 +/- 26 ml, - 18 +/- 10%; p < 0.001) in direct relation to the effective regurgitant orifice change (from 43 +/- 16 to 37 +/- 15 mm2, -17 +/- 10%; p < 0.001) but without significant change in regurgitant gradient or duration. Wide individual variability in response was observed unrelated to the magnitude of blood pressure changes. Larger reduction in regurgitant volume was observed in patients with a marked decrease in wall stress (r = 0.47, p = 0.01) and higher baseline end-diastolic volume index (r = -0.38, p = 0.03) and regurgitant volume (r = -0.45, p = 0.01). Acute improvements were sustained and unchanged at 1 month (all p > 0.15). Treatment of MR using the angiotensin receptor antagonist losartan produces a significant and sustained decrease in the degree of MR, with decreases in regurgitant volume and effective regurgitant orifice. However, the changes are of modest and variable magnitude.

Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy.

This study sought to investigate, in patients with idiopathic-dilated cardiomyopathy, the clinical and prognostic value of a Doppler-derived index of myocardial function that combines systolic and diastolic time intervals of the left heart cycle. The Doppler index was measured in 75 patients (aged 61 +/- 13 years; 45 men and 30 women) in sinus rhythm and 75 age- and sex-matched controls. Ejection time was measured from the left ventricular outflow Doppler signal. The sum of isovolumic times was obtained by subtracting the ejection time from the interval between cessation and onset of mitral inflow measured from the mitral inflow velocity profile. The index was the sum of isovolumic times divided by ejection time. The values of the Doppler index in patients with idiopathic-dilated cardiomyopathy (0.85 +/- 0.32) were significantly higher than values in controls (0.37 +/- 0.08, p < 0.001). During follow-up of 5 years, 1 patient underwent cardiac transplantation and 36 patients died, 29 of cardiac, 5 of noncardiac, and 2 of unknown causes. Univariate analysis demonstrated that the Doppler index (chi-square = 18.3, p < 0.001), ejection fraction (chi-square = 15.2, p <0.001), symptom status (chi-square = 9.2, p = 0.002), and mitral deceleration time (chi-square = 5.2, p = 0.02) were significant predictors of outcome. However, multivariate stepwise analysis of these variables showed that the Doppler index (chi-square = 10.7, p = 0.001) and ejection fraction (chi-square = 6.7, p = 0.01) were the most significant independent predictors of outcome. The Doppler index reflects disease severity and has incremental prognostic value in dilated cardiomyopathy. Ease of use, nongeometric dependency, excellent separation of clinical groups, and a strong relation to outcome enhance its appeal.

Determinants of pulmonary venous flow reversal in mitral regurgitation and its usefulness in determining the severity of regurgitation.

Pulmonary venous flow (PVF) reversal is observed in mitral regurgitation (MR) and can be detected by Doppler echocardiography. However, the determinants of PVF alterations in MR have not been analyzed with simultaneous quantitative methods, and the diagnostic accuracy of flow reversal is uncertain. Prospectively, in 128 patients with isolated MR of various degrees (regurgitant fraction 4% to 81%), Doppler echocardiography was used to measure PVF velocity simultaneously to quantify MR by 2 methods and to perform a comprehensive hemodynamic assessment. Systolic PVF velocity was 4 +/- 56 cm/s (systolic flow reversal in 39 patients) and showed the strongest correlations with mitral effective regurgitant orifice (r = -0.56, p <0.0001). In multivariate analysis, larger effective regurgitant orifice (p <0.0001), eccentric jets (p = 0.0023), longer jets (p = 0.0033), and lower mitral regurgitant velocity (p = 0.0015) were independent determinants of decreased systolic PVF velocity. In organic MR, increased filling pressures were associated with systolic PVF reversal. Blunted systolic flow was associated with shorter mitral deceleration time (p <0.0001) and enlarged left atrium (p = 0.0007). For the diagnosis of severe MR (regurgitant orifice > or = 35 mm2, regurgitant fraction > or = 50%), systolic flow reversal sensitivity was 61% and 60%, and specificity was 92% and 85%, respectively. Among 29 patients in whom surgery demonstrated severe mitral lesions, 12 (41%) had no systolic flow reversal preoperatively. In patients with MR, the determinants of systolic PVF are complex and, in addition to the degree of MR, include the hemodynamic consequences of MR, jet characteristics, left ventricular filling, and left atrial volume alterations. Consequently, systolic PVF reversal is a useful sign of severe MR but of relatively low sensitivity, emphasizing the importance of quantifying MR.

Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension.

Primary pulmonary hypertension is characterized by elevated pulmonary arterial pressure and vascular resistance, frequently producing right heart failure and death. Therefore, the Doppler right ventricular (RV) index, which is a measure of global RV function, could be a useful predictor of outcome in primary pulmonary hypertension. The Doppler RV index, defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by ejection time, was retrospectively measured in 53 patients (38 women, aged 45 +/- 14 years) with primary pulmonary hypertension. Ejection time was measured from the pulmonary outflow velocity signal. The sum of isovolumic contraction time and isovolumic relaxation time was obtained by subtracting ejection time from the duration of tricuspid regurgitation. The Doppler RV index tended to be elevated (median 0.83) compared with normal ranges. Normal Doppler RV index was 0.28 +/- 0.04. After a mean follow-up duration of 2.9 years, 4 patients underwent lung transplantation and 30 patients died; the cause was cardiac in 28, noncardiac in 1, and uncertain in 1. Univariately, the Doppler RV index (chi-square 20.7, p <0.0001), severity of tricuspid regurgitation (chi-square 8.2, p = 0.004), treatment with calcium blockers (chi-square 6.6, p = 0.01), heart rate (chi-square 5.1, p = 0.02), and symptom status (chi-square 4.9, p = 0.03) were associated with adverse outcome (cardiac deaths and lung transplantation). However, only the Doppler RV index and treatment with calcium blockers were independent predictors within the multivariate model. Our results indicate that the Doppler RV index is a useful predictor of adverse outcome in patients with primary pulmonary hypertension.

Myocardial dysfunction associated with brain death: clinical, echocardiographic, and pathologic features.

BACKGROUND: The sequelae of severe brain injury include myocardial dysfunction. We sought to describe the prevalence and characteristics of myocardial dysfunction seen in the context of brain-injury-related brain death and to compare these abnormalities with myocardial pathologic changes. METHODS: We examined the clinical course, electrocardiograms, head computed tomography scans, and echocardiographic data of 66 consecutive patients with brain death who were evaluated as heart donors. In a sub-group of patients, we compared echocardiographic findings with pathologic findings. RESULTS: Echocardiographic systolic myocardial dysfunction was present in 28 (42%) of 66 patients and was not predicted by clinical, electrocardiographic, or head computed tomographic scan characteristics. Ventricular arrhythmias were more common in the patients with, compared to those without, myocardial dysfunction (32% vs 0%; p < 0.001). Myocardial dysfunction was segmental in all 8 patients with spontaneous subarachnoid or intracerebral hemorrhage. In these patients, the left ventricular apex was often spared. Myocardial dysfunction was either segmental or global in 17 patients who suffered head trauma and in 3 patients who died of other central nervous system illnesses. In 11 autopsied hearts, we found poor correlation between echocardiographic dysfunction and pathologic findings. CONCLUSIONS: Systolic myocardial dysfunction is common after brain-injury-related brain death. After spontaneous subarachnoid or intracerebral hemorrhage, the pattern of dysfunction is segmental, whereas after head trauma, it may be either segmental or global. We found poor correlation between the echocardiographic distribution of dysfunction and light microscopic pathologic findings.

The role of intraoperative transesophageal echocardiography in patients undergoing cardiac mass removal.

To evaluate the role of intraoperative transesophageal echocardiography (IOTEE) during surgical removal of cardiac masses, we studied 75 consecutive patients (34 men, aged 56 +/- 16 years, range 17 to 82 years) who underwent surgery primarily for cardiac mass removal with the adjunct of IOTEE for the years 1993 through 1998. The IOTEE provided new information before bypass in 6 patients (8%), altering the planned surgical procedure in all. A newly discovered patent foramen ovale was closed in 2 patients, a second myxoma discovered in one patient, a mitral valve repaired in one patient, inferior vena caval cannulation site clarified in one patient, and in one patient the mass was no longer present and the surgery canceled. In 10 patients (13%), new post-bypass information was found, which prompted return to bypass for valve repair in 3 patients, altered nonsurgical management in 3 patients, and did not necessitate specific measures in 4 patients. Thus, in 75 patients coming to surgery for mass removal, IOTEE affected intraoperative management in 12 (16%).

Rapid estimation of regurgitant volume by the proximal isovelocity surface area method in mitral regurgitation: Can continuous-wave Doppler echocardiography be omitted?

The proximal isovelocity surface area (PISA) method is accurate for quantitating mitral regurgitation but requires recording both mitral maximal and integrated jet velocities using the same continuous-wave Doppler jet signal. In 272 consecutive patients with isolated mitral regurgitation, the mean ratio of maximal to integral of velocity had a narrow range of variation (mean +/- SD, 3.25 +/- 0.47). The estimated regurgitant volume, calculated as regurgitant flow/3.25, showed an excellent correlation with reference regurgitant volumes (r = 0.96 and r = 0.97; standard error of the estimate, 11 ml; both p < 0.0001), with limited overestimation and high sensitivity and specificity for severe mitral regurgitation. The estimated regurgitant volume is a useful measurement in patients in whom the continuous-wave Doppler signal of mitral regurgitation cannot be obtained.

Doppler echocardiographic index for assessment of global right ventricular function.

Echocardiographic assessment of right ventricular function remains difficult and challenging. However, there is considerable clinical need for a simple, reproducible, and reliable parameter of right ventricular function in patients with right-sided heart disease. The purpose of this study was to assess the clinical value of a Doppler-derived index, combining systolic and diastolic intervals of the right cycle, in assessing global right ventricular function in patients with primary pulmonary hypertension. The study population comprised 26 consecutive patients with primary pulmonary hypertension and 37 age-matched normal subjects. The sum of right ventricular isovolumetric contraction time and isovolumetric relaxation time was obtained by subtracting right ventricular ejection time from the interval between cessation and onset of the tricuspid inflow velocities with pulsed-wave Doppler echocardiography. An index of combined right ventricular systolic and diastolic function was obtained by dividing the sum of both isovolumetric intervals by ejection time. The index was compared with available parameters of systolic or diastolic function, clinical symptoms, and survival. Right ventricular isovolumetric contraction time and isovolumetric relaxation time were prolonged significantly in patients with primary pulmonary hypertension (85 +/- 41 msec and 135 +/- 43 msec) compared with normal subjects (38 +/- 7 msec and 49 +/- 9 msec, respectively; p < 0.001). Ejection time was shortened significantly in patients with pulmonary hypertension (241 +/- 43 msec versus normal [322 +/- 21 msec]; p < 0.001). However, the index was the single most powerful variable to discriminate patients with primary pulmonary hypertension from normal subjects (0.93 +/- 0.34 versus 0.28 +/- 0.04; p < 0.001) and was the strongest predictor of clinical status and survival. The index was not significantly affected by heart rate, right ventricular pressure, right ventricular dilation, or tricuspid regurgitation. It is well known that right ventricular systolic and diastolic dysfunction coexist in patients with primary pulmonary hypertension. This article reports the use of an easily obtainable Doppler-derived index that combines elements of systolic and diastolic function. This index appears to be a useful noninvasive means that correlates with symptoms and survival in patients with primary pulmonary hypertension.

Outcome after surgery for mitral regurgitation. Determinants of postoperative morbidity and mortality.

BACKGROUND AND AIMS OF THE STUDY: The incidence and impact of congestive heart failure and coronary artery disease on late survival after surgical correction of mitral regurgitation are poorly defined. In addition to the uncertainty about the frequency of this complication, the mechanisms of heart failure have not been fully analyzed. METHODS: To determine survival and the incidence and mechanisms of congestive heart failure after mitral valve surgery for mitral regurgitation, we analyzed the long-term outcome of 576 consecutive postoperative survivors. RESULTS: The analysis demonstrated that preserved preoperative left ventricular function (ejection fraction > or = 60%) was associated with improved survival (adjusted risk ratio 0.49; 95% C.I. 0.36-0.661) and reduced incidence of congestive heart failure (adjusted risk ratio 0.30; 95% C.I. 0.20-0.441), while concomitant coronary artery disease was associated with an excess mortality (adjusted risk ratio 1.80; 95% C.I. 1.34-2.41) and incidence of congestive heart failure (adjusted risk ratio 2.12; 95% C.I. 1.48-3.031). CONCLUSIONS: These results suggest that left ventricular dysfunction and coronary artery disease are major determinants of mortality and morbidity after surgical correction of mitral regurgitation. For the prevention of postoperative congestive heart failure, early surgical correction of mitral regurgitation should be considered before left ventricular dysfunction occurs.

Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts.

Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of omega-3 polyunsaturated fatty acids (omega3FA) reduce sudden death. Animal data show that omega3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of omega3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), omega3FA pretreatment (30 days; n=6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in omega3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in omega3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary omega3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of omega3FA against dofetilide-induced proarrhythmia observed in this animal model.

Grading of mitral regurgitation by quantitative Doppler echocardiography: calibration by left ventricular angiography in routine clinical practice.

BACKGROUND: Quantitative Doppler echocardiography and proximal flow convergence methods are validated techniques for quantifying mitral regurgitation. However, the clinical interpretation of the values calculated is hindered by the absence of calibration of ranges of severity in large numbers of patients. METHODS AND RESULTS: In 180 consecutive patients (men, 62%; mean age+/-SD, 66+/-11 years), the results of Doppler quantification of isolated mitral regurgitation were calibrated by use of left ventricular angiographic grading performed within 3 months in routine practice and without intervening events. The thresholds of the quantitative variables corresponding to the angiographic grades were identified by maximizing the sum of sensitivity and specificity and minimizing their difference. The mitral regurgitation grade by angiography was 2.7+/-1.3. The mean value and correlation with angiographic grades for effective regurgitant orifice were 43+/-37 mm and r=.79 (P<.0001); for regurgitant volume, 62+/-45 mL and r=.80 (P<.0001); and for regurgitant fraction, 45+/-17% and r=.78 (P<.0001). Despite some overlap, differences between mitral regurgitation grades were all significant (all P<.05). The thresholds for severe mitral regurgitation (grade 4) were 60 mL, 50%, and 40 mm2 for regurgitant volume, regurgitant fraction, and orifice, respectively. CONCLUSIONS: In routine practice in large numbers of patients in a clinical laboratory, Doppler echocardiographic quantification of mitral regurgitation shows highly significant correlation with qualitative angiographic grades. Despite an expected overlap between classes, the calibration by angiography of grading ranges for the quantitative variables provides a framework for their interpretation and allows the definition in clinical practice of thresholds for severe mitral regurgitation.