A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure.

AIMS: Although active-controlled trials with renin­angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34­50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21­44%; P < 0.0001) and heart failure hospitalization (49%, 39­58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15­39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27­48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16­45%; P < 0.0001) for cardiovascular death, 46% (33­56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11­39%; P < 0.0001) for all-cause mortality. CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

A new common mutation in the cardiac beta-myosin heavy chain gene in Finnish patients with hypertrophic cardiomyopathy.

BACKGROUND: In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. PATIENTS AND METHODS: Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. RESULTS: MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. CONCLUSION: Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland.

Idiopathic dilated cardiomyopathy and chronic atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is common in idiopathic dilated cardiomyopathy (IDC). We explored the clinical characteristics of IDC patients with chronic AF compared with those with sinus rhythm (SR). METHODS: A group of patients with IDC underwent extensive non-invasive and invasive evaluation during a hospitalization period. The patients were further divided into two groups with AF (n = 19) and SR (n = 68). RESULTS: Left atrial diameter was greater (P<0·001), left ventricular end-diastolic diameter smaller (P<0·05), left ventricular end-diastolic and end-systolic volumes smaller (P<0·01 for all), mean pulmonary artery pressure and pulmonary capillary wedge pressure higher (P<0·05 for both), cardiac output and maximal oxygen consumption lower (P<0·01 and P<0·05, respectively), and the levels of N-terminal pro-brain natriuretic peptide and interleukin-6 higher (P<0·05 for both) in AF group compared with SR group. Left ventricular ejection fraction and left ventricular end-diastolic pressure were similar in both groups. CONCLUSIONS: In spite of otherwise more unfavourable prognostic factor profile, left ventricular size was observed to be smaller in chronic AF compared with SR in well-characterized patients with IDC. The confirmation and possible explainers of this paradoxical phenomenon need further studies in larger patient cohorts.

Intermittent levosimendan treatment in patients with severe congestive heart failure.

OBJECTIVE: Levosimendan (LS) is a novel inodilator for the treatment of severe congestive heart failure (CHF). In this study, we investigated the potential long-term effects of intermittent LS treatment on the pathophysiology of heart failure. METHODS: Thirteen patients with modest to severe CHF received three 24-h intravenous infusions of LS at 3-week intervals. Exercise capacity was determined by bicycle ergospirometry, well-being assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ) and laboratory parameters of interest measured before and after each treatment. RESULTS: One patient experienced non-sustained periods of ventricular tachycardia (VT) during the first infusion and had to discontinue the study. Otherwise the LS infusions were well tolerated. Exercise capacity (VO2max) did not improve significantly during the study although symptoms decreased (P < 0.0001). Levels of plasma NT-proANP, NT-proBNP and NT-proXNP decreased 30-50% during each infusion (P < 0.001 for all), but the changes disappeared within 3 weeks. Although norepinephrine (NE) appeared to increase during the first treatment (P = 0.019), no long-term changes were observed. CONCLUSION: Intermittent LS treatments decreased effectively and repetitively plasma vasoactive peptide levels, but no carryover effects were observed. Patients' symptoms decreased for the whole study period although there was no objective improvement of their exercise capacity. The prognostic significance of these effects needs to be further studied.

Long-term survival after hospitalization for acute heart failure--differences in prognosis of acutely decompensated chronic and new-onset acute heart failure.

AIMS: To analyze the five-year mortality after hospitalization for acute heart failure (AHF) and compare predictors of prognosis in patients with and without a previous history of heart failure. METHODS: Patients with AHF (n=620) from the prospective multicenter FINN-AKVA study were classified as acutely decompensated chronic heart failure (ADCHF) or de-novo AHF if no previous history of heart failure was present. Both all-cause mortality during five years of follow-up and prognostic factors were determined. RESULTS: The overall mortality was 60.3% (n=374) at five years. ADCHF was associated with significantly poorer outcome compared to de-novo AHF; five-year mortality rate 75.6% vs. 44.4% (p<0.001). Initially, mortality was high (33.5% in ADCHF and 21.7% in de-novo AHF after 12 months), but in de-novo AHF the annual mortality declined markedly already after the first year. Compared to de-novo AHF, patients with ADCHF had an increased risk of death for several years after the index hospitalization. A previous history of heart failure was an independent predictor of five-year mortality (adjusted hazard ratio 1.8 (95% CI 1.4-2.2; p<0.001). Older age and impaired renal function were associated with adverse long-term prognosis in both ADCHF and de-novo AHF, while higher systolic blood pressure on admission predicted better outcome. CONCLUSION: The long-term prognosis after hospitalization for AHF is poor, with a significantly different survival observed in patients with de-novo AHF compared to ADCHF. A previous history of heart failure is an independent predictor of five-year mortality. Distinction between ADCHF and de-novo AHF may improve our understanding of patients with AHF.

Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). DESIGN: Clinical study. SETTING: Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. SUBJECTS: Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects. MAIN OUTCOME MEASURES: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected. RESULTS: Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1ß, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI. CONCLUSIONS: A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.

Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.

BACKGROUND: The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. METHODS: Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. RESULTS: Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. CONCLUSIONS: Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.

Natriuretic peptides and collagen biomarkers in patients with medical treatment for hypertension.

OBJECTIVE: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA) showed that an amlodipine-based regimen prevented more cardiovascular events than an atenolol-based regimen in patients at high risk of hypertension.The basis of this difference is partly unknown and may be due to their divergent effects on the remodelling process of hypertensive heart disease. METHODS AND RESULTS: We measured plasma levels of aminoterminal propeptide of atrial natriuretic peptide (NT-proANP) and aminoterminal propeptide of B-type natriuretic peptide and serum levels of the aminoterminal propeptide of type I procollagen (PINP), aminoterminal propeptide of type III procollagen and type I collagen telopeptide in 93 patients randomized in the ASCOT study at baseline and after two and four years and compared them with echocardiographic parameters and blood pressure. NT-proANP decreased at two years by 22 (-484 - 153) pmol/l in the amlodipine-based regimen and increased by 109 (-297 - 1545) pmol/l in the atenolol-based regimen (P < 0.001), whereas no significant difference in NT-proBNP between the arms was found. PINP levels increased by 1.8 (-29 -31) microg/l in the amlodipine-based regimen and decreased by 4.7 (-27- 31) microg/I in the atenolol-based regimen, whereas no differences were found in other collagen markers between the arms. Major echocardiographic changes were not found. CONCLUSIONS: Our results show that the two treatment regimens of ASCOT-BPLA had different effects on plasma natriuretic peptides and serological markers of collagen turnover, probably reflecting divergent effects in cardiac remodelling.

Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA) on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI) to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance.

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation.

OBJECTIVE: To evaluate the value of cardiac magnetic resonance imaging (CMRI)-assessed left ventricular hypertrophy (LVH) in differentiating between hypertensive heart disease and hypertrophic cardiomyopathy (HCM). METHODS: 95 unselected subjects with mild-to-moderate hypertension, 24 patients with HCM attributable to the D175N mutation of the α-tropomyosin gene and 17 control subjects were studied by cine CMRI. Left ventricular (LV) quantitative and qualitative characteristics were evaluated. RESULTS: LV maximal end-diastolic wall thickness, wall thickness-to-LV volume ratio, end-diastolic septum thickness and septum-to-lateral wall thickness ratio were useful measures for differentiating between LVH due to hypertension and HCM. The most accurate measure for identifying patients with HCM was the LV maximal wall thickness ≥ 17 mm, with a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95% and 91%, respectively. LV maximal wall thickness in the anterior wall, or regional bulging in left ventricular wall was found only in patients with HCM. LV mass index was not discriminant between patients with HCM and those with LVH due to hypertension. CONCLUSION: LV maximal thickness measured by CMRI is the best anatomical parameter in differentiating between LVH due to mild-to-moderate hypertension and HCM attributable to a sarcomeric mutation. CMRI assessment of location and quality of LVH is also of value in differential diagnosis.

Comparison of gated single-photon emission computed tomography with magnetic resonance imaging for evaluation of left ventricular volumes and ejection fraction in patients with idiopathic dilated cardiomyopathy.

To prospectively compare the left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), and ejection fraction (LVEF) obtained from gated perfusion single photon emission computed tomography (GSPECT) with those obtained from cardiac magnetic resonance imaging (MRI) in patients with idiopathic dilated cardiomyopathy (IDC). Twenty-one patients with IDC (6 females) with a median age of 45 years (range 17-65) were scheduled for (99m)Tc-tetrofosmin-GSPECT and MRI within a 3 h interval. In both methods LV volumes were analyzed with the Simpson method. Both GSPECT and MRI were successfully completed in 90% of patients. Close linear correlations were observed between the two methods in LVEDV (R = 0.918; P < 0.001) and LVESV (R = 0.946; P < 0.001), but correlations were significantly weaker in LVEF (R = 0.323; P = 0.082). LVEDV and LVESV were smaller in GSPECT than in MRI (161 ± 73 vs. 214 ± 87 ml, P < 0.001, and 116 ± 64 vs. 138 ± 72 ml, P < 0.001, respectively). In 4 patients (21%) the LVEDV index was considered normal by GSPECT and increased by MRI, if MRI-derived normal values were used. No difference was found between GSPECT and MRI when LVEF(MRI) was ≤ 40%, but GSPECT showed smaller LVEF when LVEF(MRI) was over 40% (33 ± 11 vs. 50 ± 5%; P < 0.05). The finding of increased LVEDV in GSPECT is reliable compared with MRI. However, LV volumes were underestimated by GSPECT and no direct comparisons can be made between methods in follow up studies. Abnormal results should be confirmed by another imaging modality, such as MRI, if these findings have therapeutic consequences.

Prevalence of pulmonary embolism in patients with suspected cardioembolic ischemic stroke.

PURPOSE: Venous thromboemboli can cause both pulmonary embolism (PE) and paradoxical embolism in the presence of a cardiac right-to-left shunt. Our aim was to prospectively assess the prevalence of PE in patients with ischemic stroke with suspected cardiogenic etiology and thereby to clarify the possible role of paradoxical embolism as a cause of ischemic stroke. MATERIALS AND METHODS: Consecutive patients with suspected cardiogenic ischemic stroke (n=113, male/female=76/37, mean age 62±11 y) underwent computed tomography angiography of the pulmonary arteries to assess for the presence of PE as an adjunct to routine computed tomography angiography of the cervicocranial arteries. Transthoracic and transesophageal echocardiography were used to evaluate for patent foramen ovale (PFO) and cardiac defects. RESULTS: PE was found in 4 patients (3.5%). Only 1 patient with PE had symptoms or signs suggestive of PE. None of the patients with PE had intracardiac defects or PFO. In the entire study population, atrial septal defect was detected in 5 (4%) patients and PFO in 13 (12%) patients. CONCLUSIONS: The prevalence of PE in patients with ischemic stroke with suspected cardiogenic etiology is low. This study does not support a significant association between PE and cardiogenic ischemic stroke.

Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy.

RATIONALE: The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels. OBJECTIVE: We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1(-/-)) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling. METHODS AND RESULTS: Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1(-/-) mice. CONCLUSIONS: Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress.

Markers of renal function and acute kidney injury in acute heart failure: definitions and impact on outcomes of the cardiorenal syndrome.

AIMS: Acute kidney injury (AKI) in patients hospitalized for acute heart failure (AHF) is part of the cardiorenal syndrome and has been associated with increased morbidity and mortality. However, definitions and prognostic impact of AKI in AHF have been variable. Cystatin C is a prospective new marker of AKI. The objective of this study was to investigate the use of cystatin C as a marker of early AKI in AHF. METHODS AND RESULTS: Patients (n = 292) hospitalized for AHF had measurements of cystatin C on admission and at 48 h. We assessed the incidence of a rise in cystatin C between the two measurements and evaluated the effect of an increase in cystatin C on outcomes up to 12 months. The population was on average 75 years old and 49% were female. On admission, median cystatin C was 1.25 mg/L (interquartile range 0.99-1.61 mg/L). A rise in cystatin C by >0.3 mg/L within 48 h after hospitalization (AKI(cysC)) occurred in 16% of patients and resulted in 3 days (P = 0.01) longer hospital stay and was associated with significantly higher in-hospital mortality, odds ratio 4.0 [95% confidence intervals (CI) 1.3-11.7, P = 0.01]. During follow-up, AKI(cysC) was an independent predictor of 90 days mortality, adjusted odds ratio 2.8 (95% CI 1.2-6.7, P = 0.02). CONCLUSION: Cystatin C appears to be a useful marker of early AKI in patients hospitalized for AHF. A decline in renal function detected by cystatin C during the first 48 h after hospitalization occurs frequently in AHF and has a detrimental impact on prognosis.

Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge-induced cough.

BACKGROUND AND AIMS: Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge-induced cough in assessing the efficacy of inhaled corticosteroid treatment. METHODS: A total of 16 steroid-naïve asthmatics and 10 non-asthmatic, symptomatic controls received 800-microg beclomethasone (Beclomet Easyhaler(R), Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV(1)(PC(20)). RESULTS: CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209-1168) to 73.6 (29.8-182) coughs per mg/mL (P = 0.002). Their PC(20) levels were 1.31 (1.07-1.60) and 1.91 (1.33-2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC(20) level, in CCR level or in symptom frequency in non-asthmatic subjects during the treatment. CONCLUSIONS: Hypertonic histamine challenge-induced cough and PC(20) are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably.

The type of acute heart failure and the costs of hospitalization.

BACKGROUND: The costs of different classes of acute HF (AHF) are not known. METHODS: AHF patients (N = 620) were divided in a national, prospective, observational study into five clinical classes: cardiogenic shock, pulmonary oedema, congestive HF, hypertensive HF, and right HF. Index episode and 6-month readmissions were assessed and hospitalization costs were evaluated. RESULTS: The length of index episode, ICU/CCU stay and costs of index episode and cumulative 6-month costs differed significantly between the clinical classes. The highest cumulative 6-month hospitalization costs, 25,963 (15,053-44778) € (mean, 95% confidence interval) incurred in cardiogenic shock, followed by pulmonary oedema, 12,912 (11,006-15,148) €, and congestive HF, 9475 (8550-10,500) €. CONCLUSIONS: AHF leads to significant need for hospital care and high costs which differ significantly between clinical classes of AHF.

The activation of the inflammatory cytokines in overweight patients with mild obstructive sleep apnoea.

It is widely accepted that obstructive sleep apnoea (OSA) is linked with cardiovascular diseases. The relationship is complex and remains still poorly understood. The presence of chronic systemic inflammation has been connected with pathogenesis of both OSA and cardiovascular diseases. While atherogenesis is believed to be a process of many years, little is known about the potential impact of the largest OSA subgroup, mild OSA, on the development of cardiovascular diseases. The aim of the present study was to assess whether untreated mild OSA is associated with an activation of inflammatory cytokine system. The adult study population consisted of two groups: 84 patients with mild OSA [apnoea-hypopnoea index (AHI) 5-15 h(-1)] and 40 controls (AHI <5 h(-1)). Serum concentrations of pro- and anti-inflammatory cytokines were measured before any interventions. After adjustments for age, sex, body mass index, fat percentage, most important cardiometabolic and inflammatory diseases, and non-steroidal anti-inflammatory medication, the mean level of tumour necrosis factor-alpha was significantly elevated (1.54 versus 1.17 pg mL(-1), P = 0.004), whereas the level of interleukin-1 beta (IL-1 beta) was reduced (0.19 versus 0.23 pg mL(-1), P = 0.004) in patients with mild OSA compared with controls. The concentrations of the protective anti-inflammatory cytokines, interleukin-10 (1.28 versus 0.70 pg mL(-1), P < 0.001) and interleukin-1 receptor antagonist (478 versus 330 pg mL(-1), P = 0.003) were elevated in the OSA group. The concentrations of C-reactive protein increased, but IL-1 beta decreased along with the increase of AHI. Mild OSA was found to be associated not only with the activation of the pro-inflammatory, but also with the anti-inflammatory systems.

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. METHODS AND RESULTS: We studied 99 patients with IDC (age 54 +/- 1 years, left ventricular ejection fraction (EF) 40 +/- 1%, maximum oxygen uptake (VO(2)max) 20 +/- 1 ml kg(-1) min(-2), mean +/- SEM) by using (123)I-metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)-ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)-6 and N-terminal B-type natriuretic peptide (NT-proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL-6 (r = 0.42, P<0.001 and r = -0.31, P<0.01) and NT-proBNP (r = 0.48, P<0.001 and r = -0.40, P<0.001). During a median follow-up of 4.1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter-defibrillator). In these patients, MIBG washout was higher (53 +/- 4 versus 40 +/- 2%, P = 0.01) and H/M ratio lower (1.38 +/- 0.04 versus 1.51 +/- 0.02, P = 0.01) than in patients without an event. CONCLUSIONS: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.