Use of statins and adverse outcomes in patients with atrial fibrillation: An analysis from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) general registry pilot phase.

BACKGROUND: Despite oral anticoagulation being highly effective in reducing stroke and thromboembolism, patients with atrial fibrillation (AF) still have a significant residual excess in mortality risk. Additional management strategies are needed to reduce the mortality risk seen in AF patients. METHODS: Ancillary analysis from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) General Pilot Registry, to evaluate 1-year outcomes in AF patients according to statin use at baseline. RESULTS: Of 2636 patients, 1286 (48.8%) patients used statins at baseline. Patients prescribed statins had more comorbidities. At 1-year follow-up, logistic regression analysis adjusted for AF type, symptomatic status and CHA2DS2-VASc score demonstrated that statin use was inversely associated with CV death (odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.30-0.82, p<0.0001), all-cause death (OR: 0.52, 95% CI: 0.37-0.73, p<0.0001) and the composite outcome of CV death/any thromboembolic event/bleeding (OR: 0.71, 95% CI: 0.52-0.98, p<0.0001). Similar findings were observed for 'high risk' subgroups including the elderly, primary prevention and high thromboembolic risk AF patients. Survival analysis showed that statins prescribed patients had a lower risk of all-cause death at follow-up (p=0.0433). Multivariate Cox regression analysis found that statin use remained independently associated with a lower risk for all-cause death (hazard ratio [HR]: 0.61, 95% CI: 0.42-0.88, p=0.0077). CONCLUSIONS: Statin use in AF patients was associated with improved outcomes, with an independent association with a lower risk of all-cause death at 1-year follow-up.

Adding serial N-terminal pro brain natriuretic peptide measurements to optimal clinical management in outpatients with systolic heart failure: a multicentre randomized clinical trial (NorthStar monitoring study).

AIMS: This study was designed to evaluate a new NT-proBNP monitoring concept in outpatients with systolic heart failure (HF). METHODS AND RESULTS: This was a multicentre, prospective randomized open-label blinded endpoint study. A total of 407 systolic HF patients were allocated to either clinical management (n = 208) or clinical management + NT-proBNP monitoring (n = 199) and followed for 2.5 years. If NT-proBNP increased >30%, a clinical checklist was completed and treatment initiated. The patients were matched at randomization and were 73 years old, 25% were females, 85% were NYHA class I-II, LVEF was 30%, and NT-proBNP 1955 pg/mL. NT-proBNP monitoring did not improve outcome, the hazard ratio for the primary composite endpoint (death or a cardiovascular admission) being 0.96 [95% confidence interval (CI) 0.71-1.29, P = 0.766]. NT-proBNP monitoring did not induce a significant change in the pharmacological strategy (P > 0.05 for all comparisons). In patients in whom NT-proBNP increased >30% (25% of the patients) during follow-up, a higher frequency of admission (69% vs. 47%, P = 0.002), a higher number of admission days (14 vs. 5 days, P = 0.003) and number of admissions (2 vs. 1, P = 0.009), and a lower quality of life (P = 0.032) and a poorer functional class (37% vs. 18% in NYHA class III-IV, P < 0.001) were observed. CONCLUSIONS: Adding serial measurements of NT-proBNP to optimal clinical management was not associated with a change in pharmacological strategy and did not improve outcome. However, survivors in whom NT-proBNP increased >30% showed a poorer functional class, clinical outcome, and quality of life. TRIAL REGISTRATION: www.centerwatch: 173491 (NorthStar).

Design and methodology of the NorthStar Study: NT-proBNP stratified follow-up in outpatient heart failure clinics -- a randomized Danish multicenter study.

BACKGROUND: Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. AIMS: The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. METHODS: A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). RESULTS: Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. CONCLUSIONS: This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.

Heart rate variability in white-coat hypertension.

OBJECTIVES: The objective of this study was to compare heart rate variability (HRV) in patients with essential hypertension, in patients with white-coat hypertension and in normotensive control individuals, and to investigate a possible relation between HRV and vasoactive hormones. METHODS: Patients with essential hypertension (n=19, 61 years, median and interquartile range: 40-66 years), patients with white-coat hypertension (n=8, 52 years, median and interquartile range: 41-64 years) and normotensive participants (n=13, 50 years, median and interquartile range: 39-57 years) participated in the study. HRV was measured at rest in the supine position, during standing and during controlled forced breathing (respiration frequency >20/min). Power spectral density was calculated using Fourier transformation. RESULTS: Controlled breathing caused a decrease in low frequency (LF) variation and LF/high frequency variation (LF/HF) in all blood pressure groups. The decrease in LF was smaller in the hypertensive group (-60 ms2) than in the normotensive group (-139 ms2) (P=0.03; hypertensive group vs. normotensive group). The decrease in LF/HF induced by controlled breathing was -0.9 ms in the hypertensive group, -2.0 ms2 in the white-coat hypertensive group and -2.8 ms2 in the normotensive group, (P=0.037; hypertensive group vs. normotensive group). We found a positive correlation between baseline plasma renin concentration and LF (r=0.330, P=0.037) and LF/HF (r=0.378, P=0.016) at rest. CONCLUSION: The observed differences in HRV might reflect the impaired responsiveness to autonomic challenge in hypertensive patients. We did not find the HRV spectrum in white-coat hypertension different from the HRV spectrum in hypertension or normotension.

Abnormally increased endothelin-1 in plasma during the night in obstructive sleep apnea: relation to blood pressure and severity of disease.

BACKGROUND: The mechanisms involved in development and maintenance of hypertension in obstructive sleep apnea (OSA) are not clarified. We hypothesize that patients with OSA have an abnormal nocturnal level of some vasoactive hormones during the night. METHODS: We studied 32 patients with OSA and 19 healthy control subjects during The night-time with serial determinations of endothelin-1 (ENDO-1), angiotensin II (Ang II), renin (PRC), aldosterone (ALDO) in plasma, and blood pressure (BP), and oxygen saturation. RESULTS: Patients with OSA had a higher plasma level of ENDO than healthy controls and the mean nocturnal level of ENDO correlated significantly to the apnea-hypopnea index (AHI) as a measure of the severity of OSA. This correlation remained statistically significant after analysis in a general linear model with correction for confounders. Patients with OSA also had a significantly higher BP than healthy controls and the ambulatory BP correlated positively to the AHI in patients with OSA. No significant differences were measured in Ang II, PRC, and ALDO between the two groups. The correlation between AHI and ENDO supports OSA as a stimulus of endothelin release or increased endothelin levels contributing to the severity of OSA. CONCLUSIONS: Endothelin seems to be a pathogenic factor in generating hypertension in OSA.

QT dynamics in risk stratification after myocardial infarction.

OBJECTIVES: The purpose of this study was to compare measures of repolarization dynamics (QT dynamics) with other Holter risk predictors, left ventricular systolic function, and demographic characteristics to establish whether QT dynamics add independent information on risk stratification after myocardial infarction (MI). A novel QT dynamics parameter, the QT/RR variability ratio (VR), was introduced in this study. BACKGROUND: Abnormal repolarization contributes to arrhythmogenesis, and quantification of QT dynamics may have prognostic value after MI. METHODS: A 24-hour Holter recording was performed in 481 consecutive MI patients. Recordings from 311 patients were included in the analysis. QT/RR slope and intercept, mean and standard deviation of all QT, QTc, and RR intervals, and VR (defined as the ratio between the standard deviation of all QT intervals and the standard deviation of all RR interval) were calculated. Ventricular premature beats and ventricular tachycardia were counted. RESULTS: During 3-year follow-up, 70 deaths from all causes occurred. All parameters except mean of all QT intervals and standard deviation of all QTc intervals univariately predicted all-cause mortality. In multivariate Cox analysis, only VR per 0.1 (hazard ratio [HR]: 1.9 [1.5-2.4]), left ventricular ejection fraction per 5% (HR: 1.2 [1.1-1.3]), ventricular premature beats per 10 beats/hour (HR: 1.03 [1.002-1.06]), and age per 10 years (HR: 1.6 [1.3-2.0]) independently predicted all-cause mortality. CONCLUSIONS: Measures of QT dynamics univariately predicted total mortality. VR, left ventricular ejection fraction, ventricular premature beats, and age made up the optimal Cox model for risk stratification after MI. VR seems to be a promising risk factor for identifying sudden arrhythmic death.

Repetitive measurements of Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in healthy control subjects and dialysis patients: a prospective study.

Infection with Chlamydia pneumoniae has been suggested to play a role in the development and maintenance of atherosclerosis. However, the course of C. pneumoniae infection is not clarified. Thus, both the persistence of C. pneumoniae DNA in blood and the tendency to recurrence have not been studied. We determined the prevalence of C. pneumoniae DNA in the white cells of the peripheral blood in 98 dialysis patients and in 52 healthy subjects. Blood samples were collected approximately 6 times from each subject during a period of 1 y with an interval of approximately 2 months and analysed with a polymerase chain reaction. C. pneumoniae DNA was detectable in 47 out of 150 subjects at least once during a y. Reinfection was a rare phenomenon and the presence of C. pneumoniae DNA in blood was of less than 2 months' duration in almost all patients. There was a significant association between the presence of C. pneumoniae DNA during 1 y and the presence of atherosclerosis in the legs of dialysis patients (OR=3.50, p=0.03). Additionally, a significant association was found between the presence of C. pneumoniae DNA and an abnormal electrocardiogram (ECG) (OR=3.16, p=0.01). These findings may support the hypothesis of an association between infection with C. pneumoniae and the presence or development of atherosclerosis.

Effect of exercise on natriuretic peptides in plasma and urine in chronic heart failure.

BACKGROUND: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in chronic heart failure (CHF). ANP is known to be increased during exercise in healthy subjects and CHF, while the response in BNP during exercise is less clear and does not exist in C-type natriuretic peptide (CNP) and aquaporin-2 (AQP2) in either healthy subjects or CHF. METHODS: Eleven patients with CHF and eleven healthy subjects performed a maximal aerobic exercise test. ANP and BNP in plasma were determined every 3 min and at maximum exercise by radioimmunoassay (RIA) and CNP and AQP2 in urine were determined before and after the exercise test by RIA. RESULTS: The absolute increase in BNP during exercise was higher in patients with CHF (CHF: 4.1 pmol/l; healthy subjects: 1.3 pmol/l, P<0.05) and was positively correlated to BNP at rest (P<0.05), while the absolute increase in ANP during exercise was the same in the two groups (CHF: 4.2 pmol/l; healthy subjects: 6.8 pmol/l, not significant, NS). In CHF, exercise did not change either u-CNP excretion (rest: 9.8 ng/mmol creatinine; after exercise: 8.8 ng/mmol, NS) or u-AQP2 (rest: 466 ng/mmol creatinine; after exercise: 517 ng/mmol creatinine, NS) as well as in healthy subjects where u-CNP (rest: 9.7 ng/mmol creatinine; after exercise: 9.2 ng/mmol creatinine) and u-AQP2 (rest: 283 ng/mmol creatinine; after exercise: 307 ng/mmol creatinine) were the same at rest and after exercise. CONCLUSION: The absolute increase in BNP during exercise is higher in patients with CHF compared to healthy subjects. It is suggested that this is a compensatory phenomenon to improve the exercise capacity in CHF, and that BNP is a more important factor in cardiovascular homeostasis during exercise in CHF than ANP.

Chlamydia pneumoniae DNA in peripheral blood mononuclear cells in healthy control subjects and patients with diabetes mellitus, acute coronary syndrome, stroke, and arterial hypertension.

Infection with Chlamydia pneumoniae has been suggested to play a role in the development and maintenance of atherosclerosis based on differences in the prevalence of antibodies against Chlamydia pneumoniae in patients with and without atherosclerotic lesions. We evaluated the prevalence of Chlamydia pneumoniae DNA in the white cells of the peripheral blood in 194 patients with diabetes mellitus, 50 patients with acute coronary syndrome, 102 hypertensive patients, 193 patients having suffered a stroke and in 368 healthy subjects with a nested polymerase chain reaction (nPCR). Overall the prevalence of Chlamydia pneumoniae DNA in peripheral blood cells was: diabetes mellitus (11.9%), stroke (10.4%), hypertension (6.9%), acute coronary syndrome (4.0%) and healthy subjects (7.9%). The prevalence of Chlamydia pneumoniae DNA in the patients was not significantly different from prevalence in the healthy subjects. However, a significant association was found between high levels of triglycerides and presence of C. pneumoniae DNA (OR = 3.27, p < 0.04). The prevalence of C. pneumoniae DNA was not associated with age, gender, smoking, BMI, HDL, CRP, plasma creatinine and symptoms or signs of ischaemic heart disease. The association between high levels of triglycerides and C. pneumoniae DNA suggests that infection by C. pneumoniae affects lipid metabolism.

Heart rate versus heart rate variability in risk prediction after myocardial infarction.

INTRODUCTION: The aim of this study was to evaluate and compare heart rate and heart rate variability (HRV) in risk prediction after acute myocardial infarction (MI) and to evaluate the effect of beta-blocker treatment on the prognostic performance of heart rate and HRV. METHODS AND RESULTS: Three hundred sixty-six patients underwent 24-hour Holter recording 1 to 6 days after an MI. HRV was expressed as the standard deviation of all normal-to-normal intervals. Left ventricular systolic function was evaluated using the wall motion index. Half of the patients were taking a beta-blocker at the time of Holter recording. Mean follow-up was 44 months (median 34) after MI. By the end of follow-up, 82 patients had died. Mortality at 1 and 3 years was 12.5% and 22.6%, respectively. HRV, heart rate, wall motion index, number of ventricular premature beats per hour, and ventricular tachycardia were all significantly (P < 0.05) associated with mortality in univariate analysis, independent of beta-blocker therapy. In multivariate Cox analysis, only heart rate, wall motion index, number of ventricular premature beats per hour, and age had independent prognostic value (P < 0.001). In any model, including heart rate, HRV had no predictive value. CONCLUSION: The prognostic information of HRV is contained completely in heart rate, which carries prognostic information further than that of HRV. This result was independent of beta-blocker treatment.

Abnormal rhythmic oscillations of atrial natriuretic peptide and brain natriuretic peptide in heart failure.

The purpose of this study was to clarify whether the secretions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are pulsatile in patients with chronic heart failure (CHF), and whether the rhythmic oscillations for ANP and BNP are abnormal in patients with CHF. Several reports have shown that ANP and especially BNP are valuable indicators of the prognosis in CHF. Previously, a pulsatile secretion has been described for ANP and BNP in healthy humans and for ANP in CHF patients. More information about the secretion pattern of BNP in heart failure is necessary to increase the clinical usefulness of BNP in patients with CHF. Patients with left ventricular systolic dysfunction and CHF ( n =12) and controls ( n =12) were investigated. Plasma ANP and BNP levels were determined every 2 min during a 2-h period by radioimmunoassay and analysed for pulsatile behaviour by Fourier transformation. All patients and controls had significant rhythmic oscillations in plasma ANP levels, and 11 patients with CHF and 10 controls had significant rhythmic oscillations in plasma BNP levels. The amplitude of the main frequency was considerably higher in patients with CHF than in controls (ANP: CHF, 4.76 pmol/l; controls, 0.75 pmol/l; P <0.01. BNP: CHF, 3.24 pmol/l; controls, 0.23 pmol/l; P <0.001; all values are medians), but the main frequency did not differ significantly between the group with CHF and the control group for either ANP or BNP. Patients with CHF demonstrate pulsatile secretion of ANP and BNP with a much higher absolute amplitude, but with the same main frequency as healthy subjects.

Prognostic importance of systolic and diastolic function after acute myocardial infarction.

BACKGROUND: Although risk stratification after acute myocardial infarction (AMI) often is focused on systolic left ventricular (LV) function, it appears that a more complete study of ventricular function including assessment of LV filling would be useful. Doppler echocardiography allows assessment of LV filling, and with the use of the Tei index (sum of isovolumic relaxation and contraction times divided by ejection time), a global estimate of ventricular function may be obtained. Therefore, the aim of this study was to determine the prognostic importance of LV systolic, diastolic, and overall LV function in a large consecutive population with AMI. METHODS: Echocardiography was performed within 6 days of AMI. LV systolic, diastolic, and global function was assessed by means of wall motion index (WMI), mitral flow pattern, and Tei index. The primary end point was all-cause death. RESULTS: Of 799 enrolled patients, 197 died during a median follow-up of 34 months. In a multivariate model including WMI and clinical parameters, WMI had important prognostic information. When mitral filling pattern and quartiles of Tei index were added to the model, restrictive filling (mitral deceleration time <140 ms) was associated with a risk ratio of 1.9 (95% CI 1.3-2.7, P <.0001, Tei index values of >0.68/0.56-0.68/0.46-0.55/<0.46 were associated with risks of 4.0 [2.1-6.9]/2.3 [1.5-3.9]/2.1 [1.2-3.6]/1.0, P <.001). In this model, WMI had no prognostic value (P =.18). CONCLUSIONS: Mitral deceleration time and the Tei index have independent and important prognostic value after AMI.