Neuregulin-2 ablation results in dopamine dysregulation and severe behavioral phenotypes relevant to psychiatric disorders.

Numerous genetic and functional studies implicate variants of Neuregulin-1 (NRG1) and its neuronal receptor ErbB4 in schizophrenia and many of its endophenotypes. Although the neurophysiological and behavioral phenotypes of NRG1 mutant mice have been investigated extensively, practically nothing is known about the function of NRG2, the closest NRG1 homolog. We found that NRG2 expression in the adult rodent brain does not overlap with NRG1 and is more extensive than originally reported, including expression in the striatum and medial prefrontal cortex (mPFC), and therefore generated NRG2 knockout mice (KO) to study its function. NRG2 KOs have higher extracellular dopamine levels in the dorsal striatum but lower levels in the mPFC; a pattern with similarities to dopamine dysbalance in schizophrenia. Like ErbB4 KO mice, NRG2 KOs performed abnormally in a battery of behavioral tasks relevant to psychiatric disorders. NRG2 KOs exhibit hyperactivity in a novelty-induced open field, deficits in prepulse inhibition, hypersensitivity to amphetamine, antisocial behaviors, reduced anxiety-like behavior in the elevated plus maze and deficits in the T-maze alteration reward test-a task dependent on hippocampal and mPFC function. Acute administration of clozapine rapidly increased extracellular dopamine levels in the mPFC and improved alternation T-maze performance. Similar to mice treated chronically with N-methyl-d-aspartate receptor (NMDAR) antagonists, we demonstrate that NMDAR synaptic currents in NRG2 KOs are augmented at hippocampal glutamatergic synapses and are more sensitive to ifenprodil, indicating an increased contribution of GluN2B-containing NMDARs. Our findings reveal a novel role for NRG2 in the modulation of behaviors with relevance to psychiatric disorders.

Pregnancy history, coronary artery calcification and bone mineral density in menopausal women.

OBJECTIVE: This study examined relationships, by pregnancy histories, between bone mineral density (BMD) and coronary artery calcification (CAC) in postmenopausal women. METHODS: Forty women identified from their medical record as having pre-eclampsia (PE) were age/parity-matched with 40 women having a normotensive pregnancy (NP). Vertebral (T4-9) BMD and CAC were assessed by quantitative computed tomography in 73 (37 with PE and 36 with NP) of the 80 women. Analyses included linear regression using generalized estimating equations. RESULTS: Women averaged 59 years of age and 35 years from the index pregnancy. There were no significant differences in cortical, trabecular or central BMD between groups. CAC was significantly greater in the PE group (p = 0.026). In multivariable analysis, CAC was positively associated with cortical BMD (p = 0.001) and negatively associated with central BMD (p = 0.036). There was a borderline difference in the association between CAC and central BMD by pregnancy history (interaction, p = 0.057). CONCLUSIONS: Although CAC was greater in women with a history of PE, vertebral BMD did not differ between groups. However, both cortical and central BMD were associated with CAC. The central BMD association was marginally different by pregnancy history, suggesting perhaps differences in underlying mechanisms of soft tissue calcification.

Endothelial function in women of the Kronos Early Estrogen Prevention Study.

OBJECTIVE: Endothelial dysfunction occurs early in the atherosclerotic disease process, often preceding clinical symptoms. Use of menopausal hormone treatment (MHT) to reduce cardiovascular risk is controversial. This study evaluated effects of 4 years of MHT on endothelial function in healthy, recently menopausal women. METHODS: Endothelial function was determined by pulse volume digital tonometry providing a reactive hyperemia index (RHI) in a subset of women enrolled in the Kronos Early Estrogen Prevention Study. RHI was measured before and annually after randomization to daily oral conjugated equine estrogen (oCEE, 0.45 mg), weekly transdermal 17ß-estradiol (tE2, 50 µg) each with intermittent progesterone (200 mg daily 12 days of the month) or placebo pills and patch. RESULTS: At baseline, RHI averaged 2.39 ± 0.69 (mean ± standard deviation; n = 83), and over follow-up did not differ significantly among groups: oCEE, 2.26 ± 0.48 (n = 26); tE2, 2.26 ± 0.45 (n = 24); and placebo, 2.37 ± 0.37 (n = 33). Changes in RHI did not correlate with changes in traditional cardiovascular risk factors, but may inversely correlate with carotid intima medial thickness (Spearman correlation coefficient ρ = -0.268, p = 0.012). CONCLUSION: In this 4-year prospective assessment of recently menopausal women, MHT did not significantly alter RHI when compared to placebo.

Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.

OBJECTIVE: Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia. METHODS: A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis. RESULTS: Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL(-1) were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the 'top' SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79 × 10(-7) ) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs. CONCLUSION: Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression.

A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide (HCTZ) in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and HCTZ response in an independent sample of 746 Caucasians and African-Americans randomized to HCTZ or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4 mmHg, P=0.0275; diastolic: 2.5 mmHg, P=0.0196) responses to HCTZ vs T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as HCTZ specific. Expression analyses in HCTZ-treated African-Americans showed differential pre-treatment leukocyte YEATS4 expression between rs7297610 genotype groups (P=0.024), and reduced post-treatment expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.

Association of KCNJ1 variation with change in fasting glucose and new onset diabetes during HCTZ treatment.

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta=8.47, P(FDR)=0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31-3.53), P(FDR)=0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.

Endothelial function and cardiovascular risk stratification in menopausal women.

BACKGROUND: Peripheral arterial, endothelium-dependent, flow-mediated reactive hyperemia is reduced in individuals with atherosclerosis. This study tested the hypothesis that digital tonometry, as a surrogate of endothelial function, is useful to stratify cardiovascular risk in recently menopausal women who are asymptomatic for cardiovascular disease. METHODS: Women undergoing screening for the Kronos Early Estrogen Prevention Study (KEEPS) were evaluated for conventional risk factors, flow-mediated reactive hyperemia by digital tonometry (RHI), carotid intima-media thickness (CIMT) by ultrasound, and coronary arterial calcium (CAC) by 64-slice CT scanner. RESULTS: One hundred and two non-diabetic Caucasian women (53.0 +/- 2.3 years old, 18.0 +/- 9.0 months past their last menses) participated; 72% were never-smokers. Fourteen women had positive CAC scores (range 0.5-133 Agatston units); CIMT ranged from 0.57 to 1.06 mm. RHI ranged from 1.26 to 5.44. RHI did not correlate with time past menopause, CAC, CIMT, total cholesterol or low density lipoprotein cholesterol. The significant negative correlation of RHI with body mass index (r = -0.21, p = 0.031) was lost in non-smokers (r = - 0.17, p = 0.14). There was also a negative correlation of high density lipoprotein cholesterol with CAC, both in the overall group and non-smokers (rho = -0.20, p = 0.05 and rho = -0.27, p = 0.02, respectively). CONCLUSIONS: RHI varies widely in healthy women within the first 3 years of menopause. RHI was not associated with standard risk assessment algorithms, CAC or CIMT. RHI may indicate an additional, independent component and non-invasive tool to further stratify cardiovascular risk in recently menopausal women. As KEEPS continues, data on RHI will provide information regarding hormonal therapy, endovascular biology and atherosclerotic risk.

High density lipoprotein mediated lipid efflux from retinal pigment epithelial cells in culture.

BACKGROUND/AIM: [corrected] The transport of radiolabelled photoreceptor outer segments (POS) lipids was investigated by cultured retinal pigment epithelial cells (RPE). Phagocytosis of POS by the RPE is essential to maintain the health and function of the photoreceptors in vivo. POS are phagocytised at the apical cell surface of RPE cells. Phagocytised POS lipids may be either recycled to the photoreceptors for reincorporation into new POS or they may be transported to the basolateral surface for efflux into the circulation. RESULTS: The authors have demonstrated that high density lipoprotein (HDL) stimulates efflux of radiolabelled lipids, of POS origin, from the basal surface of RPE cells in culture. Effluxed lipids bind preferentially to HDL species of low and high molecular weight. Effluxed radiolabelled phosphotidyl choline was the major phospholipid bound to HDL, with lesser amounts of phosphatidyl ethanolamine, phosphatidyl inosotol. Effluxed radiolabelled triglycerides, cholesterol, and cholesterol esters also bound to HDL. Lipid free apolipoprotein A-I (apoA-I) and apoA-I containing vesicles also stimulate lipid efflux. CONCLUSION: The findings suggest a role for HDL and apoA-I in regulating lipid and cholesterol transport from RPE cells that may influence the pathological lipid accumulation associated with age related macular degeneration.

Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment.

BACKGROUND: Myocardial infarction (MI) can directly cause ischemic mitral regurgitation (IMR), which has been touted as an indicator of poor prognosis in acute and early phases after MI. However, in the chronic post-MI phase, prognostic implications of IMR presence and degree are poorly defined. METHODS AND RESULTS: We analyzed 303 patients with previous (>16 days) Q-wave MI by ECG who underwent transthoracic echocardiography: 194 with IMR quantitatively assessed in routine practice and 109 without IMR matched for baseline age (71+/-11 versus 70+/-9 years, P=0.20), sex, and ejection fraction (EF, 33+/-14% versus 34+/-11%, P=0.14). In IMR patients, regurgitant volume (RVol) and effective regurgitant orifice (ERO) area were 36+/-24 mL/beat and 21+/-12 mm(2), respectively. After 5 years, total mortality and cardiac mortality for patients with IMR (62+/-5% and 50+/-6%, respectively) were higher than for those without IMR (39+/-6% and 30+/-5%, respectively) (both P<0.001). In multivariate analysis, independently of all baseline characteristics, particularly age and EF, the adjusted relative risks of total and cardiac mortality associated with the presence of IMR (1.88, P=0.003 and 1.83, P=0.014, respectively) and quantified degree of IMR defined by RVol >/=30 mL (2.05, P=0.002 and 2.01, P=0.009) and by ERO >/=20 mm(2) (2.23, P=0.003 and 2.38, P=0.004) were high. CONCLUSIONS: In the chronic phase after MI, IMR presence is associated with excess mortality independently of baseline characteristics and degree of ventricular dysfunction. The mortality risk is related directly to the degree of IMR as defined by ERO and RVol. Therefore, IMR detection and quantification provide major information for risk stratification and clinical decision making in the chronic post-MI phase.

Assessment of severity of aortic regurgitation using the width of the vena contracta: A clinical color Doppler imaging study.

BACKGROUND: The width of the vena contracta (VC-W), the smallest area of regurgitant flow, reflects the degree of valvular regurgitation and is measurable by color Doppler imaging, but this method has not been validated in aortic regurgitation (AR). METHODS AND RESULTS: We prospectively examined 79 patients with isolated AR and 80 patients without regurgitation. The VC-W was measured from the long-axis parasternal view and compared with 2 simultaneous reference methods (quantitative Doppler and 2D echocardiography). In patients without regurgitation, the agreement between methods was excellent. In patients with AR, good correlations (all P<0.0001) were obtained between VC-W and effective regurgitant orifice (ERO) area and regurgitant volume recorded by quantitative Doppler (r=0.89 and 0.90, respectively) and 2D echocardiographic (r=0.90 and 0.89, respectively) methods. These correlations were similar with eccentric or central jets (all P>0.60). The other methods used showed good correlations of VC-W with aortographic grading of AR (n=8, r=0.82, P=0.01), with the proximal flow convergence method (n=53, r=0.85, P<0.0001), and with left ventricular end-diastolic volume (r=0.81, P<0.0001). Sensitivity and specificity of VC-W >/=6 mm for diagnosing severe AR (ERO >/=30 mm(2)) were 95% and 90%, respectively. CONCLUSIONS: For assessment of the degree of AR, VC-W shows good correlations with simultaneous quantitative measures (regardless of jet direction), shows good correlations with other methods of assessment of AR, and provides a high diagnostic value for severe AR. VC-W is a simple, reliable method that can be used clinically as part of comprehensive Doppler echocardiographic assessment of AR.

Clinical profile and outcome of idiopathic restrictive cardiomyopathy.

BACKGROUND: Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function. METHODS AND RESULTS: Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years' duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected (P<0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] = 2.1), left atrial dimension >60 mm (HR = 2.3), age >70 years (HR = 2.0), and each increment of NYHA class (HR = 2.0). CONCLUSIONS: Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.

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.

Long-term outcome of patients with intermediate-risk exercise electrocardiograms who do not have myocardial perfusion defects on radionuclide imaging.

BACKGROUND: The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging. METHODS AND RESULTS: The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (-10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement. CONCLUSIONS: Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.

Exercise-induced increases in atrial natriuretic factor are attenuated by endurance training.

Short-term exercise has been associated with increased plasma levels of atrial natriuretic factor, a potent dilating and natriuretic hormone. In this study, the effect of exercise training on atrial natriuretic factor release during short-term exercise was investigated in men without a history of cardiovascular or other major disease. A well trained group of 10 men who exercised an average of 6,618 kcal/week was compared with a minimally trained group of 9 men who exercised 1,479 kcal/week. Maximal oxygen uptake was 55.2 ml/kg per min in the well trained group and 42.5 ml/kg per min in the minimally trained group (p less than 0.05). Plasma for atrial natriuretic factor, norepinephrine and epinephrine was obtained at rest, at 4 min of exercise and at maximal exercise. Atrial natriuretic factor was lower at rest in the minimally trained than in the well trained men (23 vs. 35.9 pg/ml, p less than 0.05). At maximal exercise, atrial natriuretic factor increased 2.6 times the value at rest in minimally trained men (59.8 pg/ml, p less than 0.05 vs. rest), but did not change in well trained men (34 pg/ml). In minimally trained men at rest, at 4 min of exercise and at maximal exercise, plasma levels of atrial natriuretic factor correlated with heart rate, cardiac output, mean arterial pressure and plasma levels of norepinephrine and epinephrine; these correlations were not found in the well trained group. Thus, short-term exercise results in a significant increase in atrial natriuretic factor in minimally trained but not in well trained men.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of moderate aortic stenosis.

The natural history of severe, symptomatic aortic stenosis has been well documented. However, the natural history of moderate aortic stenosis remains poorly understood. Therefore, a group of 66 patients was identified who had a diagnosis of moderate aortic stenosis at the time of cardiac catheterization (aortic valve area 0.7 to 1.2 cm2) and who did not have surgical therapy during the 1st 180 days after cardiac catheterization. During a mean follow-up period of 35 months, 14 patients died of causes attributed to aortic stenosis and 21 underwent aortic valve replacement. The estimated probability for remaining free of any complication of aortic stenosis at the end of the first 4 years was 59%. Symptomatic patients with decreased ejection fraction or hemodynamic evidence of left ventricular decompensation were at greater risk for these complications. It is concluded that patients with moderate aortic stenosis are at significant risk for the development of complications.

Effective regurgitant orifice area: a noninvasive Doppler development of an old hemodynamic concept.

OBJECTIVES: The purpose of this study was to determine the feasibility, relation to other methods and significance of the effective regurgitant orifice area measurement. BACKGROUND: Assessment of the severity of valvular regurgitation (effective regurgitant orifice area) has not been implemented in clinical practice but can be made by Doppler echocardiography. METHODS: Effective regurgitant orifice area was calculated by Doppler echocardiography as the ratio of regurgitant volume/regurgitant jet time-velocity integral and compared with color flow Doppler mapping, angiography, surgical classification, regurgitant fraction and variables of volume overload. RESULTS: In 210 consecutive patients examined prospectively, feasibility improved from the early to the late experience (65% to 95%). Effective regurgitant orifice area was 28 +/- 23 mm2 (mean +/- SD) for aortic regurgitation (32 patients), 22 +/- 13 mm2 for ischemic/functional mitral regurgitation (50 patients) and 41 +/- 32 mm2 for organic mitral regurgitation (82 patients). Significant correlations were found between effective regurgitant orifice and mitral jet area by color flow Doppler mapping (r = 0.68 and r = 0.63, p < 0.0001, respectively) and angiographic grade (r = 0.77, p = 0.0004). Effective regurgitant orifice area in surgically determined moderate and severe lesions was markedly different in mitral regurgitation (35 +/- 12 and 75 +/- 33 mm2, respectively, p = 0.009) and in aortic regurgitation (21 +/- 8 and 38 +/- 5 mm2, respectively, p = 0.08). Strong correlations were found between effective regurgitant orifice area and variables reflecting volume overload. A logarithmic regression was found between effective regurgitant orifice area and regurgitant fraction, underlining the complementarity of these indexes. CONCLUSIONS: Calculation of effective regurgitant orifice area is a noninvasive Doppler development of an old hemodynamic concept, allowing assessment of the lesion severity of valvular regurgitation. Feasibility is excellent with experience. Effective regurgitant orifice area is an important and clinically significant index of regurgitation severity. It brings additive information to other quantitative indexes and its measurement should be implemented in the comprehensive assessment of valvular regurgitation.

Intermittent claudication: an objective office-based assessment.

OBJECTIVES: We sought to compare standard lower extremity vascular laboratory treadmill exercise with the office-based active pedal plantarflexion technique. BACKGROUND: Intermittent claudication is relatively common in elderly patients and is an important predictor of cardiovascular morbidity and mortality. Noninvasive testing using resting and posttreadmill exercise ankle:brachial systolic blood pressure indices is often required to confirm the diagnosis and objectively assess the severity of lower extremity arterial occlusive disease. This is traditionally performed in a formal vascular laboratory setting. METHODS: Fifty consecutive patients (100 lower extremities) with known or suspected intermittent claudication referred for lower extremity treadmill exercise testing were also tested with active pedal plantarflexion using a prospective, randomized crossover design. Supine ankle:brachial systolic blood pressure indices were measured immediately before and after each form of exercise. RESULTS: There was an excellent correlation (r = 0.95, 95% confidence interval 0.93 to 0.97) between mean postexercise ankle:brachial systolic blood pressure indices for treadmill exercise and active pedal plantarflexion. There was no significant difference in outcome based on the order of testing or the severity of arterial occlusive disease. Symptoms of angina or dyspnea occurred in 11 patients (22%) with treadmill exercise versus zero patients with active pedal plantarflexion. CONCLUSIONS: Active pedal plantarflexion is an office-based test that compares favorably with treadmill exercise for the noninvasive, safe, objective and economical assessment of lower extremity arterial occlusive disease.

The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis.

The natural history of asymptomatic, hemodynamically significant, valvular aortic stenosis in adults was documented. Of 471 patients with aortic stenosis identified by Doppler echocardiography (peak systolic flow velocity greater than or equal to 4 m/s) from January 1984 through August 1987, 143 were asymptomatic and had isolated valvular aortic stenosis. Thirty patients underwent aortic valve intervention within 3 months (group 1); the remaining 113 patients did not have an intervention within 3 months (group 2). Follow-up information was available for all patients; the mean duration of follow-up study was 20 months (range 6 to 48). Three cardiac events occurred in the 30 group 1 patients after operation (two deaths, one reoperation). Among the 113 group 2 patients, three had cardiac death presumed to be a result of the aortic stenosis; all three developed symptoms at least 3 months before death. The actuarial probability of remaining free of symptoms of angina, dyspnea or syncope for group 2 was 86% at 1 year and 62% at 2 years. For this group, the 1 and 2 year probabilities of remaining free of cardiac events, including aortic valve intervention or cardiac death, were 93% and 74%, respectively. Of all clinical and echocardiographic variables (group 2), only Doppler flow velocity (p = 0.004) and ejection fraction (p = 0.01) were independent predictors of subsequent cardiac events. Among the 44 patients (groups 1 and 2) with a flow velocity greater than or equal to 4.5 m/s, the relative risk of sustaining a cardiac event (by Cox regression analysis) was 4.9 (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Color flow imaging compared with quantitative Doppler assessment of severity of mitral regurgitation: influence of eccentricity of jet and mechanism of regurgitation.

OBJECTIVES: To determine the influence of jet eccentricity and mechanism of mitral regurgitation, we examined 1) the relation between jet extent and severity of mitral regurgitation, and 2) the use of Doppler color flow imaging for quantitation of mitral regurgitation. BACKGROUND: Doppler color flow imaging is widely used to assess mitral regurgitation. However, whether, how and in which subgroups it can quantify regurgitation remain controversial. METHODS: In 80 patients with mitral regurgitation, results of color flow Doppler studies obtained in two orthogonal apical views were prospectively compared with quantitative Doppler measurement of the regurgitant volume and the regurgitant fraction. Comparisons were made according to the eccentricity of the jet (group 1 eccentric jets, n = 29; group 2 central jets, n = 51); group 2 was subdivided according to the mechanism of mitral regurgitation (group 2a organic, n = 27; group 2b ischemic or functional, n = 24). RESULTS: Globally, weak correlations were found between regurgitant volume and jet area (r = 0.57) and regurgitant fraction and jet area/left atrial area ratio (r = 0.65). Groups 1 and 2 showed a correlation between regurgitant volume and jet area (r = 0.68 and r = 0.65, respectively, p < 0.0001), but the slope was steeper in group 2 than in group 1 (0.22 vs. 0.06, p < 0.0001). The same jet area corresponded to more severe regurgitation in group 1 than in group 2 (jet > or = 8 cm2, regurgitant volume 113 +/- 55 vs. 43 +/- 21 ml, p < 0.0001). Similarly, for comparable regurgitant volumes (24 +/- 22 vs. 29 +/- 11 ml, p = NS), group 2a had a smaller jet area than did group 2b (5.3 +/- 6 vs. 9.6 +/- 6 cm2, p < 0.02). Quantitation of regurgitation by Doppler color flow imaging was unreliable in group 1; in group 2b, the regression line between regurgitant fraction and jet area/left atrial area ratio was close to the identity line. CONCLUSIONS: Mitral regurgitant jet eccentricity and mechanism influence jet extent. The same regurgitant volume produces smaller jet areas for eccentric compared with central jets and for central organic compared with ischemic or functional regurgitation. Quantitation of regurgitation using Doppler color flow imaging is possible in ischemic or functional regurgitation but inappropriate in eccentric jets, where quantitative Doppler study should be recommended.

Percutaneous transluminal angioplasty in patients with multivessel coronary disease: how important is complete revascularization for cardiac event-free survival?

The relative influences of revascularization status and baseline characteristics on long-term outcome were examined in 867 patients with multivessel coronary disease who had undergone successful coronary angioplasty. These patients represented 83% of a total of 1,039 patients in whom angioplasty had been attempted with an in-hospital mortality and infarction rate of 2.5% and 4.8%, respectively. Emergency coronary bypass surgery was needed in 4.9%. Of the 867 patients, 41% (group 1) were considered to have complete revascularization and 59% (group 2) to have incomplete revascularization. Univariate analysis revealed major differences between these two groups with patients in group 2 characterized by advanced age, more severe angina, a greater likelihood of previous coronary surgery and infarction, more extensive disease and poorer left ventricular function. Over a mean follow-up period of 26 months, the probability of event-free survival was significantly lower for group 2 only with respect to the need for coronary artery surgery (p = 0.004) and occurrence of severe angina (p = 0.04). The difference in mortality was of borderline significance (p = 0.051) and there were no significant differences between groups 1 and 2 in either the incidence of myocardial infarction or the need for repeat angioplasty. Multivariate analysis identified independent baseline predictors of late cardiac events that were then used to adjust the probabilities of event-free survival. This adjustment effectively removed any significant influence of completeness of revascularization on event-free survival for any of the above end points including the combination of death, myocardial infarction and need for coronary artery surgery. Therefore, late outcome in these patients is not significantly influenced by revascularization status but depends more on baseline patient characteristics.