Kenneth Caidahl

Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.

BACKGROUND Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established. METHODS AND RESULTS Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP: P < .0001; N-ANP: P = .0002; BNP: P < .0001). In a multivariate model, plasma BNP (P = .021) but not ANP (P = .638) or N-ANP (P = .782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (P = .003) and N-ANP (P = .027) but not BNP (P = .14) were significantly associated with a left ventricular ejection fraction < or = 45%. CONCLUSIONS These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.

N-Terminal Pro-B–Type Natriuretic Peptide and Long-Term Mortality in Acute Coronary Syndromes

Background—B-type natriuretic peptide (BNP) is a predictor of short- and medium-term prognosis across the spectrum of acute coronary syndromes (ACS). The N-terminal fragment of the BNP prohormone, N-BNP, may be an even stronger prognostic marker. We assessed the relation between subacute plasma N-BNP levels and long-term, all-cause mortality in a large, contemporary cohort of patients with ACS. Methods and Results—Blood samples for N-BNP determination were obtained in the subacute phase in 204 patients with ST-elevation myocardial infarction (MI): 220 with non-ST segment elevation MI and 185 with unstable angina in the subacute phase. After a median follow-up of 51 months, 86 patients (14%) had died. Median N-BNP levels were significantly lower in long-term survivors than in patients dying (442 versus 1306 pmol/L;P <0.0001). The unadjusted risk ratio of patients with supramedian N-BNP levels was 3.9 (95% confidence interval, 2.4 to 6.5). In a multivariate Cox regression model, N-BNP (risk ratio 2.1 [95% confidence interval, 1.1 to 3.9]) added prognostic information above and beyond Killip class, patient age, and left ventricular ejection fraction. Adjustment for peak troponin T levels did not markedly alter the relation between N-BNP and mortality. In patients with no evidence of clinical heart failure, N-BNP remained a significant predictor of mortality after adjustment for age and ejection fraction (risk ratio, 2.4 [95% confidence interval, 1.1 to 5.4]). Conclusions—N-BNP is a powerful indicator of long-term mortality in patients with ACS and provides prognostic information above and beyond conventional risk markers.

Long-term beta-blockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol.

To evaluate the short- and long-term effects of beta-adrenergic blockade (metoprolol) as well as the reaction to withdrawal and readministration of metoprolol in severe heart failure, 33 patients (25 men and eight women; mean age, 47.6 +/- 14.0 years) with dilated cardiomyopathy were studied by right and left heart catheterization, right ventricular biopsy, two-dimensional and Doppler echocardiography, and external pulse recordings. Twenty-six of 33 patients survived more than 6 months, and 24 of the 26 patients improved their functional class (from mean 3.3 to 1.8, p less than 0.0001). These 24 patients were subjected to withdrawal of metoprolol until the number of symptoms increased and deterioration occurred as observed noninvasively (group 1, n = 16), whereas the eight patients did not deteriorate during a 12-month period (group 2). During long-term treatment with metoprolol, there was an increase in ejection fraction from 0.24 to 0.42 (p less than 0.0001), whereas there was a decrease in the left ventricular (LV) end-diastolic dimension (from 7.3 to 6.4 cm, p less than 0.0001), in the grade of mitral regurgitation (from 1.7 to 0.4, p less than 0.0001), and in the grade of tricuspid regurgitation (from 0.6 to 0.05, p less than 0.007). There was a decrease in pulmonary wedge pressure (from 23.8 to 10.7 mm Hg, p less than 0.0001), LV end-diastolic pressure (from 24.1 to 13.4 mm Hg, p less than 0.002), and systolic vascular resistance (from 1,782 to 1,499 dynes/sec/cm, p less than 0.04). There was an increase in systolic blood pressure (from 116 to 132 mm Hg, p less than 0.003), cardiac index (from 2.17 to 2.58 l/min/m2, p less than 0.005), and LV stroke work index (from 31 to 65 g.m/m2, p less than 0.0001). During withdrawal of metoprolol, the heart rate and left atrial dimension increased (p less than 0.0001), whereas ejection fraction decreased (p less than 0.0001). The 12 (of 16) patients in group 1 who survived the withdrawal period had metoprolol readministered, and subsequently, ejection fraction increased (from 0.23 to 0.33, p less than 0.002). Patients had a low number of ventricular beta-adrenergic receptors compared with healthy control subjects (30.3 +/- 2.9 vs. 97.4 +/- 8.7 fmol/mg protein, p less than 0.001), but long-term treatment with metoprolol caused a moderate up-regulation (from 30.3 +/- 2.9 to 49.0 +/- 7.1 fmol/mg protein, p less than 0.05), which may facilitate a more normal response to sympathetic stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

A DOUBLE-BLIND CROSS-OVER 12-MONTH STUDY OF l-THYROXINE TREATMENT OF WOMEN WITH ‘SUBCLINICAL’ HYPOTHYROIDISM

Twenty women, who had been randomly selected from women with subclinical hypothyroidism identified in a population study were treated with l‐thyroxine and placebo in a double‐blind cross‐over design during 2·6 months. Three women did not complete the study, one because she moved to another part of the country, and two because of nervousness and sense of tachycardia. None of these ‘drop‐outs’ had any objective signs of overtreatment; they had normal pulse rate and a serum T3 concentration within the reference interval. During l‐thyroxine treatment serum procollagen‐III‐peptide concentration increased in 13 women out of the 17 women completing the study and at the end of treatment the mean concentration was significantly raised (P>0·001). Serum concentrations of procollagen‐III‐peptide then correlated with those of free thyroxine (P>0·01), total thyroxine (P>0·05), and reverse triiodothyronine (P>0·05). The same comparison revealed little or no effect on the concentrations of serum creatine kinase activity, transcortin or sex‐hormone binding globulin. Heart rate‐corrected preejection period and symptom score decreased (P>0·05). Four women starting with l‐thyroxine showed a marked and prolonged (4–6 months) rise in thyrotrophin concentration during the subsequent placebo period, but remained clinically euthyroid. Four women (of 17) improved during therapy as judged by psychometric testing and their own rating. We could not by pretreatment observations identify these four women apart from serum free and total 3,5,3′‐triiodothyronine concentrations in the lower part of the health‐associated reference interval. Subclinical hypothyroidism is common among middle‐aged and old women, and our findings indicate that approximately one woman in four with this ‘subclinical’ condition will benefit from L‐thyroxine treatment.

Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea.

To evaluate cardiac structure and function as well as blood pressure in the obstructive sleep apnoea syndrome (OSAS), we investigated 61 male patients and 61 male controls with M-mode and two-dimensional echocardiography. All patients had a history of habitual snoring and a diagnosed light to severe OSAS by previous investigations of nocturnal oxygen saturation status. No subject in the control group had a history of OSAS or hypertension. Body weight was higher in the OSAS patients than in the controls (P less than 0.001). Fifty per cent (31 out of 61) of the OSAS patients had systemic hypertension; 17 of these 31 were on pharmacological antihypertensive treatment. Neither the systolic nor the diastolic blood pressures were found to correlate to the severity of the OSAS (desaturation index). The heart rate was higher at rest in the OSAS patients with or without systemic hypertension compared to the controls with or without a blood pressure level above 165/95 mmHg (P less than 0.05 and P less than 0.01, respectively). Left ventricular (LV) internal dimensions as assessed by echocardiography did not differ between the two groups, while the interventricular septum and the LV posterior wall were thicker in the OSAS group. Thus, the LV mass and the LV mass index were significantly higher among the OSAS patients (P less than 0.001 and P less than 0.001). The LV mass index was approximately 15% higher among the 30 normotensive OSAS patients with no history of cardiac disease compared with the normotensive controls (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction

Background Small studies suggest that postconditioning reperfusion interrupted by brief repetitive cycles of reocclusions, may protect the myocardium in the clinical setting. Objective To test the hypothesis that postconditioning limits infarct size in relation to the area at risk in patients with ST elevation myocardial infarction (STEMI). Methods 76 patients (aged 37–87 years) eligible for primary percutaneous coronary intervention due to STEMI were randomised to standard percutaneous coronary intervention (n=38) or postconditioning, consisting of four cycles of 60 s reperfusion and 60 s of reocclusion before permanent reperfusion (n=38). Results The area at risk was determined from angiographic abnormally contracting segments. Infarct size was quantified from delayed enhancement MRI on days 6–9. Infarct size, expressed in relation to the area at risk, did not differ between the control group (44%; 30, 56) (median and quartiles) and the post-conditioned group (47%; 23, 63). The slope of the regression lines relating infarct size to the area at risk differed between the two groups. Infarct size was significantly (p=0.001) reduced by postconditioning in patients with large areas at risk. The area under the curve and peak troponin T release and CKMB during 48 h did not differ between patients in the control and postconditioning groups. Conclusions This prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk. Clinical trial registration information Karolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014.

New concept in echocardiography: harmonic imaging of tissue without use of contrast agent

BACKGROUND Endocardial border detection is important for echocardiographic assessment of left-ventricular function. Second harmonic imaging of contrast agents enhances this border detection. We discovered that harmonic imaging improves tissue visualisation even before contrast injection. We therefore sought objectively to demonstrate the degree of enhancement of endocardial and myocardial visualisation. METHODS An ATL HDI-3000 scanner with software for contrast harmonic imaging was used to record short-axis images of the left ventricle in 27 patients with possible myocardial disease and 22 controls, in the fundamental mode and with harmonic imaging. A computer program measured the relative grey-scale values within six segments of the endocardium and myocardium. An Acuson Sequoia scanner equipped with software for tissue harmonic imaging was used to investigate the reproducibility of ejection-fraction calculations in 22 patients with ischaemic heart disease. FINDINGS Harmonic imaging produced brighter endocardium within each segment. Relative to the mean grey value of the total imaging sector, the values for harmonic and fundamental imaging were 171.5 vs 85.6% (p<0.0001) in end diastole and 194.1 vs 106.7% (p<0.0001) in end systole. Results for the myocardial segments were also significantly better for harmonic imaging. Structure enhancement of similar magnitude was seen among patients and healthy controls. Use of harmonic imaging reduced the proportion of unacceptable images by 14-46% in different views and improved the reproducibility of biplane ejection-fraction measurements. INTERPRETATION In comparison with fundamental imaging, the relative endocardial and myocardial brightness is enhanced by harmonic imaging.

Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle

Interleukin (IL)-6 is a proinflammatory cytokine shown to modify insulin sensitivity. Elevated plasma levels of IL-6 are observed in insulin-resistant states. Interestingly, plasma IL-6 levels also increase during exercise, with skeletal muscle being the predominant source. Thus, IL-6 has also been suggested to promote insulin-mediated glucose utilization. In this study, we determined the direct effects of IL-6 on glucose transport and signal transduction in human skeletal muscle. Skeletal muscle strips were prepared from vastus lateralis biopsies obtained from 22 healthy men. Muscle strips were incubated with or without IL-6 (120 ng/ml). We found that IL-6 increased glucose transport in human skeletal muscle 1.3-fold (P < 0.05). A 30-min pre-exposure to IL-6 did not affect insulin-stimulated glucose transport. IL-6 also increased skeletal muscle glucose incorporation into glycogen, as well as glucose oxidation (1.5- and 1.3-fold, respectively; P < 0.05). IL-6 increased phosphorylation of STAT3 (signal transducer and activator of transcription 3; P < 0.05), AMP-activated protein kinase (P = 0.063), and p38 mitogen-activated protein kinase (P < 0.05) and reduced phosphorylation of S6 ribosomal protein (P < 0.05). In contrast, phosphorylation of protein kinase B/Akt, AS160 (Akt substrate of 160 kDa), and GSK3α/β (glycogen synthase kinase 3α/β) as well as insulin receptor substrate 1–associated phosphatidylinositol 3-kinase activity remained unaltered. In conclusion, acute IL-6 exposure increases glucose metabolism in resting human skeletal muscle. Insulin-stimulated glucose transport and insulin signaling were unchanged after IL-6 exposure.

Prospective study of left ventricular function after radiofrequency ablation of atrioventricular junction in patients with atrial fibrillation.

BACKGROUND--In patients with drug resistant incessant supraventricular tachycardia, radiofrequency induced ablation of the atrioventricular junction and pacemaker implantation have hitherto been considered a treatment of last resort. OBJECTIVE--To assess the short and long term effects of ablation of the atrioventricular junction on systolic and diastolic left ventricular function in patients with atrial fibrillation with and without impaired left ventricular function. PATIENTS--29 patients (19 men; mean age 65 (SD 7) years (range 50-76)) undergoing ablation of the atrioventricular junction for drug refractory atrial fibrillation were examined a mean of 2, 65, and 216 days after ablation of the bundle of His. MAIN OUTCOME MEASURES--Left ventricular ejection fraction and early filling deceleration times (Edec) were assessed by Doppler echocardiography after 1 to 2 hours of ventricular pacing at a rate of 80 beats/minute. RESULTS--In 14 patients with a left ventricular ejection fraction < 50% left ventricular ejection fraction increased significantly from 32% (11%) to 39% (11%) (65 days) and 45% (11%) (216 days) (P < 0.001); Edec increased from 142 (46) ms to 169 (57) ms (65 days) and 167 (56) ms (216 days) (P < 0.05). In 15 patients with an ejection fraction > or = 50% at the initial examination no significant change in systolic function was observed. CONCLUSIONS--In patients with left ventricular dysfunction long term improvement of systolic and diastolic left ventricular function was seen after ablation of the atrioventricular junction for rate control of atrial fibrillation. This procedure had no adverse effects on normal left ventricular function.

Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known.