Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma.

PURPOSE: A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti-insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871. PATIENTS AND METHODS: After informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871. RESULTS: No CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry. CONCLUSION: These data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.

Comparison of clinical and morphological characteristics of Staphylococcus aureus endocarditis with endocarditis caused by other pathogens.

OBJECTIVES: To analyse clinical, echocardiographic, and prognostic characteristics of Staphylococcus aureus infective endocarditis (IE) compared with endocarditis caused by other pathogens. DESIGN: Cohort study. METHODS: 194 consecutive patients with definite IE according to the Duke criteria prospectively examined by transthoracic and transoesophageal echocardiography were enrolled. Patients without identified microorganisms were excluded. The S aureus IE group (n = 61) was compared with the group with IE caused by other pathogens (n = 133). RESULTS: Compared with IE caused by other pathogens, S aureus IE was characterised by severe co-morbidity, a shorter duration of symptoms before diagnosis, and a higher prevalence of right sided IE, cutaneous portal of entry, and history of renal failure. Severe sepsis, major neurological events, and multiple organ failure were more frequent during the acute phase in S aureus IE. In-hospital mortality (34% v 10%, p < 0.001) was higher in patients with S aureus IE and the 36 month actuarial survival rate was lower in S aureus IE than in IE caused by other pathogens (47% v 68%, p = 0.002). Multivariate analyses identified S aureus infection as a predictive factor for in-hospital mortality and for overall mortality. CONCLUSIONS: S aureus IE compared with IE caused by other pathogens occurs in a more debilitated clinical setting and is characterised by a higher prevalence of severe sepsis, major neurological events, and multiple organ failure leading to higher mortality.

[New concepts on the physiopathology and therapy of aortic stenosis]. / Nouveaux concepts physiopathologique et thérapeutique de la sténose aortique.

Calcified "degenerative" aortic stenosis is currently the most common valvulopathy in industrialised countries. In the course of the last decade, experimental studies have allowed a better understanding of the physiopathology of this vavlulopathy. The latest development is the evidence for the initiation and progression of this disease, similar to those described for atherosclerosis. Lipid disturbances, in particular hypercholesterolaemia, constitute an important factor in the initiation of valvular lesions, but also in aortic orifice calcification. Certain preliminary clinical studies are in favour of the significance of statins for slowing the progression of aortic stenosis. This potential beneficial effect requires confirmation by randomised prospective studies and raises hopes for medical therapy in order to avoid the evolution of ordinary aortic sclerosis into tight calcified aortic stenosis.

[When should one operate for asymptomatic chronic aortic insufficiency?]. / Quand opérer une insuffisance aortique chronique asymptomatique?

In the presence of symptomatic aortic insufficiency, the indication for surgery is accepted. On the other hand, when the patient is asymptomatic, there is hesitation between intervening too early because of the operative risk and complications of valvular prostheses, and operating too late because of the progressive spontaneous risk of aortic parietal complications, sudden death or irreversible left ventricular dysfunction. Before any discussion, it is logical to verify the asymptomatic character of the patient with a stress test. On knowing the severity of the aortic insufficiency, which is usually confirmed by Doppler echocardiography, the decision is based partly on the left ventricular effects and the ascending aortic diameters, and partly on the operative risk modified by age and associated pathologies. In this article, drawing on the data in the literature we set out to discuss the operative indications in asymptomatic chronic aortic insufficiency.

[Determinants and prognosis of ischemic mitral regurgitation]. / Insuffisances mitrales ischémiques: mécanisme et pronostic.

Ischemic mitral regurgitation (IMR) is mitral regurgitation (MR) due to complications of coronary artery disease. Two mechanisms can be individualized. Acute MR secondary to ruptured papillary muscle is a rare but often fatal complication of myocardial infarction. We focus on functional MR, much more common, which occurs without any intrinsic valve disease. It was often underrated because of low murmur intensity but is observed between 15 and 20% after a myocardial infarction. The presence and degree of the regurgitation are related to local left ventricular remodeling. The apical and posterior displacement of papillary muscles leads to excess valvular tenting which in turn, in association with loss of systolic annular contraction, determines the severity of the regurgitation. IMR presence is associated with an excess mortality. The mortality risk is directly related to the degree of the regurgitation and a regurgitant volume > or = 30 ml or an effective regurgitant orifice > or = 20 mm2 define a high-risk group. In current clinical practice, IMR is mainly corrected with ring annuloplasty. However, this technique does not correct local alterations of left ventricular remodeling and its benefits on long-term outcome remains to be demonstrated.

Very long-term survival and durability of mitral valve repair for mitral valve prolapse.

BACKGROUND: Mitral regurgitation (MR) due to mitral valve prolapse (MVP) is often treatable by surgical repair. However, the very long-term (>10-year) durability of repair in both anterior leaflet prolapse (AL-MVP) and posterior leaflet prolapse (PL-MVP) is unknown. METHODS AND RESULTS: In 917 patients (aged 65+/-13 years, 68% male), surgical correction of severe isolated MR due to MVP (679 repairs and 238 replacements [MVRs]) was performed between 1980 and 1995. Survival after repair was better than survival after MVR for both PL-MVP (at 15 years, 41+/-5% versus 31+/-6%, respectively; P=0.0003) and AL-MVP (at 14 years, 42+/-8% versus 31+/-5%, respectively; P=0.003). In multivariate analysis adjusting for predictors of survival, repair was independently associated with lower mortality in PL-MVP (adjusted risk ratio [RR] 0.61, 95% CI 0.44 to 0.85; P=0.0034) and in AL-MVP (adjusted RR 0.67, 95% CI 0.47 to 0.96; P=0.028). The reoperation rate was not different after repair or MVR overall (at 19 years, 20+/-5% for repair versus 23+/-5% for MVR; P=0.4) or separately in PL-MVP (P=0.3) or AL-MVP (P=0.3). However, the reoperation rate was higher after repair of AL-MVP than after repair of PL-MVP (at 15 years, 28+/-7% versus 11+/-3%, respectively; P=0.0006). From the 1980s to the 1990s, the RR of reoperation after repair of AL-MVP versus PL-MVP did not change (RR 2.5 versus 2.7, respectively; P=0.58), but the absolute rate of reoperation decreased similarly in PL-MVP and AL-MVP (at 10 years, from 10+/-3% to 5+/-2% and from 24+/-6% to 10+/-2%, respectively; P=0.04). CONCLUSIONS: In severe MR due to MVP, mitral valve repair compared with MVR provides improved very long-term survival after surgery for both AL-MVP and PL-MVP. Reoperation is similarly required after repair or replacement but is more frequent after repair of AL-MVP. Recent improvement in long-term durability of repair suggests that it should be the preferred mode of surgical correction of MVP whether it affects anterior or posterior leaflets and is an additional incentive for early surgery of severe MR due to MVP.

Contrast echocardiography improves the accuracy and reproducibility of left ventricular remodeling measurements: a prospective, randomly assigned, blinded study.

OBJECTIVES: We sought to assess the impact of contrast injection and harmonic imaging, on the measure by echocardiography of left ventricular (LV) remodeling. BACKGROUND: Left ventricular remodeling is a precursor of LV dysfunction, but the impact of contrast injection and harmonic imaging on the accuracy or reproducibility of echocardiography is unclear. METHODS: We prospectively collected LV images by using simultaneous methods. Then, LV volumes were measured off-line, in blinded manner and in random order. The accuracy of echocardiography was determined in comparison to electron beam computed tomography (EBCT) in 26 patients. The reproducibility of echocardiography was assessed by three blinded observers with different training levels in 32 patients. RESULTS: End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and ejection fraction (EF), as measured by EBCT (195 +/- 55, 58 +/- 24 and 137 +/- 35 ml and 71 +/- 5%, respectively) and echocardiography with harmonic imaging and contrast injection (194 +/- 51, 55 +/- 20 and 140 +/- 35 ml and 72 +/- 4%, respectively), showed no differences (all p > 0.15) and excellent correlations (all r > 0.87). In contrast, echocardiography using harmonic imaging without contrast injection underestimated the EBCT results (all p < 0.01). Reproducibility was superior with rather than without contrast injection for intraobserver and interobserver variabilities (all p < 0.001). Values measured by different observers were different without contrast injection, but were similar with contrast injection (all p > 0.18). Consequently, intrinsic patient differences represented a larger and almost exclusive proportion of global variability with contrast injection for EDV (94 vs. 79%), ESV (93 vs. 82%), SV (87 vs. 53%) and EF (84 vs. 41%), as compared with harmonic imaging without contrast injection (all p < 0.005). CONCLUSIONS: For assessment of LV remodeling, echocardiography with harmonic imaging and contrast injection improved the accuracy and reproducibility, as compared with imaging without contrast injection. With contrast injection, variability was almost exclusively due to intrinsic patient differences. Therefore, when evaluation of LV remodeling is deemed important, assessment after contrast injection should be the preferred echocardiographic approach.

Pathophysiologic determinants of third heart sounds: a prospective clinical and Doppler echocardiographic study.

PURPOSE: We sought to determine the importance of a third heart sound (S(3)) and its relation to hemodynamic and valvular dysfunction. SUBJECTS AND METHODS: We prospectively enrolled 580 patients who had isolated valvular regurgitation (mitral, n = 299; aortic, n = 121) or primary left ventricular dysfunction with or without functional mitral regurgitation (n = 160). We analyzed the associations between the clinical finding of an audible S(3) (as noted in routine clinical practice by internal medicine physicians) and hemodynamic alterations measured by comprehensive quantitative Doppler echocardiography. RESULTS: S(3) was more prevalent in patients with primary left ventricular dysfunction (46%, n = 73) than in organic mitral (16%, n = 47) or aortic (12%, n = 14) regurgitation (P <0.001). Patients with an S(3) were more likely to have class III-IV symptoms (55% [74 of 137] vs. 18% [80 of 443] of those without an S(3), P <0.001) and had a higher mean [+/- SD] pulmonary pressure (55 +/- 15 vs. 41 +/- 11 mm Hg, P <0.001). An S(3) was also related to a higher early filling velocity due to a greater filling volume, restrictive filling, or both. An S(3) was a marker of severe regurgitation (regurgitant fraction > or =40%) in patients with primary left ventricular dysfunction (odds ratio [OR] = 2.4; 95% confidence interval [CI]: 1.1 to 5.5), mitral regurgitation (OR = 17; 95% CI: 5.8 to 52), and aortic regurgitation (OR = 7.1; 95% CI: 1.8-28). An S(3) was also associated with restrictive filling in primary left ventricular dysfunction (OR = 3.0; 95% CI, 1.6 to 5.9), marked dilatation in mitral regurgitation (OR = 20; 95% CI: 6.8 to 58), and an ejection fraction (<50%) in aortic regurgitation (OR = 19; 95% CI: 6.0 to 62). CONCLUSION: An audible S(3) is an important clinical finding, indicating severe hemodynamic alterations, and should lead to a comprehensive assessment and consideration of vigorous medical or surgical treatment.

Echocardiographic assessment of mitral regurgitation.

Although the natural history of mitral regurgitation (MR) is poorly defined, evidence has been found for excess mortality and morbidity in patients with severe MR who are managed conservatively. With improved mortality and morbidity in the surgical management of this condition, we are becoming increasingly aggressive in offering surgery to patients with severe MR. Surgery may be offered even in the absence of symptoms or left ventricular dysfunction, provided that the valve seems reparable, the patient's MR is severe, and the surgical team is experienced in valve repair. Echocardiography is critically important in determining the feasibility of valve repair and accurately assessing the severity of the patient's MR. It also allows assessment of the effect of MR on the left ventricle and the left atrium.

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.

Timing of surgery in patients with chronic, severe mitral regurgitation.

Patients with severe mitral regurgitation (MR) who are managed conservatively sustain excess mortality and morbidity. With improved mortality and morbidity rates being achieved with surgical management, cardiologists and cardiac surgeons are becoming more aggressive in treating patients with severe MR with surgery. Recent data indicate that even in the absence of symptoms or left ventricular dysfunction, surgery should be offered as a treatment for MR, provided that the regurgitation is severe, the valve seems to be repairable, and the surgeon is experienced in valve repair and is aided by intraoperative transesophageal echocardiography.

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.

[Mitral valve insufficiency and surgical repair]. / Insuffisance mitrale et chirurgie conservatrice.

Management of mitral regurgitation have benefited over the last 10 years from the better understanding of its natural history and from the advent of new echocardiographic quantitative methods. The dismal prognosis displayed by patients with flail leaflet and severe mitral regurgitation medically treated in one hand and the demonstration of the dramatic consequences of impaired pre-operative left ventricular function in the other, have been a strong incentive for early surgical correction of the disease. In the same time, mitral valve repair developed because of the improvement in the surgical techniques, of changes in aetiology and because of the widespread use of intra-operative transoesophageal echocardiography. Mitral repair has been shown to be an independent and beneficial predictor of overall survival, operative mortality and late survival and consequently became the support of early surgical strategies. But it is not the only factor to predict mortality and morbidity, and one must not forget the decisive and independent part played by age, preoperative symptoms and above all pre-operative left ventricular function. Therefore, mitral valve repair must not be considered as a pretext to postpone intervention but should be an other reason to intervene earlier.

Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: A quantitative clinical study.

BACKGROUND: Functional mitral regurgitation (FMR) occurs with a structurally normal valve as a complication of systolic left ventricular dysfunction (LVD). Determinants of degree of FMR are poorly defined; thus, mechanistic therapeutic approaches to FMR are hindered. METHODS AND RESULTS: In a prospective study of 21 control subjects and 128 patients with LVD (defined as ejection fraction <50%, mean 31+/-9%) in sinus rhythm, we quantified simultaneously by echocardiography the effective regurgitant orifice (ERO) of FMR by using 2 methods: mitral deformation (valve and annulus) and left ventricular (LV) global (volumes, stress, function, and sphericity) and local (papillary muscle displacements and regional wall motion index) remodeling. A wide range of ERO (15+/-14 mm(2), 0 to 87 mm(2)) was observed, unrelated to ejection fraction (P:=0.32). The major determinant of ERO was mitral deformation, ie, systolic valvular tenting and annular contraction in univariate (r=0.74 and r=-0.61, respectively; both P:<0.0001) and multivariate (both P:<0. 0001) analyses, independent of global LV remodeling. Systolic valvular tenting was strongly determined by local LV alterations, particularly apical (r=0.75) and posterior (r=0.70) displacement of papillary muscle, with confirmation in multivariate analysis (both P:<0.0001), independent of LV volumes, function, and sphericity. CONCLUSIONS: The presence and degree of FMR complicating LVD are unrelated to the severity of LVD. Local LV remodeling (apical and posterior displacement of papillary muscles) leads to excess valvular tenting independent of global LV remodeling. In turn, excess tenting and loss of systolic annular contraction are associated with larger EROs. These determinants of FMR warrant consideration for specific approaches to the treatment of FMR complicating LVD.

Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study.

OBJECTIVE: We sought to evaluate the vena contracta width (VCW) measured using color Doppler as an index of severity of tricuspid regurgitation (TR). BACKGROUND: The VCW is a reliable measure of mitral and aortic regurgitation, but its value in measuring TR is uncertain. METHODS: In 71 consecutive patients with TR, the VCW was prospectively measured using color Doppler and compared with the results of the flow convergence method and hepatic venous flow, and its diagnostic value for severe TR was assessed. RESULTS: The VCW was 6.1+/-3.4 mm and was significantly higher in patients with, than those without, severe TR (9.6+/-2.9 vs. 4.2 +/- 1.6 mm, p<0.0001). The VCW correlated well with the effective regurgitant orifice (ERO) by the flow convergence method (r = 0.90, SEE = 0.17 cm2, p<0.0001), even when restricted to patients with eccentric jets (r = 0.93, p < 0.0001). The VCW also showed significant correlations with hepatic venous flow (r = 0.79, p < 0.0001), regurgitant volume (r = 0.77, p<0.0001) and right atrial area (r = 0.46, p< 0.0001). A VCW > or =6.5 mm identified severe TR with 88.5% sensitivity and 93.3% specificity. In comparison with jet area or jet/right atrial area ratio, the VCW showed better correlations with ERO (both p<0.01) and a larger area under the receiver operating characteristic curve (0.98 vs. 0.88 and 0.85, both p<0.02) for the diagnosis of severe TR. CONCLUSIONS: The VCW measured by color Doppler correlates closely with severity of TR. This quantitative method is simple, provides a high diagnostic value (superior to that of jet size) for severe TR and represents a useful tool for comprehensive, noninvasive quantitation of TR.

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.

Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study.

OBJECTIVES: The objective was to determine the independent association between atrial fibrillation (A-Fib) and activation of natriuretic peptides. BACKGROUND: The association of A-Fib with activation of N-terminal atrial and brain natriuretic peptides (N-ANPs and BNPs, respectively) is uncertain but of great importance for the diagnostic utilization of natriuretic peptides. This uncertainty is related to the lack of appropriate controls, with left ventricular (LV) and atrial overload similar to A-Fib. METHODS: We prospectively measured N-terminal atrial and BNPs and endothelin-1 levels in 100 patients and 14 age- and gender-matched control subjects. The 32 patients with A-Fib were compared with 68 patients in sinus rhythm and similar LV and atrial overload (due to mitral regurgitation or LV dysfunction) measured simultaneously with hormonal levels with comprehensive Doppler echocardiography. RESULTS: Patients with A-Fib compared with those in sinus rhythm had similar symptoms, comorbid conditions, cardioactive medications, pulmonary pressure, left atrial volume, and LV ejection fraction and filling characteristics but demonstrated higher N-ANP levels (2,613 +/- 1,681 vs. 1,654 +/- 1,323 pg/ml, p = 0.007) even after adjustment for the underlying cardiac disease (p < 0.0001). Conversely, BNP levels were similar in both groups (165 +/- 163 vs. 160 +/- 269 pg/ml, p = 0.9). In multivariate analysis, a higher N-ANP level was associated with A-Fib (p = 0.0003), symptom class (p < 0.0001) and endothelin-1 level (p = 0.032) independently of left atrial volume and LV ejection fraction. Conversely, BNP showed no independent association with and was most strongly associated with LV ejection fraction (p < 0.0001). CONCLUSIONS: Atrial fibrillation is an independent determinant of higher N-ANP levels and blurs its association with LV dysfunction. Conversely, the BNP is not independently associated with A-Fib and is strongly determined by LV dysfunction, for which it is an independent marker.

Sudden death in mitral regurgitation due to flail leaflet.

OBJECTIVES: We sought to assess the incidence and determinants of sudden death (SUD) in mitral regurgitation due to flail leaflet (MR-FL). BACKGROUND: Sudden death is a catastrophic complication of MR-FL. Its incidence and predictability are undefined. METHODS: The occurrence of SUD was analyzed in 348 patients (age 67 +/- 12 years) with MR-FL diagnosed echocardiographically from 1980 through 1994. RESULTS: During a mean follow-up of 48 +/- 41 months, 99 deaths occurred under medical treatment. Sudden death occurred in 25 patients, three of whom were resuscitated. The sudden death rates at five and 10 years were 8.6 +/- 2% and 18.8 +/- 4%, respectively, and the linearized rate was 1.8% per year. By multivariate analysis, the independent baseline predictors of SUD were New York Heart Association (NYHA) functional class (p = 0.006), ejection fraction (p = 0.0001) and atrial fibrillation (p = 0.059). The yearly linearized rate of sudden death was 1% in patients in functional class I, 3.1% in class II and 7.8% in classes III and IV. However, of 25 patients who had SUD, at baseline, 10 (40%) were in functional class I, 9 (36%) were in class II and only 6 (24%) in class III or IV. In five patients (20%), no evidence of risk factors developed until SUD. In patients with an ejection fraction > or =60% and sinus rhythm, the linearized rate of SUD was not different in functional classes I and II (0.8% per year). Surgical correction of MR (n = 186) was independently associated with a reduced incidence of SUD (adjusted hazard ratio [95% confidence interval] 0.29 [0.11 to 0.72], p = 0.007). CONCLUSIONS: Sudden death is relatively common in patients with MR-FL who are conservatively managed. Patients with severe symptoms, atrial fibrillation and reduced systolic function are at higher risk, but notable rates of SUD have been observed without these risk factors. Correction of MR appears to be associated with a reduced incidence of SUD, warranting early consideration of surgical repair.