Daniela Torzillo

Effects of beta blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction

This study analyzed, with spectral techniques, the effects of atenolol or metoprolol on RR interval variability in 20 patients 4 weeks after the first uncomplicated myocardial infarction. Beta blocker-induced bradycardia was associated with a significant increase in the average 24-hour values of RR variance (from 13,886 +/- 1,479 to 16,728 +/- 1,891 ms2) and of the normalized power of the high-frequency component (from 22 +/- 1 to 28 +/- 2 normalized units), whereas the low-frequency component was greatly reduced (from 60 +/- 3 to 50 +/- 3 normalized units). When considering day and nighttime separately, the effects of both drugs were more pronounced in the daytime. In addition, a marked attenuation was observed in the circadian variation of the low-frequency component after beta blockade. As a result, the early morning increase of the spectral index of sympathetic modulation was no longer detectable. These results indicate that beta-blocker administration has important effects on RR interval variability and on its spectral components. The observed reduction in signs of sympathetic activation and the increase in vagal tone after beta blockade help to explain the beneficial effects of these drugs after myocardial infarction. However, the potential clinical relevance of the increase in RR variance remains to be established.

Linear and nonlinear dynamics of heart rate variability after acute myocardial infarction with normal and reduced left ventricular ejection fraction

We analyzed heart rate variability (HRV) in 2 groups of patients after acute myocardial infarction with normal and reduced ejection fraction (EF) by considering both the power of the 2 major harmonic components at low and high frequency and 2 indexes of nonlinear dynamics, namely the 1/f slope and the correlation dimension D2. HRV of patients with a reduced EF was characterized by a diminished RR variance as well as a different distribution of the residual power in all frequency ranges, with lower values of the low-frequency component expressed in both absolute and normalized units, and of the low- to high-frequency ratio. In these patients we also observed a steeper slope of the negative regression line between power and frequency in the very low frequency range. The presence of a smaller fractal dimension was suggested by a lower D2. Thus, in patients after acute myocardial infarction with a reduced EF, the reduction in HRV is associated with a different distribution of the residual power in the entire frequency range, which suggests a diminished responsiveness of sinus node to neural modulatory inputs.

Heart rate variability in the early hours of an acute myocardial infarction.

The occurrence of an autonomic disturbance early in acute myocardial infarction (AMI) has been reported: signs of sympathetic activation were mainly observed in relation to an anterior localization, whereas signs of vagal overactivity were more frequent in inferior wall AMI. Information is limited in relation to the persistence of these alterations during the early hours of AMI. We studied 33 patients with an AMI within 188 +/- 16 minutes from the onset of symptoms and 1 week after hospital admission. From a 20-minute Holter recording, we computed with autoregressive methodology, time and frequency domain indexes of heart rate variability. At admission, patients with an anterior wall AMI exhibited a smaller RR variance (593 +/- 121 ms2) than did those with an inferior wall AMI (1,122 +/- 191 ms2). In both groups the spectral profile was characterized by a predominant (73 +/- 4 and 61 +/- 4 normalized units) low frequency and by a small (13 +/- 2 and 22 +/- 3 normalized units) high-frequency component, indicating the presence of a sympathetic excitation and of a diminished vagal modulation. Although signs of sympathetic activation were more evident in patients with anterior wall AMI, no evidence of a vagal hyperactivity was observed in patients with inferior wall AMI. In the latter group, we noticed 1 week after the acute event an increase in the low-frequency component, which reached the values observed in patients with anterior wall AMI. Thrombolysis did not affect heart rate variability parameters. Thus, this study suggests the presence of an autonomic disturbance characterized by signs of sympathetic excitation and of a reduced vagal modulation, which was more evident in patients with an anterior localization early after AMI.

Beta-blocking effect of propafenone based on spectral analysis of heart rate variability

RR variability was analyzed in 15 patients with ventricular arrhythmias to evaluate whether the antiarrhythmic action of propafenone is associated with alteration of neural control mechanisms. Before drug administration, spectral analysis of RR variability was characterized by 2 major components at low and high frequency, which are considered to reflect sympathetic and parasympathetic modulation of the heart period. After propafenone (600 to 900 mg/day), there was a marked reduction in RR variance (826 +/- 184 to 412 +/- 77 ms2; p < 0.05), although the mean RR interval was unchanged. The drug significantly reduced the low-frequency component (52 +/- 6 to 28 +/- 4 nu) and augmented the high-frequency component (39 +/- 6 to 55 +/- 5 nu). As a result, the low-/high-frequency ratio (an index of sympathovagal balance) decreased from 2.0 +/- 0.4 to 0.6 +/- 0.1. A positive correlation between serum levels and drug-induced changes in the low-frequency component was also observed. Furthermore, the increase in the low-frequency component induced by tilt (53 +/- 5 to 79 +/- 3 nu) was markedly attenuated after drug administration (27 +/- 5 to 54 +/- 7 nu). Thus, propafenone administration is associated with changes in spectral components that are consistent with a beta-blocking effect of the drug.

Standard and pocket-size lung ultrasound devices can detect interstitial lung disease in rheumatoid arthritis patients

OBJECTIVES Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA associated with increased mortality. High-resolution CT (HRCT) is used for diagnosis and follow-up, but its accuracy is counterbalanced by high costs and radiological risk. In the presence of ILD, lung US (LUS) detects vertical artefacts called B-lines. The aims of the present study were to evaluate the accuracy of LUS in the diagnosis of ILD in RA and to validate the use of a pocket-size US device (PS-USD) as a screening tool. METHODS LUS was performed with standard equipment by a trained physician through longitudinal scans following anatomical lines: 72 segments were considered (28 anteriorly and 44 posteriorly) and B-lines were counted in each segment. A B-lines score >10 identified a positive examination (presence of ILD). A second LUS session for positive/negative judgment was performed by a short-trained physician using a PS-USD. RESULTS Thirty-nine patients were studied. The sensitivity and specificity of standard LUS vs HRCT were 92% and 56%, respectively. The B-line score was significantly correlated with HRCT score (r = 0.806). A total of 29 patients were studied with a PS-USD. Sensitivity and specificity for PS-USD vs HRCT were 89% and 50%. CONCLUSION The sensitivity of LUS in the detection of ILD supports its use as a screening test for ILD in RA patients, even in the ambulatory setting with a PS-USD. The strong correlation between echographic and HRCT scores indicates LUS is a valid tool for grading and follow-up of ILD.

High frequency of adverse reactions and discontinuation with benznidazole treatment for chronic Chagas disease in Milan, Italy.

TO THE EDITOR—We read with interest the experience by Miller et al regarding the tolerance to benznidazole treatment in a cohort of patients affected by chronic Chagas disease in Los Angeles, California [1]. In the last decade, physicians from Europe and the United States have been increasingly observing chronic Chagas disease in Latin American immigrants and have concomitantly been facing uncertainties about how to make a correct diagnosis and treat affected patients [2]. Both these issues have been dealt with in the Latin American literature due to the lack of previous direct experience by physicians from nonendemic areas [3]. In this context, 2 problems recently emerged regarding the treatment of the chronic indeterminate form and the mild cardiomyopathy of Chagas disease: (1) the shift from an attitude limited to counseling and follow-up to a position of actively offering treatment to all adult patients aged 19–50 years based on results indicating a reduced risk of progression of the disease and on new concepts of immunopathogenesis [3–5]; (2) the emergence of benznidazole as the best drug option available over nifurtimox (the other drug considered to be active against Trypanosoma cruzi) and posaconazole (an antifungal drug active in murine models) [6]. However, the use of a drug for which there is no direct (firsthand) experience requires the preliminary acquisition of complete information about its side effects and their relative rate of appearance. In this regard, in one of the major textbooks of internal medicine, it is reported that for benznidazole “adverse effects include rash, peripheral neuropathy, and rarely, agranulocytosis” [7]. A meta-analysis including studies published in the literature until October 2008 indicated that between 1% and 18% (median, 10%) of patients discontinued benznidazole treatment due to toxicity [4]. In the US guidelines, it is indicated that approximately “30% of patients experience both dermatologic adverse effects (usually mild to moderate) and a dose-dependent peripheral neuropathy. Bone marrow suppression is rare . . . additional reported adverse effects include anorexia and weight loss, nausea and/or vomiting, insomnia and dysgeusia” [8]. Moreover, other than the article by Miller et al, few reports have recently addressed the problem of the tolerance of benznidazole both in adults and children [9–15]; from the analysis of other studies (mainly conducted to evaluate drug efficacy) [3, 16–19], a higher than expected prevalence of dermatologic side effects, as well as higher rates of permanent drug discontinuation, emerge (Table 1). However, Miller et al underline in their work the high frequency of neuropathy (an expected adverse event) and angioedema (an unexpected adverse event). In this regard, we report our recent experience in Milan, Italy. Starting from July 2013 we began, with the collaboration of Médecins Sans Frontières, a screening program for Chagas disease directed to Latin American immigrants living in the nothern Italian city of Milan. Diagnosis of Chagas disease was performed through 2 positive serological tests according to World Health Organization recommendations: a chemiluminescent immunoassay with recombinant antigens (Abbott Architect Chagas, Abbott PRISM, Abbott Diagnostics) and an enzyme-linked immunosorbent assay with crude antigen (BioELISA Chagas III, BiosChile). Up to July 2014, 497 subjects (98% born in Central or South America) were enrolled in the study. Forty-four (8.8%) were found to be seropositive for T. cruzi: 39 (88.6%) from Bolivia, 4 (9.3%) from El Salvador, and 1 (2.3%) from Argentina. At present, 23 have completed assessments for cardiac involvement (eg, 12-lead electrocardiogram, chest radiograph, and echocardiogram) and gastrointestinal involvement (eg, esophagogram following the Rezende classification and barium enema). Eighteen patients have started treatment with benznidazole (Abarax, ELEA, Industria Argentina, 100 mg) at a dosage of 5 mg/kg/day in 2 divided doses (maximum dose 300 mg/day) for 60 days. As reported in Table 1, rash was observed in 6 (55%) patients and was the principal reason of drug discontinuation in 5 of them. Two patients (11%) presented

Lung ultrasound and short-term prognosis in heart failure patients.

BACKGROUND Heart failure (HF) is the leading cause of hospitalization for patients older than 65years, with a 30-day readmission rate of 20-25%. Although several markers have been evaluated to stratify timing of follow-up after an acute decompensation is mostly based on clinical judgment. Lung ultrasound (LUS) has been demonstrated to be a valid tool for the assessment and monitoring of pulmonary congestion. Aim of our study was to evaluate if LUS performed in HF patients at discharge could predict 100-day hospital readmission or death. METHODS One-hundred fifty patients were enrolled. The anterolateral chest was scanned to evaluate the presence of B-lines. A sonographic score was calculated attributing 1 to each positive (≥3 B-lines) sector. Clinical, biochemical and echocardiographic data were recorded. A Cox proportional hazard regression analysis was performed to evaluate the association between variables and 100-day events. RESULTS Follow-up was obtained in 149 patients. Thirty-four events were recorded. Sonographic score was significantly associated with events (HR 1.19; CI 1.05 to 1.34; p=0.005). On average, the increase of 1 point in the sonographic score was associated with an increase of approximately 24% in the risk of event within 100days. At multivariate analysis NTproBNP remained the only independent prognostic factor. CONCLUSIONS We confirmed that B-lines at discharge are a prognostic marker for hospital readmission and death at 100days in HF patients. Nevertheless, further randomized clinical studies are needed to definitely support the routine use of LUS in the clinical management of HF patients, in combination or not with NT-proBNP.

Brain natriuretic peptide as a marker of cardiac toxicity in patients with multiple sclerosis treated with mitoxantrone.

Sirs: The use of mitoxantrone (MTX) in multiple sclerosis (MS) is limited by the risk of dose-dependent and irreversible cardiac toxicity. Monitoring of cardiac function in MTX-treated patients is usually performed by bidimensional echocardiography with measurement of left ventricular ejection fraction (LVEF). In the search for alternate humoral markers of heart failure, particular attention has been drawn to natriuretic peptides. Brain natriuretic peptide (BNP) is released as an inactive prehormone mainly by the ventricular myocardium in response to wall stress [1]. The circulating levels of BNP and of the more stable, N-terminal pro-hormone fragment (NTproBNP) have been extensively used as a marker of myocardial overload and subsequent congestive heart failure [2]. We planned to evaluate the changes in circulating NT-proBNP during MTX treatment in a group of patients affected by multiple sclerosis. We selected 5 patients (3 women, 2 men, aged 39–65 years) affected by secondary progressive multiple sclerosis, with EDSS scores ranging from 3.5 to 6.5 and established disease progression (increment of ≥ 1 EDSS point over the past 12 months) despite oral immunosuppressive therapy. All patients had received previous treatment with azathioprine (1 mg/kg PO) which was withdrawn at least 6 months before MTX treatment. MTX (10 mg/ square meter IV) was administered once monthly for 8 consecutive doses. After 10 and 20 days from each MTX infusion blood counts were obtained in order to adjust MTX dose if necessary, according to changes in neutrophilic count. Before the first MTX administration all patients underwent bidimensional echocardiogram with measurement of LVEF. All exams were performed by the same operator (D.T.). Four patients had a normal baseline LVEF (exceeding 65 %) whereas one patient, a 65year old male, showed depressed LVEF (40 %). The decision to start MTX treatment in this patient was made after clinical evaluation and favorable advice by the consultant cardiologist. NT-proBNP was measured in serum by a commercially available kit (ELECSYS NT-proBNP, Roche Diagnostics, Milan, Italy). Normal upper values for NTproBNP according to sex and age range are 153 (males) and 88 (females) ng/L for age below 50 and 334 (males) and 227 (females) ng/L for age between 50 and 65. NTproBNP was measured at baseline and subsequently at each MTX administration. Echocardiogram was repeated before the 4th and 8th MTX infusion in all patients except in the one with baseline depressed LVEF, who had it repeated at monthly intervals. Clinical examination was performed at each visit in order to exclude the presence of overt heart failure. The four patients with baseline normal cardiac function completed the MTX infusion cycle without remarkable side effects. Mean NTproBNP concentrations in these patients changed from 37.5 ± 23.3 ng/L at baseline to 37.3 ± 18.9 ng/L after the 8th MTX infusion (P = NS by paired Student’s T-test), remaining in any case within normal limits for sex and age. None of these patients showed significant changes in LVEF. In the patient with depressed baseline LVEF NT-proBNP concentration increased from 637 ng/L at baseline to 1089 ng/L after 3 months. At the same time no significant changes in LVEF were evident. It was therefore decided to continue MTX treatment. One month later NT-proBNP concentration increased to 1440 ng/L and echocardiogram indicated the LVEF had decreased to 30 %; MTX therapy was therefore stopped. The patient was however still free from signs of congestive heart failure and remained stable from the cardiologic point of view at a subsequent visit after 3 months. Further monitoring of NT-proBNP was not feasible due to technical reasons. Our findings confirm the necessity to monitor cardiac function during MTX treatment. Although echocardiography remains the gold standard to this purpose, its routine use in patients under chronic therapy with potentially cardiotoxic drugs can be a limitation in some settings. Circulating NTproBNP can be useful as alternative means of evaluating ventricular contractility. The main advantages are represented by the lower cost, rapid availability with no need for LETTER TO THE EDITORS

Bedside focused cardiac ultrasound in the evaluation of systolic dysfunction.

The assessment of left ventricular systolic function (LVSF) plays a crucial role in the diagnosis, management and risk stratification of many cardiac diseases, such as myocarditis, acute coronary syndrome (ACS) and heart failure (HF). Transthoracic echocardiographic (TTE) imaging is the method of choice to evaluate LVSF because of its high accuracy, safety, and low cost; however, formal TTE may not be always immediately available [1]. History, physical examination, chest X-ray study, serum chemistries and electrocardiography have poor accuracy in identifying impaired LVSF [1, 2]. The delay in performing a TTE may be harmful in unstable patients: shock, dyspnoea and chest pain are the main symptoms requiring a bedside echocardiography in the medical emergency setting. Distinguishing patients with impaired LVSF is of pivotal importance to identify the correct therapeutic strategy as is true on medical wards, particularly when approaching patients with decompensated HF or volume-depleted patients. Moreover, early recognition of impaired LVSF permits an avoidance of harmful therapies. Bedside cardiac ultrasound consists of a focused approach, mainly used to reveal ‘presence’ or ‘absence’ of significant abnormalities. The assessment of LVSF can be performed by clinicians at the bedside with any portable device. Although bedside cardiac ultrasound does not replace in any case a comprehensive TTE, it can be part of the first clinical evaluation increasing diagnostic accuracy when added to traditional clinical assessment [1, 2].