Drawing up the public national Rational Pharmacotherapy Action Plan as part of social and health services reform in Finland: a bottom-up approach involving stakeholders.

BACKGROUND: Ensuring equal access to medicines and their appropriate and safe use at reasonable costs are core functions of health systems. Despite that, few descriptions of national medicines policies' development processes and implementation strategies have been published. This study aimed to describe the government program-based development of the Rational Pharmacotherapy Action Plan in Finland as a part of the undergoing major health and social service system reform, also covering the implementation of rational pharmacotherapy in the reformed system and processes. METHODS: The data of this qualitative study consisted of public reports and Steering Group meeting memos related to the development of the national Rational Pharmacotherapy Action Plan that the Ministry of Social Affairs and Health coordinated. Qualitative content analysis applying systems theory and the conceptual framework of integrated services as theoretical frameworks was used as an analysis method. RESULTS: The national Rational Pharmacotherapy Action Plan covering 2018-2022 was created in a bottom-up development process involving a wide range of stakeholders. Rational pharmacotherapy was redefined by adding equality as the fifth pillar to complement the previously defined pillars of being effective, safe, high-quality, and cost-effective. The Action Plan formed a normative framework for long-term development, with a vision and principles focusing on people-centeredness, better coordination and management of the medication use processes, the continuity of treatment paths and the flow of patient and medicines information through partnerships, and evidence-informed policies and practices. CONCLUSION: Through intensive stakeholder participation, the bottom-up approach created a national vision and principles of rational pharmacotherapy along with strong commitment to implementing the goals and measures. The concern lies in ensuring the continuity of the Action Plan implementation and achieving a balanced long-term development aligned with the integrated and reformed national social and health services system. The development of the pharmaceutical system has several national and EU-level dependencies requiring political long-term commitment. While the Action Plan differs from the national medicines policy, it forms a good basis for long-term development covering important parts of medicine policy at the micro, meso, and macro levels of the service system.

Free vs total pregnancy-associated plasma protein A (PAPP-A) as a predictor of 1-year outcome in patients presenting with non-ST-elevation acute coronary syndrome.

BACKGROUND: The free fraction of pregnancy-associated plasma protein A (FPAPP-A) was found to be the PAPP-A form released to the circulation in acute coronary syndrome (ACS). We estimated the prognostic value of FPAPP-A vs total PAPP-A (TPAPP-A) concentrations in forecasting death and nonfatal myocardial infarction (combined endpoint) in patients with non-ST-elevation ACS. METHODS: We recruited 267 patients hospitalized for symptoms consistent with non-ST-elevation ACS and followed them for 12 months. FPAPP-A, TPAPP-A, C-reactive protein (CRP), and cardiac troponin I (cTnI) were measured at admission; cTnI was also measured at 6-12 h and 24 h. Because of the recently shown interaction between PAPP-A and heparin, we excluded patients treated with any heparin preparations before the admission blood sampling. RESULTS: During the follow-up, 57 (21.3%) patients met the endpoint (22 deaths and 35 nonfatal myocardial infarctions). According to FPAPP-A (<1.27, 1.27-1.74, >1.74 mIU/L) and TPAPP-A (<1.98, 1.98-2.99, >2.99 mIU/L) tertiles, this endpoint was met by 12 (13.5%), 18 (20.2%), 27 (30.3%) (P = 0.02), and 17 (19.1%), 17 (19.1%), 23 (25.8%) (P = 0.54) patients, respectively. After adjusting for age, sex, diabetes, previous myocardial infarction, and ischemic electrocardiogram (ECG) findings, FPAPP-A >1.74 mIU/L [risk ratio (RR) 2.0; 95% CI 1.0-4.1, P = 0.053), increased cTnI, and CRP >/=2.0 mg/L were independent predictors of an endpoint. The prognostic performance of TPAPP-A was inferior to that of FPAPP-A. CONCLUSIONS: FPAPP-A seems to be superior as a prognostic marker compared to TPAPP-A, giving independent and additive prognostic information when measured at the time of admission in patients hospitalized for non-ST-elevation ACS.

The etiology and prognostic significance of cardiac troponin I elevation in unselected emergency department patients.

BACKGROUND: Cardiac troponin elevations are associated not only with acute coronary syndromes (ACS) but also with multiple other cardiac and non-cardiac conditions. STUDY OBJECTIVES: To investigate the etiology and clinical significance of cardiac troponin I elevations in an unselected Emergency Department (ED) patient cohort. METHODS: The study population consisted of 991 consecutive troponin-positive patients admitted to the ED of a university hospital with ACS as the presumptive diagnosis. Cardiac troponin I was measured on admission and a follow-up sample was obtained at 6-12 h. Clinical diagnosis was ascertained retrospectively using all the available information including electrocardiogram, clinical data, laboratory tests, and available coronary angiograms. RESULTS: At admission, 805 (81.2%) patients were already troponin positive; of these, the troponin elevation was related to myocardial infarction (MI) in 654 (81.2%) patients. Finally, 83.0% of the troponin elevations were due to MI, 7.9% were related to other cardiac causes, and 9.1% to non-cardiac diseases. The leading non-cardiac causes were pulmonary embolism, renal failure, pneumonia, and sepsis. Non-cardiac patients with elevated troponin I at admission showed significantly higher in-hospital mortality (26.7% vs. 13.4%, p = 0.002) compared to cardiac patients. CONCLUSION: Elevated troponin levels for reasons other than MI are common in the ED and are a marker of poor in-hospital prognosis.

Reversal of atrial remodeling after cardioversion of persistent atrial fibrillation measured with magnetocardiography.

BACKGROUND: Atrial fibrillation (AF) causes electrical, functional, and structural changes in the atria. We examined electrophysiologic remodeling caused by AF and its reversal noninvasively by applying a new atrial signal analysis based on magnetocardiography (MCG). METHODS: In 26 patients with persistent AF, MCG, signal-averaged electrocardiography (SAECG), and echocardiography were performed immediately after electrical cardioversion (CV), and repeated after 1 month in 15 patients who remained in sinus rhythm (SR). Twenty-four matched subjects without history of AF served as controls. P-wave duration (Pd) and dispersion (standard deviation of Pd values in individual channels) and root mean square amplitudes of the P wave over the last 40 ms portions (RMS40) were determined. RESULTS: In MCG Pd was longer (122.8 +/- 18.2 ms vs 101.5 +/- 14.6 ms, P < 0.01) and RMS40 was higher (60.4 +/- 28.2 vs 46.9 +/- 19.1 fT) in AF patients immediately after CV as compared to the controls. In SAECG Pd dispersion was increased in AF patients. Mitral A-wave velocity and left atrial (LA) contraction were decreased and LA diameter was increased (all P < 0.01). After 1 month, Pd in MCG still remained longer and LA diameter greater (both P < 0.05), while RMS40 in MCG, Pd dispersion in SAECG, mitral A-wave velocity, and LA contraction were recovered. CONCLUSIONS: Magnetocardiographically detected atrial electrophysiologic alterations in persistent AF diminish rapidly although incompletely during maintained SR after CV. This might be related to the known early high and late lower, but still existent tendency to AF relapses.

The heme oxygenase inducer hemin protects against cardiac dysfunction and ventricular fibrillation in ischaemic/reperfused rat hearts: role of connexin 43.

Cardiac expression of cytoprotective gene heme oxygenase-1 (HO-1) is modulated by ischaemia and reperfusion (I/R). We therefore hypothesized that pretreatment with hemin, an inductor of HO-1, would precondition the heart against post-ischaemic dysfunction and ventricular fibrillation (VF). Male Wistar rats were given either hemin or HO enzyme inhibitor zinc protoporphyrin IX (ZnPP IX). Isolated hearts were subjected to 30 min global ischaemia followed by 120 min of reperfusion or were aerobically perfused in a time-matched non-ischaemic protocol. Control animals received no pretreatment. Compared to non-perfused controls, pretreatment with hemin increased HO-1 mRNA 13-fold (p<0.001) and HO-1 protein 3.5-fold (p

Direct Immunoassay for Free Pregnancy-Associated Plasma Protein A (PAPP-A).

BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A), especially in its noncomplexed form (fPAPP-A), is linked to vulnerable atherosclerotic plaques and risk of cardiac events. An assay for sensitive detection of fPAPP-A has been lacking. Our aim was to develop and validate a direct fPAPP-A assay to meet this need. METHODS: Monoclonal antibodies binding exclusively fPAPP-A were produced by immunizing mice with recombinant PAPP-A. In the optimized immunoassay, we used an fPAPP-A-specific capture antibody together with a lanthanide-chelate-labeled monoclonal antibody recognizing all PAPP-A forms. The assay was evaluated with CLSI guidelines and compared to a 2-assay subtractive fPAPP-A approach. Clinical performance was assessed with acute coronary syndrome patients. RESULTS: The limits of detection and quantitation were 0.4 mIU/L and 1.3 mIU/L, respectively, and the assay was linear up to 1000 mIU/L (R2 = 0.999). Both serum and heparin plasma were suitable matrices, and the complexed form of PAPP-A caused no significant interference. Correlation between the developed assay and the 2-assay approach was fair (Pearson's r = 0.819). Median concentration in healthy individuals was 1.0 mIU/L. fPAPP-A concentration was higher in patients who had myocardial infarction or died during the 1-year follow-up period than in those who did not (1.13 mIU/L vs 0.82 mIU/L, P = 0.008, model adjusted with age and sex). fPAPP-A measured with this direct assay predicted this end point as well as (follow-up 1 year) or better (30 days) than the 2-assay fPAPP-A alone or in combination with cTnI. CONCLUSIONS: The new assay enables sensitive and reliable measurement of low cardiac-related fPAPP-A concentrations from blood samples.

Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment.

BACKGROUND AND AIMS: Cardiomyocyte apoptosis (CA) is a common feature of end-stage heart failure. We examined whether CA is associated with cardiac dysfunction and remodelling in heart failure due to dilated cardiomyopathy and studied the effect of human growth hormone (hGH) on CA. METHODS AND RESULTS: We studied 38 patients, included in a phase III multi-center, randomised, double-blind and placebo-controlled trial of biosynthetic hGH treatment in dilated cardiomyopathy, at baseline and after 14 weeks treatment. Twenty-six patients received hGH and 12 received placebo. CA was quantified in endomyocardial biopsies using the TUNEL assay. CA correlated with left ventricular size (r=0.43, p=0.007). Compared to patients with CA below the median of 0.53%, patients with CA above the median had significantly larger left ventricular volumes and lower ejection fractions (EF) by echocardiography (median (interquartile range)) 200 ml (84) vs. 257 ml (134) and 27% (11) vs. 23% (9). Expression of the Fas receptor was associated with a high rate of CA. hGH treatment significantly increased serum IGF-1 levels, but it had no effect on CA or cardiac structure and function. CONCLUSION: CA is related to left ventricular enlargement and dysfunction in dilated cardiomyopathy. CA is not affected by short-term treatment with hGH.

Association of cell-free plasma DNA with hospital mortality and organ dysfunction in intensive care unit patients.

OBJECTIVE: To investigate the concentration of cell-free plasma DNA and its association with organ dysfunction and hospital mortality in intensive care unit patients. DESIGN AND SETTING: Prospective cohort study in a medical and two medical-surgical intensive care units in a university hospital. PATIENTS: 228 critically ill patients admitted to the ICUs between January 2004 and July 2005. MEASUREMENTS AND RESULTS: Blood samples were collected as soon as possible after ICU admission, the following morning, and 48[Symbol: see text]h after the second sample. The cell-free plasma DNA was measured by real-time quantitative PCR assay for the beta-globin gene. Physiological and mortality data were collected to the clinical database. Hospital mortality rate and SOFA scores were primary outcome measures. The maximum plasma DNA concentrations were correlated significantly with APACHE II points and with maximum SOFA scores. Cell-free plasma DNA concentrations were higher in hospital non-survivors than in survivors (median 9,366 vs. 6,506 GE/ml). Using logistic regression analysis, the maximum plasma DNA was an independent predictor of hospital mortality. CONCLUSIONS: The maximum plasma DNA concentration measured during the first 96[Symbol: see text]h of intensive care is associated with the degree of organ dysfunction and disease severity. Moreover, the maximum DNA concentration is independently associated with hospital mortality.

Circulating pregnancy-associated plasma protein a predicts outcome in patients with acute coronary syndrome but no troponin I elevation.

BACKGROUND: Risk stratification in troponin (cTn)-negative acute coronary syndrome (ACS) remains a clinical challenge. We investigated the predictive value of circulating pregnancy-associated plasma protein A (PAPP-A), a novel marker of atherosclerotic plaque activity, in these patients. METHODS AND RESULTS: Two hundred consecutive hospitalized ACS patients were included, of whom 136 (69 men and 67 women; mean+/-SD age, 66+/-16 years) remained cTnI-negative for up to 24 hours. PAPP-A was measured at admission, 6 to 12 hours, and 24 hours. During 6-month follow-up, 26 (19.1%) of the cTnI-negative patients reached a primary end point (cardiovascular death, myocardial infarction, or revascularization). At a cutoff level of 2.9 mIU/L, elevated PAPP-A was an independent predictor of adverse outcome (adjusted risk ratio [RR], 4.6; 95% confidence interval, 1.8 to 11.8; P=0.002). Another independent predictor was admission CRP >2.0 mg/L (RR, 2.6; P=0.03). CONCLUSIONS: Measurement of plasma PAPP-A, a zinc-binding matrix metalloproteinase, is a strong independent predictor of ischemic cardiac events and need of revascularization in patients who present with suspected myocardial infarction but remain troponin negative.

Cytomegalovirus infection of the heart is common in patients with fatal myocarditis.

BACKGROUND: Although enteroviruses and adenoviruses are considered to be the leading causes of the usually mild clinical myocarditis, little is known about the etiology of severe or fatal myocarditis. METHODS: We collected all available clinical records and myocardial autopsy samples for patients who had myocarditis recorded as the underlying cause of death in Finland during the period of 1970-1998. Findings for all available patients (20 men and 20 women; median age, 49 years) with myocarditis that fulfilled the Dallas criteria and who had sufficient data were included in the study. Twelve subjects who had died accidentally served as control subjects. Polymerase chain reaction (PCR) and in situ hybridization assays were used for detection of viral genomes (adenovirus, cytomegalovirus, enterovirus, human herpesvirus 6, influenza A and B viruses, parvovirus B19, and rhinovirus) in heart samples. RESULTS: Viral nucleic acids were found in the hearts of 17 patients (43%), including cytomegalovirus (15 patients), parvovirus B19 (4 patients), enterovirus (1 patient), and human herpesvirus 6 (1 patient). In 4 patients, cytomegalovirus DNA was found in addition to parvovirus B19 or enterovirus genomes. No adenoviruses, rhinoviruses, or influenza viruses were detected in this study of fatal myocarditis. In 67% of the patients for whom PCR was positive for cytomegalovirus, in situ hybridization revealed viral DNA in cardiomyocytes. Only 1 of these patients was immunocompromised. In the control group, only human herpesvirus 6 (1 subject) and parvovirus B19 (1 subject) DNA were detected. CONCLUSIONS: In this population-based study, cytomegalovirus was found to be the most common specific finding in immunocompetent patients with fatal myocarditis. This may have important clinical implications for the treatment of severe acute myocarditis.

Comparative accuracy of manual versus computerized electrocardiographic measurement of J-, ST- and T-wave deviations in patients with acute coronary syndrome.

Accurate and rapid electrocardiographic interpretation is of crucial importance in acute coronary syndrome (ACS). Computerized electrocardiographic algorithms are often used in out-of-hospital settings. Their accuracy should be carefully validated in ACS, particularly in ST-elevation myocardial infarction. This study evaluated the comparative accuracy of lead-specific computer-based versus manual measurements of the J-point, ST-segment, and T-wave deviations in standard 12-lead electrocardiograms (ECGs) (excluding lead aVR). Sixty-nine consecutive patients with suspected ACS were included. The interobserver reliability in the determination of ST-segment deviation>or=0.2 mV in leads V2 and V3 was very good (kappa=0.94 and 0.93, respectively). Agreement between a cardiologist and the computer regarding ST elevation>or=0.2 mV in lead V2 was moderate (kappa=0.72) and in V3 was very good (kappa=0.85). For ST depression or elevation>or=0.05 mV in lead LIII, agreement was good and moderate (kappa=0.79 and 0.51, respectively). Bland-Altman analysis demonstrated clinically acceptable limits of agreement comparing measurements of the J point and the T wave, but clinically inadequate limits of agreement with respect to ST-segment deviation, between the electrocardiographer and the computer. The optimal cut-off points were 0.115 mV (sensitivity 89%, specificity 98%) for the computer program to detect ST elevation>or=0.2 mV and 0.045 mV (sensitivity 74%, specificity 99%) for revealing ST elevation>or=0.1 mV. It was found that automatically measured ST-segment deviations were smaller than those manually measured. In conclusion, a correction should be performed to obtain optimal results in the automated analysis of ECGs, because the results have important implications for clinical decision making.

Diagnosis and presentation of fatal myocarditis.

The clinical presentation of myocarditis is highly variable, and histopathology is thus considered to be the cornerstone of diagnosis. We studied how accurately myocarditis was diagnosed in a series of routine autopsies and how fatal myocarditis presents clinically. All death certificates with myocarditis recorded as the underlying cause of death in Finland in 1970 to 1998 were collected retrospectively (N = 639). All cases with cardiac autopsy samples and clinical data available (n = 142; median age, 51 years) were included in this study. The cardiac samples were reexamined for the presence of myocarditis by 3 experienced independent pathologists using the Dallas criteria. The clinical data were evaluated for the presenting signs and symptoms of myocarditis. Histopathologic reanalysis showed that only 32% of the 142 subjects met the Dallas criteria for myocarditis (75% of pediatric and 28% of adult patients, P = .001). Clinicians had suspected myocarditis in only one third of the hospitalized Dallas-positive patients. Dallas-positive patients presented more often with features of myocardial infarction (26% versus 9%, P = .026) or heart failure (35% versus 10%, P = .001) than Dallas-negative subjects. The signs and symptoms of infectious disease were also more common in Dallas-positive patients (61% versus 23%, P < .001). In contrast, Dallas-negative subjects died suddenly or were found dead more frequently (68% versus 39%, P = .004). The most evident cause of death in the Dallas-negative subjects was ischemic heart disease (n = 78, 55% of all cases). Our study provides evidence that myocarditis is overdiagnosed on routine autopsies, particularly in patients who have died suddenly or are found dead. Fatal myocarditis appears to present equally often as heart failure, sudden death, or mimicking myocardial infarction.

Hemodynamic variables related to outcome in septic shock.

OBJECTIVE: To assess the impact of hemodynamic variables on the outcome of critically ill patients in septic shock and to identify the optimal threshold values related to outcome with special reference to continuously monitored mean arterial pressure (MAP) and mixed venous oxygen saturation (SvO2). DESIGN AND SETTING: Retrospective cohort study in a university hospital intensive care unit (ICU). PATIENTS: All consecutive 111 patients with septic shock treated in our ICU between 1 Jan. 1999 and 30 Jan. 2002. MEASUREMENTS AND RESULTS: The data on the hemodynamic and respiratory monitoring and circulation-related laboratory tests over the first 48 h of treatment in the ICU were collected from the clinical data management system. Data from 6 h and 48 h were analyzed separately. The 30-day mortality rate was 33% (36 of 111). Univariate analysis and forward stepwise logistic regression analysis were performed using the 30-day mortality as the primary endpoint. Mean MAP and lactate on arrival during 6 h, while mean MAP, the area of SvO2 under 70%, and mean CVP during 48 h were independently associated with mortality. MAP level of 65 mmHg and SvO2 of 70% had the highest areas under receiver characteristics curves. CONCLUSIONS: MAP, SvO2, CVP, and initial lactate were independently associated with mortality in septic shock, with threshold values supporting those published in recent guidelines.

Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction.

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.

Exercise training in chronic heart failure: beneficial effects on cardiac (11)C-hydroxyephedrine PET, autonomic nervous control, and ventricular repolarization.

UNLABELLED: Abnormalities of autonomic nervous function are associated with a poor prognosis of patients with chronic heart failure (CHF). We studied the effects of a 6-mo exercise training program on Q-T interval dispersion, heart rate and blood pressure variability, baroreflex sensitivity, myocardial blood flow (MBF), and presynaptic sympathetic innervation in 13 patients with New York Heart Association class II-III heart failure. METHODS: MBF was measured with the H(2)(15)O and C(15)O technique. Cardiac presynaptic innervation was studied by (11)C-hydroxyephedrine (HED) retention assessed with PET. Heart rate and blood pressure variability and baroreflex sensitivity were tested with the phenylephrine method. All studies were performed before and after a 6-mo exercise training program. The exercise capacity was determined by spiroergometry, and Q-T dispersion was measured from a standard 12-lead electrocardiogram. RESULTS: Q-T dispersion was reduced after the training period (mean +/- SEM, from 52 +/- 5 to 36 +/- 5 ms [P = 0.01]). Global (11)C-HED retention improved from 0.228 +/- 0.099 to 0.263 +/- 0.066 s(-1) (P < 0.05). Global MBF was not affected by training, but MBF increased in areas of low initial perfusion in patients with coronary artery disease (from 0.382 +/- 0.062 to 0.562 +/- 0.083 mL/g/min [P < 0.005]). The high-frequency spectrum and total R-R interval variability increased (from 4.53 +/- 0.30 to 5.02 +/- 0.36 ms(2) [P < 0.05] and from 3.60 +/- 0.34 to 4.31 +/- 0.37 ms(2) [P < 0.005], respectively). Both changes correlated significantly with the observed change in (11)C-HED retention. There was a significant reduction of total and a near-significant reduction of low-frequency (LF) systolic blood-pressure (SBP) variability (from 4.89 +/- 1.03 to 3.18 +/- 0.48 [P < 0.05] and from 2.79 +/- 0.38 to 1.76 +/- 0.24 [P = 0.059], respectively). The decrease in LF SBP variability correlated inversely with the enhancement of (11)C-HED retention (r = -0.66; P < 0.05). Baroreflex sensitivity increased from 5.83 +/- 0.82 to 10.15 +/- 1.66 ms/mm Hg (P < 0.05). CONCLUSION: Exercise training induces beneficial changes in functional and imaging measures of cardiovascular autonomic nervous control. These observations point to a training-induced shift toward normalization of the compensatory autonomic nervous imbalance in CHF.

Apoptotic cardiomyocyte death in fatal myocarditis.

Acute myocarditis is often a self-limited process with a good outcome. Experimental animal studies have found that cardiomyocyte apoptosis occurs in severe forms of myocarditis. We studied whether cardiomyocyte apoptosis plays a role in the development of fatal acute human myocarditis. Myocardial autopsy samples from subjects who died of acute myocarditis in Finland between 1970 and 1998 were studied. Thirty-three of these cases(16 men and 17 women; 45 +/- 6 years old) were randomly selected for this study. All cases fulfilled the histopathologic Dallas criteria for myocarditis. Eight subjects who had died accidentally served as controls. Apoptotic DNA fragmentation (terminal transferase-mediated DNA nick end labeling) and activation of caspase-3 (immunohistochemistry) were detected. The mode of death was determined retrospectively from all available clinical data. In fatal myocarditis, large amounts of cardiomyocytes showed apoptotic DNA fragmentation or contained active caspase-3 (2.0 +/- 0.3% and 2.8 +/- 0.4%, respectively). In the controls, few apoptotic cardiomyocytes were found (0.008 +/- 0.003% by terminal transferase-mediated DNA nick end labeling and 0.009 +/- 0.003% by detection of active caspase-3, p <0.001 vs myocarditis). The amount of apoptosis did not correlate with the age or gender of the cases, recognized viral etiology, histologic features, or duration of disease. However, more apoptotic cardiomyocytes were detected in the subjects who had myocarditis and had died of heart failure (n = 18) than in those who had myocarditis and died suddenly of cardiac arrest (n = 15; 2.6 +/- 0.4% vs 1.1 +/- 0.2%, p <0.001). In conclusion, cardiomyocyte apoptosis is a common mechanism of myocardial damage in severe acute human myocarditis. Moreover, higher rates of cardiomyocyte apoptosis are associated with the development of fatal heart failure in acute myocarditis.

Anxiety and hostility are associated with reduced baroreflex sensitivity and increased beat-to-beat blood pressure variability.

OBJECTIVE: The purpose of this study was to determine whether psychological factors are associated with heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) among healthy middle-aged men and women. METHODS: A population-based sample of 71 men and 79 women (35-64 years of age) was studied. Five-minute supine recordings of ECG and beat-to-beat photoplethysmographic finger systolic arterial pressure and diastolic arterial pressure were obtained during paced breathing. Power spectra were computed using a fast Fourier transform for low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) powers. BRS was calculated by cross-spectral analysis of R-R interval and systolic arterial pressure variabilities. Psychological factors were evaluated by three self-report questionnaires: the Brief Symptom Inventory, the shortened version of the Spielberger State-Trait Anger Expression Inventory, and the Toronto Alexithymia Scale. RESULTS: Psychological factors were not related to HRV. Anxiety was associated with decreased BRS (p = 0.001) and higher low-frequency (p = 0.002) power of systolic arterial pressure variability. These associations were independent of age, gender, other psychological factors, heart rate, and systolic and diastolic blood pressures. Hostility was an independent correlate of increased low-frequency power of diastolic arterial pressure (p = 0.001) and increased high-frequency power of systolic arterial pressure (p = 0.033) variability. CONCLUSIONS: Anxiety and hostility are related to reduced BRS and increased low-frequency power of BPV. Reduced BRS reflects decreased parasympathetic outflow to the heart and may increase BPV through an increased sympathetic predominance.

Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis.

INTRODUCTION: Viruses are known to induce apoptosis in their host cells. We studied whether cardiomyocyte apoptosis occurs upon coxsackievirus B3 (CVB3) infection and whether virus-associated apoptosis plays a role in the pathogenesis of experimental myocarditis. METHODS: BALB/c mice were infected with two variants of CVB3 causing either mild or severe myocarditis. Myocardial and serum samples were collected from Day 1 to Day 14 after virus inoculation. Apoptosis was detected in myocardial tissue sections using the terminal transferase-mediated DNA nick end labelling (TUNEL) assay and staining of active caspase 3, and compared with the presence of infectious CVB3 and viral proteins in cardiomyocytes. RESULTS: Compared with the noninfected control mice, infection with either CVB3 variant resulted in significantly increased cardiomyocyte apoptosis, which peaked on Day 5 after infection. At this time, the average percentages of apoptotic cardiomyocytes were 0.17% (SD 0.04; P=.03) and 0.77% (SD 0.11; P<.01) in mild and severe disease forms, respectively. The amount of apoptosis correlated with titers of infectious CVB3 in the heart muscle. Viral proteins were detected in the TUNEL-positive cells by immunohistochemistry. In the late stages of disease, apoptosis, together with inflammatory infiltrates persisted only in the severe disease form. CONCLUSIONS: CVB3-associated myocardial damage involves cardiomyocyte apoptosis. In the early stages of the disease, it appears to be triggered by viral replication in the cardiomyocytes.

Soluble tumor necrosis factor receptor levels identify a subgroup of heart failure patients with increased cardiomyocyte apoptosis.

BACKGROUND: We studied whether the presence of cardiomyocyte apoptosis (CA) in explanted failing hearts is related to previous exposure to the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). METHODS: Serum levels of TNF-alpha and its soluble type two receptors (sTNFRII) were measured with ELISAs in 15 cardiac transplant recipients. CA was quantified with TUNEL assay in the explanted failing hearts and autopsy samples from six normal hearts. RESULTS: The number of CA was significantly higher in explanted failing hearts than in normal hearts (0.041% vs. 0.007%, p<0.01). In heart failure patients, serum TNF-alpha was highly variable and did not correlate with CA. In contrast, serum sTNFRII showed a significant correlation (Pearson's r=0.74, p=0.002) with the amount of CA in explanted hearts. sTNFRII level >4500 pg/ml identified seven patients with 2.7 times higher percentage of CA than the other heart failure patients. CONCLUSION: Increased levels of sTNFRII identify a heart failure patient subgroup with high CA activity.

Ramipril Enhances Autonomic Control in Essential Hypertension: A Study Employing Spectral Analysis of Heart Rate Variation.

We estimated the effect of an angiotensin-converting enzyme inhibitor, ramipril, on the sympathetic and parasympathetic input to the sinoatrial node of hypertensive patients using spectral and time domain analysis of heart rate variation (HRV). The heart rate of patients with essential hypertension was recorded during spontaneous breathing at rest and during controlled deep breathing. The periodic HRV was quantified at low-frequency (0.025--0.075 Hz), mid-frequency (0.075--0.125 Hz) and high-frequency (0.15--0.40 Hz) bands. Ramipril changed the balance of autonomic nervous system assessed by spectra: the parasympathetic tone increased (p < 0.05) and the sympathetic tone decreased (p < 0.01). There was an inverse correlation between the decrease in diastolic blood pressure and increase in the mid-frequency HRV, which is connoted with resetting of the baroreceptor reflex by ramipril. Thus, ramipril treatment was associated with improved autonomic control of the circulatory system.