Leakage of cardiac troponin I in aortic valve stenosis.

OBJECTIVE: Degeneration and death of cardiomyocytes contribute to the genesis of heart failure (HF) in aortic valve stenosis (AS). We studied whether the ongoing myocyte damage in AS can be detected from circulating cardiac troponin I (cTnI) concentrations. DESIGN AND SETTING: A cross-sectional cohort study in a university hospital. SUBJECTS AND METHODS: We examined 131 adult patients undergoing echocardiography and cardiac catheterization for isolated AS. Blood was sampled from the aortic root and, in a subset of 49 patients, also from the coronary sinus for the determination of cTnI using a sensitive immunoanalysis. RESULTS: Seventy-three patients (56%) had detectable aortic cTnI (> or =5 ng L(-1)) with 30 of them (23% of the total group) having cTnI above the reference limit in healthy subjects (>14 ng L(-1)). Patients with detectable cTnI had a higher prevalence of HF than those with undetectable cTnI (42% vs. 19%, P = 0.004). Plasma cTnI rose from the aorta to the coronary sinus by > or =5 ng L(-1) in 13 of 49 patients with AS (27%) versus in none of 12 control patients free of structural heart disease (P = 0.044). AS patients with transcardiac cTnI gradients > or =5 ng L(-1) had lower left ventricular (LV) ejection fractions than AS patients with gradients <5 ng L(-1) (mean +/- SD, 52 +/- 14% vs. 61 +/- 11%; P = 0.011). CONCLUSIONS: Detectable circulating cTnI is not uncommon in AS and shows a moderate association with the presence of HF. Leakage of cTnI into the coronary sinus associates with impairment of LV systolic function. Monitoring cTnI could provide a means to expose incipient clinical deterioration in AS.

Diagnosing heart failure in aortic valve stenosis.

OBJECTIVE: In aortic valve stenosis (AS), heart failure (HF) omens a high risk of death and is an indication for prompt valve replacement. We studied whether its detection can be facilitated by measuring plasma N-terminal B-type natriuretic peptide (Nt-BNP) or by estimating pulmonary capillary wedge pressure (PCWP) using echocardiography. DESIGN AND SETTING: A cross-sectional cohort study in a university hospital. SUBJECTS AND METHODS: We studied 137 consecutive adult patients referred to our unit for invasive evaluation of isolated AS. All patients underwent cardiac catheterization, measurement of plasma Nt-BNP and estimation of PCWP by Doppler echocardiography of transmitral and pulmonary venous flow velocities. The final diagnosis of HF was based on the combined criteria of dyspnoea on ordinary effort and PCWP >14 mmHg at cardiac catheterization. The performance of Nt-BNP and the PCWP estimate in the detection of HF were studied using receiver operating characteristic (ROC) analysis. RESULTS: Totally 42 patients had HF. A cardiologist's clinical diagnosis of HF had high specificity (94%) but poor sensitivity (66%). With an optimized cut-off point, plasma Nt-BNP had moderate sensitivity (77%) and specificity (79%) for HF; the ROC area was 0.83. The echocardiographic PCWP estimate classified 90% of patients correctly as having normal or truly elevated (>14 mmHg) PCWP. Its sensitivity and specificity for the diagnosis of HF were 80 and 95% respectively; the ROC area was 0.88. With a cut-off point of 12 mmHg, the sensitivity of the PCWP estimate was 85% and specificity, 88%. CONCLUSION: The recognition of HF in patients with AS can be improved by estimating PCWP using Doppler echocardiography of transmitral and pulmonary venous flow velocities.

Influence of negative intrathoracic pressure on right atrial and systemic venous dynamics.

To investigate the effect of a sustained fall in intrathoracic pressure (Mueller manoeuvre) on blood flow through the right heart and on systemic venous dynamics, 16 patients were studied using thermodilution, cinevenograms and simultaneous pressure recordings with two micromanometric transducers. The reductions in airway pressure (median [range]) during two graded Mueller manoeuvres were 25 (20-30) and 42 (22-52) mmHg. Right atrial mean pressure decreased by 17 (2-25) mmHg during the former and 38 (0-49) mmHg during the latter, and simultaneously, pressure gradients of 23 (1-32) and 45 (1-82) mmHg developed between the inferior vena cava and right atrium (P < 0.003 for all). Internal jugular venous pressure decreased by 16 (4-25) and 24 (4-43) mmHg (P < 0.03 for both), respectively, and no pressure gradient developed between internal jugular and superior caval veins. The minimum diameter of the proximal inferior vena cava decreased by 69 (-49-84)% (P = 0.002) during the greater manoeuvre. Cardiac index tended to increase by 26 (-17-40)% (P < 0.066) during the lesser manoeuvre but did not change statistically significantly during the greater. In conclusion, during negative intrathoracic pressure caused acutely by the Mueller manoeuvre, right atrial pressure decreases and the inferior vena cava collapses partially at or below the diaphragm. Despite a significant venous obstruction between the lower body and right atrium, blood flow through the right heart increases or remains constant.

Effect of negative intrathoracic pressure on left ventricular pressure dynamics and relaxation.

To investigate the effect of a fall of intrathoracic pressure on left ventricular (LV) hemodynamics and relaxation, simultaneous micromanometric recordings of LV and aortic pressures were performed at rest and during two graded Mueller maneuvers in 16 patients undergoing cardiac catheterization for aortic valve stenosis (n = 8) or chest pain (n = 8). The reductions (means +/- SE) of airway pressure during the lesser and greater maneuvers were 26 +/- 1 and 42 +/- 1 mmHg, respectively. Simultaneously, LV isovolumic-developed pressure increased by 9 +/- 3 and 21 +/- 4 mmHg, respectively (P < 0.03 for both). During the greater maneuver, the individual changes of the time constant of LV isovolumic relaxation (tau) correlated with the changes of LV isovolumic-developed pressure (r = 0.73; P = 0.002). In patients with a > 20-mmHg rise in isovolumic-developed pressure, tau increased by 10.3 +/- 4.6 ms. By multiple-regression analysis, the change of tau was related directly to the change of isovolumic-developed pressure (standardized coefficient beta = 0.80; P = 0.001) and inversely related to the resting systolic LV-aortic pressure gradient (beta = -0.37; P = 0.050). The other hemodynamic changes were independent of aortic valve stenosis. In conclusion, during the Mueller maneuver, the LV isovolumic contraction load increases and tau lengthens, particularly with higher elevations of LV systolic load.

Periprosthetic leakage after aortic valve replacement.

During the period 1968-1985, aortic valve replacement was performed in 871 patients, 617 males and 254 females aged 49.6 years in mean (15 to 75). Up to the end of 1988, 42 patients (4.8%) were reoperated on because of periprosthetic leakage. In primary surgery, annular calcification was found in 27 of these patients (64%), 17 patients (40%) had a bicuspid valve, and a positive culture from the excised valve was diagnosed in one of three patients with active native endocarditis. Two patients had Marfan's syndrome and two others postendocardial regurgitation. At primary surgery, mechanical prostheses were inserted in every case. Differences between the prosthetic models used could not be shown as regards to the occurrence of periprosthetic leakage. To implant the valve, interrupted everted U-mattress sutures with pledgets appeared to be the best method. Leakage occurred in 21 patients (50%) during their hospital stay and in 18 patients (43%) during the follow-up period of four months. Three others developed leakage two to four years from primary surgery. The main indication for reoperation was congestive heart failure alone or combined with heamolytic anaemia in 37 (88%) of cases. Four patients required the reoperation due to infectious dehiscence. Preoperatively, 34 patients (81%) were in NYHA (The New York Heart Association) Class III-IV. A new prosthetic valve was implanted in 23 cases, a composite graft once and in 18 cases refixation was performed. Two patients died in association with surgery, both due to the low output syndrome. During the follow-up time of 6.4 years, eight patients developed recurrent leakage. Four of them were found during their hospital stay and four others later. The role of prosthetic infection was remarkable in these eight cases; three patients with preoperative infectious dehiscence of the prosthesis had recurrence and one patient developed prosthetic endocarditis with leakage later. Three patients required more reoperations. At follow-up study, leakage was diagnosed in five of 28 living patients. Three of them were not significant and two moderate. 24 patients (86%) were in NYHA Class I-II.

Exclusion of coronary artery disease by exercise thallium-201 tomography in patients with aortic valve stenosis.

In many patients with valvular aortic stenosis (AS), management decisions may be possible without invasive studies if coexistent coronary artery disease (CAD) can be ruled out noninvasively. The use of thallium-201 single-photon emission computed tomography to the exclusion of CAD was studied in 44 patients aged 41 to 78 years with AS. In addition to cardiac catheterization and selective coronary angiography, patients underwent a cardiac ultrasound study and thallium-201 myocardial perfusion imaging at rest and after bicycle ergometer exercise. Two thirds of the patients had critical AS (valve area index less than or equal to 0.5 cm2/m2) but none had left ventricular systolic dysfunction. Twenty-one patients had angiographically significant CAD (greater than or equal to 50% diameter stenosis in greater than or equal to 1 coronary artery), whereas 23 had either a fully normal angiogram (n = 17) or mild (less than 50%) stenoses (n = 6). Each patient with significant CAD had an abnormal thallium-201 tomogram, either a strictly segmental perfusion defect (n = 19), or a patchy nonsegmental abnormality (n = 2); however, 10 of 23 patients free of significant CAD had similar results. Thus, the sensitivity and specificity of an abnormal scintigram were 100 and 57%, respectively. If only segmental perfusion defects typical of CAD had been considered abnormal, then the sensitivity of the test would have been 90% and the specificity 70%. Patients with false abnormal scintigrams had more severe AS and more angiographically nonsignificant CAD than those with true normal findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic valve replacement in patients aged over 70 years.

During a 12-year period, 58 patients aged over 70 years underwent aortic valve replacement. Sixty-six % of them had pure stenosis, 24% were with combined aortic valve disease, and six patients had only regurgitation. Preoperatively, 81% were in NYHA III and the remaining in NYHA IV. The pressure gradient in the AS-group was 105 +/- 27 mmHg and in combined-group, 99 +/- 32 mmHg. The mean ejection fraction was 54 +/- 14%. Thirty-seven mechanical and 21 biological prostheses were placed. Concomitant procedures consisted of annular dilating plasty for five patients while 16 others had coronary by-pass grafting. Hospital mortality was 12%, with the leading causes being low output syndrome and infection complications. The causes of all late deaths were non-cardiac. During the follow-up period of 2.8 +/- 2.5 years, 74% of patients with mechanical valves and 62% of patients with bioprostheses were free from late complications. Prosthetic valve endocarditis (two patients) and valve failure (one patient) occurred only in patients with tissue valves. Embolic complications were equally distributed between the groups. All patients with mechanical valves were placed on permanent anticoagulation therapy, with two of them developing significant complications. On echocardiographic examination, moderate periprosthetic leakage was found in three patients, two of them having mechanical valves. There was a significant increase in EF and regression of left ventricular hypertrophy. At follow-up examination, all 47 living patients found their performance capacity improved.

Latent human leukocyte collagenase can be activated by gold thioglucose and gold sodium thiomalate, but not by auranofin.

Gold thioglucose and gold sodium thiomalate were shown to be potent activators of latent human leukocyte collagenase. No activation by auranofin was noted. The activation may proceed through the action of gold on the essential sulfhydryl groups of latent enzyme and, thereby, mimick the action of the known organomercurial activators.

Gold sodium thiomalate activates latent human leukocyte collagenase.

Gold sodium thiomalate, a drug used widely in the therapy of rheumatoid arthritis, was found to be an activator of latent human polymorphonuclear leukocyte collagenase. The activation was demonstrated by two distinct and independent collagenase assays: by recording with a spectrophotometer at 227 nm the enzyme-induced increase in ultraviolet difference absorbance of native type I collagen connected to the cleavage of collagen at 37 degrees C [(1986) Eur. J. Biochem. 156, 1-4] and by SDS-polyacrylamide gel electrophoresis analysis of formation of specific products of collagen resulting from collagenase cleavage at 25 degrees C. Activation of latent collagenase by gold sodium thiomalate appeared to be of the same magnitude as by the known activator phenylmercuric chloride.

Hyperchromic effect of collagen induced by human collagenase.

Loss of the highly ordered triple-helix structure of native collagen on denaturation or enzymatic degradation involves a helix-to-coil transition, which can be seen as an increase at 227 nm in its ultraviolet difference absorption spectrum. We report here the successful use of this hyperchromic effect to quantify collagen in solution and to follow up the time-course of collagen degradation catalyzed by collagenase. Using 14C-labelled collagen substrate we show the excellent correlation between enzyme-induced increase in ultraviolet difference absorption and formation of specific cleavage products. The novel method was found to be suitable to characterize the enzymatic properties of human leukocyte collagenase. Activation of latent collagenase to the active enzyme could be followed continuously and an activation lag estimated.

Increased collagenase activity in human rheumatoid meniscus.

Collagenase activity of the knee joint menisci of patients suffering from rheumatoid arthritis was approximately 3-fold higher than that found in menisci of control patients. The mean collagenase activity in the macroscopically more diseased parts of the rheumatoid menisci was significantly higher than that in the less damaged areas. The specific degradation products resulting from the cleavage of human meniscoid type II collagen by rheumatoid meniscoid collagenase were demonstrated by SDS-polyacrylamide gel electrophoresis. Addition of N-ethylmaleimide, which activates latent mammalian collagenases, did not further increase collagenase activity in rheumatoid menisci. Thus in rheumatoid meniscus, collagenase may be synthesized and then activated, probably by proteolytic enzymes involved in the inflammatory reaction.

Renal complications of polyarteritis nodosa: CT findings.

Three patients with multiple renal complications of polyarteritis nodosa are described. The arteriographic findings in these patients were multiple arterial aneurysms and tissue infarctions, with the development of spontaneous intrarenal, subcapsular, and perirenal hemorrhagic complications. Computed tomography showed the hemorrhages and multiple renal infarcts; acute and late forms could be differentiated on the basis of contrast medium enhancement and scar formation.

Partial purification and characterization of latent human leukocyte collagenase.

Latent and active collagenase were extracted from human polymorphonuclear leukocytes. Separation of the two forms of the enzyme was performed by gel filtration on Sepharose 6 B. The latent form of the enzyme was detected from chromatographic fractions after a brief treatment with trypsin or exposure of the fractions to the sulfhydryl reagent phenylmercuric chloride. Latent enzyme eluted before active enzyme from the column, indicating a higher apparent molecular weight. Partially purified latent enzyme exhibited an apparent molecular size of 70-75 kDa as estimated by gel filtration. A value of 50-55 kDa was obtained for active enzyme. Without activation the latent enzyme did not degrade soluble collagen substrate. This was demonstrated by a quantitative viscometric assay and also by sodium dodecyl sulfate polyacrylamide gel electrophoresis, when no typical cleavage products of collagen could be seen. Latent enzyme could not be obtained unless serine protease inhibitors were present during the extraction and purification procedures. The effects of the activators trypsin, phenylmercuric chloride, phenylmethyl sulfonyltrypsin, and N-ethylmaleimide on the latent human polymorphonuclear leukocyte collagenase were studied. Contrary to the suggestion that inactive proteases activate latent human polymorphonuclear leukocyte collagenase, the inactive phenylmethyl sulfonyl-trypsin could not activate latent collagenase.

Overdrive pacing as treatment of sotalol-induced ventricular tachyarrhythmias (torsade de pointes).

Four patients with ventricular arrhythmias due to sotalol intoxication were successfully treated with overdrive pacing. In three patients the reason for sotalol overdose was a suicidal attempt and in the fourth patient the reason was unknown. In all cases a prolongation of the Q-T interval was seen, which is a typical feature of sotalol overdose. Other features of beta-blocker intoxication like bradycardia were found in all patients and hypotension in two patients. Three of four patients received lidocaine, but with no effect on multiple ventricular premature beats (VPB) or ventricular tachycardia (VT) of "torsade de pointes"-type. Overdrive pacing abolished immediately VPBs and VTs in three patients, and in the fourth patient there was apparent decrease in dysrhythmia. Temporary overdrive pacing is suggested as treatment of ventricular arrhythmias in association with prolonged Q-T interval caused by overdose of sotalol.