Inflammatory Markers and Incident Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study

Background: Inflammation is associated with heart failure (HF) risk factors and also directly affects myocardial function. However, the association between inflammation and HF risk in older adults has not been adequately evaluated. Methods: The association of baseline serum concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF- ), and C-reactive protein (CRP) with incident HF was assessed with Cox proportional hazards models among 2610 older persons without prevalent HF enrolled in the Health, Aging, and Body Composition (Health ABC) Study (age, 73.6±2.9 years; 48.3% men; 59.6% white). Results: Median (interquartile range) baseline concentrations of IL-6, TNF- , and CRP were 1.80 (1.23, 2.76) pg/mL, 3.14 (2.41, 4.06) pg/mL, and 1.64 (0.99, 3.04) µg/mL, respectively. On follow-up (median, 9.4 years), 311 participants (11.9%) developed HF. In models controlling for clinical predictors of HF and incident coronary heart disease, doubling of IL-6, TNF- , and CRP concentrations was associated with 34% (95% CI, 18 -52%; P<.001), 33% (95% CI, 9 - 63%; P=.006), and 13% (95% CI, 3-24%; P=.01) increase in HF risk, respectively. In models including all 3 markers, IL-6 and TNF- , but not CRP, remained significant. Findings were similar across sex and race. Post-HF ejection fraction (EF) was available in 239 (76.8%) cases. When only cases with preserved EF were considered (n=105), IL-6 (HR per doubling, 1.57; 95% CI, 1.28 -1.94; P<.001), TNF- (HR per doubling, 1.59; 95% CI, 1.12-2.26; P=.01), and CRP (HR per doubling, 1.23; 95% CI, 1.05-1.44; P=.01) were all associated with HF risk in adjusted models. In contrast, when only cases with reduced EF (n=134) were considered, only IL-6 attained marginal significance in adjusted models (HR per doubling, 1.20; 95% CI, 0.99 -1.46; P=.06). Participants with 2 or 3 markers above median had pronounced HF risk in adjusted models (HR, 1.66; 95% CI, 1.12-2.46; P=.01; and HR, 1.76; 95% CI, 1.16 -2.65; P=.007, respectively). Addition of IL-6 to the clinical Health ABC HF model improved discrimination (C index from 0.717 to 0.734; P=.001) and fit (decreased Bayes information criterion by 17.8; P<.001). Conclusions: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Calcium, vitamin D and cardiovascular disease.

The relationship between calcium and cardiovascular diseases (CVD) has been explored for a long time. Studies exploring the effect of calcium intake or calcium supplementation on cardiovascular risk suggest that systolic blood pressure increases under low calcium intake and decreases with calcium supplementation. A lower calcium intake has been associated with an increased risk of stroke. However, the impact of calcium supplementation on stroke risk remains unclear. Calcium supplementation may increase the risk of myocardial infarction. The relationship between vitamin D and CVD has been explored more recently. Negative correlations between vitamin D levels and the risk of hypertension, myocardial infarction, and stroke have been reported in several observational studies. The effect of vitamin D supplementation on blood pressure is still unclear and no effect of vitamin D supplementation on coronary heart disease or stroke has been clearly demonstrated. There is a lack of randomized clinical trials primarily addressing the effect of these parameters on CVD. Therefore, the real impact of calcium and vitamin D on cardiovascular outcomes remains to be documented by appropriate experimental data.

Influence of gender on long-term prognosis of patients with chronic heart failure seen in heart failure clinics.

BACKGROUND Controversy exists concerning the influence of gender in the prognosis of patients with heart failure and no evidence is available from specific heart failure clinics. HYPOTHESIS Women with ambulatory heart failure are managed differently than men, although their prognosis might be better than men. METHODS AND RESULTS We analyzed the clinical characteristics, complementary test results, treatment, and prognosis in 4720 patients with chronic heart failure seen in 62 specialized clinics forming part of a multicenter registry during a mean follow-up of 40 months. The mean age was 65 +/- 12 years and 71% were men. The men were younger than the women and more often had a history of hyperlipidemia and ischemic heart disease. The men had a more advanced heart failure New York Heart Association (NYHA) functional class (III-IV) than the women and a greater frequency of systolic ventricular dysfunction. The men more often received treatment with beta-blockers, vasodilators, and antiplatelet aggregators as well as higher mean doses as compared with the women. The overall survival after the follow-up was similar for both genders, although the women had lower rates of survival free of admission for heart failure. CONCLUSIONS Despite the mortality of women and men with heart failure being similar, the rate of readmission for heart failure is greater in women in specialized heart failure clinics. These results may be associated with the pharmacological treatment differences observed.

Congenital transmission of Trypanosoma cruzi in central Brazil. A study of 1,211 individuals born to infected mothers

Transmission of Trypanosoma cruziduring pregnancy is estimated to occur in less than 20% of infected mothers; however, the etiopathogenesis is not completely understood. The Centre for Studies on Chagas Disease provides confirmation of T. cruziinfection for individuals living in central Brazil. In this retrospective hospital-based study, all requests for diagnosis of T. cruziinfection in individuals less than 21 years old from 1994-2014 were searched. We end with 1,211 individuals and their respective infected mothers. Congenital transmission of infection was confirmed in 24 individuals (2%) in central Brazil, an area where the main T. cruzi lineage circulating in humans is TcII. This low prevalence of congenital Chagas disease is discussed in relation to recent findings in the south region of Brazil, where TcV is the main lineage and congenital transmission has a higher prevalence (approximately 5%), similar to frequencies reported in Argentina, Paraguay and Bolivia. This is the first report to show geographical differences in the rates of congenital transmission of T. cruziand the relationship between the prevalence of congenital transmission and the type of Tc prevalent in each region.

Spatial analysis of the relationship between mortality from cardiovascular and cerebrovascular disease and drinking water hardness.

Previously published scientific papers have reported a negative correlation between drinking water hardness and cardiovascular mortality. Some ecologic and case-control studies suggest the protective effect of calcium and magnesium concentration in drinking water. In this article we present an analysis of this protective relationship in 538 municipalities of Comunidad Valenciana (Spain) from 1991-1998. We used the Spanish version of the Rapid Inquiry Facility (RIF) developed under the European Environment and Health Information System (EUROHEIS) research project. The strategy of analysis used in our study conforms to the exploratory nature of the RIF that is used as a tool to obtain quick and flexible insight into epidemiologic surveillance problems. This article describes the use of the RIF to explore possible associations between disease indicators and environmental factors. We used exposure analysis to assess the effect of both protective factors--calcium and magnesium--on mortality from cerebrovascular (ICD-9 430-438) and ischemic heart (ICD-9 410-414) diseases. This study provides statistical evidence of the relationship between mortality from cardiovascular diseases and hardness of drinking water. This relationship is stronger in cerebrovascular disease than in ischemic heart disease, is more pronounced for women than for men, and is more apparent with magnesium than with calcium concentration levels. Nevertheless, the protective nature of these two factors is not clearly established. Our results suggest the possibility of protectiveness but cannot be claimed as conclusive. The weak effects of these covariates make it difficult to separate them from the influence of socioeconomic and environmental factors. We have also performed disease mapping of standardized mortality ratios to detect clusters of municipalities with high risk. Further standardization by levels of calcium and magnesium in drinking water shows changes in the maps when we remove the effect of these covariates.

Experience and intermediate-term results using the Contegra heterograft for right ventricular outflow reconstruction in adults.

OBJECTIVES: The Contegra bioprosthesis (valved heterologous bovine jugular vein) is used for reconstruction of the right ventricular outflow tract (RVOT) in congenital heart malformations and pulmonary valve replacement in different settings. Compared to pulmonary homografts, the Contegra conduit is readily available 'on the shelf'. So far, its use was mainly described in children. The aim of this study is to evaluate the feasibility and the outcome of Contegra graft implantation in the adult. METHODS: Between November 1999 and December 2007, a total of 32 Contegra grafts were implanted in 31 patients (24 men and 7 women), with a mean age of 35.7+/-10.5 years (range 18-54 years). All operations have been completed through median sternotomy with cardiopulmonary bypass. Indications included: Ross procedure for aortic valve disease (n=22); re-operation of corrected Fallot-tetralogy (n=5); isolated pulmonary valve disease (n=2); re-operation of double outlet right ventricle (DORV) (n=1); pulmonary stenosis in congenital dilated cardiomyopathy (DCM) (n=1). Conduit sizes included 22 mm (n=31), 20 mm (n=1). RESULTS: There was no hospital mortality and no valved conduit related early morbidity. In the median follow-up of 38 months (range 1-99 months) of 28 patients there was one late death, not conduit related (total mortality 3.6%). Re-operation for symptomatic graft stenosis was realised in two patients, 7 and 16 months after primo-implantation, corresponding to graft related late morbidity of 7.1%. CONCLUSIONS: In this small review of 32 operations using the Contegra graft for RVOT reconstruction in adult cardiac surgery for different indications, we observed good postoperative mid-term results concerning conduit function. Mean transpulmonary pressure gradients remain low (13.3+/-6.6 mmHg postoperative, 14.5+/-7.9 mmHg at follow-up). The use of the Contegra graft seems to be a good alternative to the homograft with low operative mortality and morbidity. Long-term outcome data are not available and further investigations must be performed to evaluate results.

The Swiss registry for pulmonary arterial hypertension: the paediatric experience.

Pulmonary arterial hypertension is a rare disease with a poor prognosis. Epidemiological data are scarce, particularly in the paediatric population. A registry was recently developed in order to collect epidemiological data on patients with pulmonary arterial hypertension (PAH) in Switzerland. This is the first description of the paediatric data. Paediatric patients aged 0-18 years with the diagnosis of PAH were enrolled in the registry from 1999 to 2005 with informed consent from their parents. Patient characteristics, PAH aetiology, functional capacity, exercise capacity, treatments and outcome were among the most important data collected. A total of 23 patients (12 male, 11 female) have been thus far included in the registry. Median age at time of diagnosis was 3 years (range 1 month-18 years) and median follow-up was 3.47 years (range 1 day-12.6 years). PAH aetiologies are diagnosed as idiopathic in 8/23 patients (34.8%) and associated with congenital heart diseases in 12/23 (52.2%) or with pulmonary diseases in 3/23 patients (13.0%). Death occurred in 1 patient before treatment was initiated. Single treatments include medications with a calcium channel blocker in 2/23 patients, with bosentan in 10/23, and with inhaled iloprost in 1/23. Combined therapies include bosentan and inhaled iloprost in 7/23 patients, bosentan and sildenafil in 2/23 patients, and bosentan, sildenafil and inhaled iloprost in 2/23 patients. Additional oral anticoagulation is given to 14/23 patients and 8/23 patients are on oxygen therapy. NYHA class at baseline visit was obtained in 22/23 patients (4 NYHA 2, 17 NYHA 3 and 1 NYHA 4). Changes in NYHA class were observed over a 2-year period in 3/22 patients who improved from NYHA 3 to NYHA 2. Initial improvement of 6-minute walk distance was observed in 6/13 patients with a sustained improvement in 4. These preliminary results provide information on the epidemiology of PAH in children in Switzerland and demonstrate that most paediatric patients show stabilisation of the disease under new treatments. This underscores the utility of registries for rare diseases in providing crucial information in the era of new therapies. It may also help to improve the future medical approach.

Epidemiology of incident heart failure in a contemporary elderly cohort: the health, aging, and body composition study.

BACKGROUND: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. METHODS: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. RESULTS: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P < .001). CONCLUSIONS: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts.

Pilot licensing after aortic valve surgery.

Background and aim of the study: Bicuspid aortic valve is the most common congenital heart malformation, and a high percentage of patients with this condition will develop complications over time. It is rare that pilots undergo aortic valve surgery, and the confirmation of flight-licensing requirements after aortic valve replacement (AVR) is a challenge for the patient's cardiac surgeon and, particularly, for the Aeromedical Examiner (AME). Only AMEs are able to determine the flight status of pilots. Furthermore, in military and in civil aviation (e.g., Red Bull Air Race), the high G-load environment experienced by pilots is an exceptional physiological parameter, which must be considered postoperatively. Methods: A review was conducted of the aeronautical, surgical and medical literature, and of European pilot-licensing regulations. Case studies are also reported for two Swiss Air Force pilots. Results: According to European legislation, pilots can return to flight duty from the sixth postoperative month, with the following limitations: that an aortic bioprosthesis presents no restrictions in cardiac function, requires no cardioactive medications, yet requires a flight operation with co-pilot, the avoidance of accelerations over +3 Gz and, in military aviation, restricts the pilot to non-ejection-seat aircraft. The patient follow up must include both echocardiographic and rhythm assessments every six months. Mechanical prostheses cannot be certified because the required anticoagulation therapy is a disqualifying condition for pilot licensing. Conclusion: Pilot licensing after aortic valve surgery is possible, but with restrictions. The +Gz exposition is of concern in both military and civilian aviation (aerobatics). The choice of bioprosthesis type and size is determinant. Pericardial and stentless valves seem to show better flow characteristics under high-output conditions. Repetitive cardiological controls are mandatory for the early assessment of structural valve disease and rhythm disturbances. A pre-emptive timing is recommended when reoperation is indicated, without waiting for clinical manifestations of structural valve disease.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Sarcomeric M-band alterations as a marker for human dilated cardiomyopathy

Purpose: The M-band is an important cytoskeletal structure in the centre of the sarcomere, believed to cross-link the thick filament lattice. Its main components are three closely related modular proteins from the myomesin gene family: Myomesin, M-protein and myomesin-3. Each muscle is characterized by its unique M-band protein composition, depending on the contractile parameters of a particular fiber. To investigate the role of the M-band in one of the most relevant and clinically increasing cardiac diseases, we analyzed the expression of myomesin proteins in dilated cardiomyopathy (DCM).Methods: In a previous study we analyzed mouse models suffering from DCM, demonstrating that the embryonic heart specific EH-myomesin splicing isoform was up-regulated directly corresponding to the degree of cardiac dysfunction and ventricular dilation. Based on this study, human ventricular and atrial samples (n=32) were obtained during heart surgery after informed consent and approval by an institutional review board. Patients were aged 30-70 years and suffered from dilated cardiomyopathy (DCM;n=13), Hypertrophic Cardiomyopathy (HCM;n=10) or served as controls (n=9). Patients suffering from DCM or HCM were in endstage heart-failure (NYHA III-IV) and either underwent heart transplantation or Left Ventricular Assist Device (LVAD) implantation. Heart samples from patients who underwent valve surgery or congenital heart surgery served as controls. Heart Samples were analyzed using RT-PCR, Western blot, and immunofluorescence.Results: By investigating the expression pattern of myomesins, we found that DCM is accompanied by specific M-band alterations, which were more pronounced in ventricular samples compared to the atrium. Changes in the amounts of different myomesins during DCM occurred in a cell-specific manner, leading to a higher heterogeneity of the cytoskeleton in cardiomyocytes through the myocardial wall with some cells switching completely to an embryonic phenotype.Conclusions: Here we present that the embryonic heart specific EH-myomesin isoform is up-regulated in human DCM. The alterations of the M-band protein composition might be part of a general adaptation of the sarcomeric cytoskeleton to unfavorable working conditions in the failing heart and may modify the mechanical properties of the cardiomyocytes. We suggest that the upregulation of EH-myomesin might play a pivotal role in DCM and might support classical imagingas a novel sarcomeric marker for this disease.

Mortality associated with diabetes mellitus in comparison with history of cardiovascular disease in older women.

BACKGROUND: Women with diabetes mellitus have an increased risk of cardiovascular disease (CVD) mortality and current treatment guidelines consider diabetes to be equivalent to existing CVD, but few data exist about the relative importance of these risk factors for total and cause-specific mortality in older women. METHODS: We studied 9704 women aged ≥65 years enrolled in a prospective cohort study (Study of Osteoporotic Fractures) during a mean follow-up of 13 years and compared all-cause, CVD and coronary heart disease (CHD) mortality among non-diabetic women without and with a prior history of CVD at baseline and diabetic women without and with a prior history of CVD. Diabetes mellitus and prior CVD (history of angina, myocardial infarction or stroke) were defined as self-report of physician diagnoses. Cause of death was adjudicated from death certificates and medical records when available (>95% deaths confirmed). Ascertainment of vital status was 99% complete. Log-rank tests for the rates of death and multivariate Cox hazard models adjusted for age, smoking, physical activity, systolic blood pressure, waist girth and education were used to compare mortality among the four groups with non-diabetic women without CVD as the referent group. Results are reported as adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: At baseline mean age was 71.7±5.3 years, 7.0% reported diabetes mellitus and 14.5% reported prior CVD. 4257 women died during follow-up, 36.6% were attributed to CVD. The incidence of CVD death per 1000 person-years was 9.9 and 21.6 among non-diabetic women without and with CVD, respectively, and 23.8 and 33.3 among diabetic women without and with CVD, respectively. Compared to nondiabetic women without prior CVD, the risk of CVD mortality was elevated among both non-diabetic women with CVD (HR=1.82, CI: 1.60-2.07, P<0.001) and diabetic women without prior CVD (HR=2.24, CI: 1.87-2.69, P<0.001). CVD mortality was highest among diabetic women with CVD (HR=3.41, CI: 2.61-4.45, P<0.001). Compared to non-diabetic women with CVD, diabetic women without prior CVD had a significantly higher adjusted HR for total and CVD mortality (P<0.001 and P<0.05 respectively). CHD mortality did not differ significantly between non-diabetic women with CVD and diabetic women without prior CVD. CONCLUSION: Older diabetic women without prior CVD have a higher risk of all-cause and CVD mortality and a similar risk of CHD mortality compared to non-diabetic women with pre-existing CVD. For older women, these data support the equivalence of prior CVD and diabetes mellitus in current guidelines for the prevention of CVD.

Prevalence of vascular disease in systemic lupus erythematosus compared with type-1 diabetes mellitus: A cross-sectional study of two cohorts.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with considerable cardiovascular morbidity that has not yet been directly compared with other diseases with known cardiovascular risk. METHODS: Two hundred and forty-one patients of the multicentre Swiss SLE cohort study (SSCS) were cross-sectionally assessed for coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). SLE patients were compared with a cohort of 193 patients with type-1 diabetes mellitus being followed at the University Hospital Basel. A subgroup analysis of 50 age- and sex-matched patients from the University Hospital Basel was performed. RESULTS: Of patients within the SSCS 13.3% had one or more vascular events: 8.3% CHD, 5% CVD and 1.2% PAD. In type-1 diabetes mellitus patients, 15% had vascular events: 9.3% CHD, 3.1% CVD and 5.6% PAD. In the matched subgroup, 26% of SLE patients had vascular events (14% CHD) compared with 12% in type-1 DM patients (2% CHD). Cardiovascular risk factors were similar in both groups. Vascular events in SLE patients were associated with age, longer disease duration, dyslipidaemia, and hypertension. CONCLUSION: Cardiovascular morbidity in SLE is at least as frequent as in age- and sex-matched type-1 diabetes mellitus patients. Therefore, aggressive screening and management of cardiovascular risk factors should be performed.

Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.

RATIONALE: The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self-antigen-presenting cells and promotes autoreactive CD4(+) T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease. OBJECTIVE: The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure. METHODS AND RESULTS: Using alpha-myosin heavy chain peptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cell responses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure. CONCLUSIONS: Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.

Heart to Heart, March 2010

Heart to Heart is a publication on new heart disease and stroke information and other related topics by the Department of Public Health.