Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy.

A peptide corresponding to the sequence 169-193 of the second extracellular loop of the human muscarinic acetylcholine receptor-2 was used as an antigen to screen sera from patients with idiopathic dilated cardiomyopathy (DCM, n = 36) and healthy blood donors (HBD, n = 40). The sera from 14 patients with DCM (38.8%) and 3 HBD (7.5%) recognized the muscarinic receptor peptide at dilutions varying from 1:20 to 1:160 in ELISA. A highly significant correlation (P = 0.006) was found between the presence of antimuscarinic receptor-2 autoantibodies and anti-beta-adrenoceptor-1 autoantibodies in the patients' sera. Affinity-purified autoantibodies from positive sera of patients with DCM recognized on the electrotransferred protein of rat ventricular membrane a major band of about 80 kD. Incubation of autoantibodies with membrane resulted not only in a decrease in the maximal binding sites (Bmax) but also in an increase in Kd of radioligand binding in a concentration-dependent manner. This suggests a mixed-type of inhibition. Moreover, preincubation with atropine abolished the inhibitory effect of autoantibodies on the receptor binding whereas carbachol appeared to have no effect on the activity of the autoantibodies. These data define a subgroup of patients with idiopathic DCM who have in their sera functionally active autoantibodies against muscarinic receptor-2.     

Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter?

Beta-blockers have several beneficial cardiovascular effects in patients with hypertension, angina pectoris, myocardial infarction, and congestive heart failure. In patients with myocardial infarction and congestive heart failure some beta-blockers have been found to reduce mortality and morbidity. The beta-blockers with a proven effect on prognosis include timolol, metoprolol, propranolol, bisoprolol, and carvedilol. One important question is whether all cardiovascular effects obtained by beta-blockers can be considered to be class effects. The beta-blockers with favorable effects on prognosis include two with more selective beta₁-receptor blockade (metoprolol and bisoprolol) and three non-selective (timolol, propranolol and carvedilol). One non-selective beta-blocker, which also has a more pronounced class III effect, sotalol, has been studied in a large postinfarction study without a significant effect on mortality. However, sotalol reduced the incidence of reinfarction similarly to the other beta-blockers with proven effect on mortality after myocardial infarction. Sotalol had no influence at all on sudden cardiac death, while all the other beta-blockers referred to above have a very marked effect on sudden cardiac death, in fact more marked than on overall mortality. The beta-blockers with proven effect on mortality and on sudden death have one property in common and that is some degree of lipophilicity. Sotalol and atenolol are hydrophilic. From animal experimental data it has been suggested that beta-blockers with some degree of lipophilicity penetrate into the brain and have an indirect effect on vagal activity, which is of importance for prevention of ventricular fibrillation and sudden cardiac death. It can be summarized that some beta-blockers have been found to reduce mortality and sudden cardiac death in patients after myocardial infarction and in congestive heart failure, while others have not. It seems that the major properties of the beta-blockers with proven effects on mortality and sudden cardiac death are beta₁-receptor blockade and some degree of lipophilicity. Until we know more about the mechanisms behind prevention of death and especially sudden cardiac death by beta-blockers, only drugs with proven effects on prognosis should be used.     

Patients with uncomplicated coronary artery disease have reduced heart rate variability mainly affecting vagal tone

AIM: To investigate whether uncomplicated chronic coronary artery disease causes changes in heart rate variability and if so, whether the heart rate variability pattern is different from that described in patients with acute myocardial infarction. METHODS: Heart rate variability was studied in 65 patients with angina who had no previous myocardial infarcts, no other diseases, and were on no drug that could influence the sinus node. Results were compared with 33 age matched healthy subjects. The diagnosis of coronary artery disease in angina patients was established by coronary angiography in 58, by thallium scintigraphy in six, and by exercise test only in one. Patients and controls were Holter monitored 24 hours outside hospital, and heart rate variability was calculated in the frequency domain as global power (GP: 0.01-1.00 Hz), low frequency peak (LF: 0. 04-0.15 Hz), high frequency peak (HF: 0.15-0.40 Hz), LF/HF in ms(2), and in the time domain as SDNN (SD of normal RR intervals), SDANN (SD of all five minute mean normal RR intervals), SD (mean of all five minute SDs of mean RR intervals), rMSSD (root mean square of differences of successive normal RR intervals) (all in ms), and pNN50 (proportion of adjacent normal RR intervals differing more than 50 ms from the preceding RR interval) as per cent. RESULTS: The mean age in patients and controls was 60.4 (range 32-81) and 59.1 (32-77) years, respectively (NS), the male/female ratio, 57/65 and 24/33 (NS), and the mean time of Holter monitoring, 23.0 (18-24) and 22.8 (18-24) hours (NS). Mortality in angina patients was 0% (0/65) at one year, 0% (0/56) at two years, and 3% (1/33) at three years. Compared with healthy subjects angina patients showed a reduction in GP (p = 0.007), HF (p = 0.02), LF (p = 0.02), SD (p = 0.02), rMSSD (p = 0.01), and pNN50 (p = 0.01). No significant difference was found in RR, LF/HF, SDNN, or SDANN. CONCLUSIONS: Uncomplicated coronary artery disease without previous acute myocardial infarction was associated with reduced high and low frequency heart rate variability, including vagal tone. SDANN and SDNN, expressing ultra low and very low frequencies which are known to reflect prognosis after acute myocardial infarction, were less affected. This is in agreement with the good prognosis in uncomplicated angina in this study.     

Long-term prognosis in relation to ECG findings in acute myocardial infarction

In 680 patients with acute myocardial infarction the prognosis during the following 5 years was related to observations made in a standard electrocardiogram (ECG) and 24 precordial chest leads. Patients with a Q-wave infarction (based on a 12-lead standard ECG) had a mortality rate during hospitalization of 10.2% which was much higher than that in patients with a non-Q-wave infarction (1.9%, p less than 0.001). At 5 years' follow-up 33.6% of those with a Q-wave infarction had died versus 28.4% of those with a non-Q-wave infarction (p greater than 0.2). Corresponding mortality rate among patients with no previous infarction (n = 587) was 32.1% and 25.2%, respectively (p = 0.17). In patients with anterior infarction and no previous infarction there was no correlation between Q- and R-wave changes in the 24 chest leads 4 days after admission to hospital and 5-year mortality rate. We thus conclude that patients with a Q-wave infarction had a higher in-hospital mortality compared with non-Q-wave infarction as judged from standard ECG, whereas 5-year mortality was similar. Similarly, there was no correlation between Q- and R-wave changes in an increased number of chest leads and 5-year mortality rate.     

Ventilator-associated tracheobronchitis: the impact of targeted antibiotic therapy on patient outcomes

Nosocomial lower respiratory tract infections are a common cause of morbidity and mortality in ICU patients receiving mechanical ventilation. Many studies have investigated the management and prevention of ventilator-associated pneumonia (VAP), but few have focused on the role of ventilator-associated tracheobronchitis (VAT). The pathogenesis of lower respiratory tract infections often begins with tracheal colonization that may progress to VAT, and in selected patients to VAP. Since there is no well-established definition of VAT, discrimination between VAT and VAP can be challenging. VAT is a localized disease with clinical signs (fever, leukocytosis, and purulent sputum), microbiologic information (Gram stain with bacteria and leukocytes, with either a positive semiquantitative or a quantitative sputum culture), and the absence of a new infiltrate on chest radiograph. Monitoring endotracheal aspirates has been used to identify and quantify pathogens colonizing the lower airway, to diagnose VAT or VAP, and to initiate early, targeted antibiotic therapy. Recent data suggest that VAT appears to be an important risk factor for VAP and that targeted antibiotic therapy for VAT may be a new paradigm for VAP prevention and better patient outcomes.     

Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy.

Adrenergic beta-blocking agents were given to 7 patients with advanced congestive cardiomyopathy who had tachycardia at rest (98 plus or minus 13 beats/min). The patients were on beta-adrenergic receptor blockade for 2 to 12 months (average 5-4 months). One patient was given alprenolol 50 mg twice daily and the other patients were given practolol 50 to 400 mg twice daily. Virus infection had occurred in 6 of the patients before the onset of symptoms of cardiac disease. All patients were in a steady state or were progressively deteriorating at the start of beta-adrenergic receptor blockade. Conventional treatment with digitalis and diuretics was unaltered or reduced during treatment with beta-blocking agents. An improvement was seen in their clinical condition shortly after administration of the drugs. Continued treatment resulted in an increase in physical working capacity and a reduction of heart size. Noninvasive investigations including phonocardiogram, carotid pulse curve, apex cardiogram, and echocardiogram showed improved ventricular function in all cases. The present study indicates that adrenergic beta-blocking agents can improve heart function in at lease some patients with congestive cardiomyopathy. Furthermore, it is suggested that increased catecholamine activity may be an important factor for the development of this disease, as has been shown in animal experiments.     

CPAP of 4 cm H(2)O Has No Short-Term Benefit at Term in Infants with BPD

Background: Lung development and function is compromised at term in infants with bronchopulmonary dysplasia (BPD), characterized by reduced functional residual capacity (FRC) and impaired gas-mixing efficiency in distal airways. Objective: To determine whether continuous positive airway pressure (CPAP) improves FRC, ventilation, distal airway function, and gas exchange in spontaneously breathing infants with BPD. Design/Methods: Twenty-one infants with BPD (median birth weight 0.72 kg (range 0.50-1.27) and median gestational age 26 weeks (range 23-28)) were studied before and after CPAP of 4 cm H(2)O was applied by a facemask system. A multiple-breath nitrogen washout method was used to assess FRC, ventilation, and gas-mixing efficiency. Moment analysis and lung clearance index was calculated from the nitrogen-decay curve for assessment of gas-mixing efficiency. Transcutaneous (Tc) PO(2)/PCO(2) was monitored during stable infant conditions before each washout test. Results: When CPAP was raised from 0 to 4 cm H(2)O, FRC increased significantly together with a significant increase in moment ratios (M(1)/M(0) and M(2)/M(0)). Tc PO(2) decreased significantly and the breathing pattern changed, with significantly reduced respiratory rate, minute ventilation, and alveolar ventilation. There was also an increase in tidal volume and dead space. Conclusions: CPAP of 4 cm H(2)O applied with a facemask at term to infants with BPD did not improve ventilation, gas-mixing efficiency in distal airways, or oxygenation despite an increase in FRC. We speculate that instead of promoting recruitment of unventilated lung volumes, increasing the end-expiratory pressure in infants with BPD may lead to an overexpansion of already ventilated parts of the lung, causing further compromise of lung function.