James Hobkirk

Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure

AIMS The epidemiology of pulmonary arterial hypertension (PAH) in patients with heart failure (HF) is poorly described. Our aim was to investigate the determinants and prognostic significance of PAH in a large representative outpatient population with HF. METHODS AND RESULTS Routine measurement of right ventricular tricuspid pressure gradient (RVTG) was attempted among unselected, consecutive referrals to an HF clinic. The diagnosis of HF was based on symptoms, signs, echocardiography, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Of 2100 patients referred, 1380 were diagnosed as HF, of whom 1026 had left ventricular systolic dysfunction (LVSD) and 354 did not. Right ventricular tricuspid pressure gradient could be measured in 270 (26%) patients with and 143 (40%) without LVSD. The highest RVTG quartile [RVTG > 35 mmHg equivalent to an estimated PA systolic pressure (PASP) > 45 mmHg] constituted 7% of all those with HF and was associated with higher LV filling pressures, LV end-diastolic volume, LVSD, and more severe mitral regurgitation (MR). During a median (inter-quartile range) follow-up of 66 (56-74) months, mortality was 40.3%. Mortality was similar in the lowest quartile of RVTG and in those in whom RVTG could not be measured and rose with increasing RVTG quartile (log-rank: 26.9; P < 0.0001). The highest RVTG quartile, age, blood pressure, and log NT-proBNP independently predicted mortality. Right ventricular tricuspid pressure gradient >35 mmHg had a 96% specificity to discriminate between those with and without HF in patients without LVSD. CONCLUSION Using a definition of PASP > 45 mmHg, 7% of the patients with HF have PAH, which is associated with worse LV function, MR, and prognosis. Whether PAH is a target for therapy in this population remains to be elucidated.

Does the physical examination still have a role in patients with suspected heart failure

The prognostic value of signs of congestion in patients suspected of having chronic heart failure (CHF) is unknown. Our objectives were to define their prevalence and specificity in diagnosing CHF and to determine their prognostic value in patients in a community heart failure clinic.

Effects of reducing inspired oxygen concentration for one hour in patients with chronic heart failure: implications for air travel.

The objective of this study was to establish the acute effects of hypoxia on clinical, spirometric, haemodynamic, and echocardiographic variables. Reducing inspired oxygen to 15%, as experienced during commercial air travel, decreases arterial oxygen saturation, increases respiratory rate and pulmonary artery pressure in healthy subjects. The effect on patients with chronic heart failure is unknown.

The metabolic inter-relationships between changes in waist circumference, triglycerides, insulin sensitivity and small, dense low-density lipoprotein particles with acute weight loss in clinically obese children and adolescents

Small, dense LDL is highly atherogenic and the prevalence is higher in obesity. Weight loss lowers the prevalence of small, dense LDL.

The Predictive Ability of Triglycerides and Waist (Hypertriglyceridemic Waist) in Assessing Metabolic Triad Change in Obese Children and Adolescents

BACKGROUND The metabolic triad [fasting insulin, apolipoprotein B, and low-density lipoporotein (LDL) peak particle density] is characteristic of increased intra-abdominal adipose tissue and insulin resistance and can be predicted by the simple and adoptable screening tool, the hypertriglyceridemic waist. The associations between hypertriglyceridemic waist components [fasting triglycerides (TG) and waist circumference cut-points derived from a child-specific metabolic syndrome definition] with the metabolic triad were examined in obese youth before and after weight loss. METHODS A continuous metabolic triad score (MTS) was calculated as a cumulative and standardized residual score of fasting insulin, apolipoprotein B, and LDL peak particle density (z-scores of the metabolic triad variables regressed onto age and sex). The predictive ability of TG and waist in assessing metabolic triad change was undertaken in 75 clinically obese boys and girls, aged 8-18, body mass index (BMI) 34.2±6.4 kg/m(2) before and after weight loss. RESULTS Fasting TG concentrations (r(2)=0.216, P<0.0001) and waist circumference (r(2)=0.049, P=0.019) were both significant independent predictors of the cumulative MTS, together accounting for 26.5% of its total variance. All cardiometabolic risk factors [except a reduction in high-density lipoprotein cholesterol (HDL-C)] were favorably modified following weight loss. Fasting TG change was the only significant predictor of the MTS change (r(2)=0.177, P<0.0001). Waist circumference was not a significant predictor of MTS change. CONCLUSION The reduction in fasting TG concentration (but not waist circumference) was the only significant predictor of MTS change. Fasting TG may be the most important metabolic syndrome component to best characterize the metabolic heterogeneity in obese cohorts and the changes in metabolic risk in clinically obese youth.

On the Functional Overlap between Complement and Anti-Microbial Peptides

Intriguingly, activated complement and anti-microbial peptides share certain functionalities; lytic, phagocytic, and chemo-attractant activities and each may, in addition, exert cell instructive roles. Each has been shown to have distinct LPS detoxifying activity and may play a role in the development of endotoxin tolerance. In search of the origin of complement, a functional homolog of complement C3 involved in opsonization has been identified in horseshoe crabs. Horseshoe crabs possess anti-microbial peptides able to bind to acyl chains or phosphate groups/saccharides of endotoxin, LPS. Complement activity as a whole is detectable in marine invertebrates. These are also a source of anti-microbial peptides with potential pharmaceutical applicability. Investigating the locality for the production of complement pathway proteins and their role in modulating cellular immune responses are emerging fields. The significance of local synthesis of complement components is becoming clearer from in vivo studies of parenchymatous disease involving specifically generated, complement-deficient mouse lines. Complement C3 is a central component of complement activation. Its provision by cells of the myeloid lineage varies. Their effector functions in turn are increased in the presence of anti-microbial peptides. This may point to a potentiating range of activities, which should serve the maintenance of health but may also cause disease. Because of the therapeutic implications, this review will consider closely studies dealing with complement activation and anti-microbial peptide activity in acute inflammation (e.g., dialysis-related peritonitis, appendicitis, and ischemia).

In vitro Modulation of the LPS-Induced Proinflammatory Profile of Hepatocytes and Macrophages- Approaches for Intervention in Obesity?

Low grade endotoxemia is a feature of obesity which is linked to development of steatohepatitis in non-alcoholic fatty liver disease. In this study, macrophages (J774) and hepatocytes (HepG2) were stimulated with lipopolysaccharide (LPS) from E. coli 0111: B4 and analyzed for modulation of this response when preconditioned or stimulated subsequent to LPS, with different doses of Vitamin D3 or docosahexaenoic acid (DHA) over a time period of 1 and 5 days. Pro-inflammatory TNFα and pro-fibrotic TGFβ released into the supernatants were measured by ELISA; qPCR was performed for Srebp-1c and PPARα mRNA (genes for products involved in fatty acid synthesis and catabolism, respectively). Vitamin D3 and DHA exerted a consistent, dose dependent anti-inflammatory effect, and increased PPARα relative to Srebp-1c in both cell types. By contrast, addition of free fatty acids (FFA, oleic acid/palmitic acid 2:1) caused aggravation of LPS-induced inflammatory reaction and an increase of Srebp-1c relative to PPARα. Our results argue in favor of dietary supplementation of Vitamin D3 or DHA (and avoidance of monounsaturated/saturated fatty acids) to alleviate development of fatty liver disease.

Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure

Background: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafils acute cardiovascular effects. Methods and Results: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (−1 ± 2%; P = 0.043), systemic vascular resistance (−87 ± 156 dyn·s−1·cm−2; P = 0.034), and RVTG (−2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. Conclusions: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation–perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

Vitamin D3 supplementation of a high fat high sugar diet ameliorates prediabetic phenotype in female LDLR(-/-) and LDLR(+/+) mice.

Fatty liver disease is prevalent in populations with high caloric intake. Nutritherapeutic approaches are being considered, such as supplementary Vitamin D3, to improve aspects of metabolic syndrome, namely fatty liver disease, hyperlipidemia, and insulin resistance associated with obesity.

015 PROGNOSTIC SIGNIFICANCE OF PLASMA CONCENTRATIONS OF PROCALCITONIN IN PATIENTS WITH SUSPECTED HEART FAILURE

Background Heart failure is associated with an increase in plasma concentrations of markers of inflammation and fibrosis. Some have hypothesised that this may reflect absorption of endotoxins from gut bacteria or bacterial translocation into the gut wall. This might provoke an increase in markers of infection, such as procalcitonin (PCT). Methods Patients with suspected heart failure referred from the local community to a specialist clinic were invited to participate. Consenting patients underwent a systematic evaluation including prior medical history, medications, symptoms, signs, electro- and echocardiograms, standard haematology and biochemistry profiles and measurement of PCT and amino-terminal pro-brain natriuretic peptide (NT-proBNP). Results Of 1891 patients enrolled, the median age was 72 years (IQR 64–78), 669 were women, 807 had left ventricular systolic dysfunction (LVSD), 400 had no major echocardiographic abnormalities other than LVSD, 192 had no major echo abnormality but an NT-proBNP >400 ng/l (of whom 65 had atrial fibrillation and 15 had eGFR <30 ml/min) and 492 had none of the above. Median (IQR) PCT overall was 22(17–47) pg/ml and for each of the four sub-groups was 23(18–32), 22(17–31), 24(19–35) and 20(16–25)pg/ml respectively. Of patients with LVSD, 698 had a second blood sample taken after 12 months follow-up. Paired values in this subset were 22(18–29) pg/ml at baseline and 22(17–29) pg/ml at follow-up. The correlation coefficient between log(PCT) at baseline and follow-up is r=0.63; p<0.0001, suggesting relatively stable concentrations over time. Over a median follow-up of 5.0 (IQR 3.4–7.1) years, 783 patients died, 447 of cardiovascular causes. In univariable analysis, log(PCT) was strongly related to all-cause, cardiovascular and non-cardiovascular mortality (HR 1.91 with 95% CI (1.73 to 2.11), HR 1.94 (1.71–2.21) and HR1.89 (1.61–2.22) respectively, p<0.001 for all). In a multi-variable Cox regression model, PCT provided additional prognostic information to 17 standard clinical variables (age, sex, aetiology, diabetes, COPD, symptoms, quality of life, NYHA, BMI, heart rate and rhythm, systolic blood pressure, oedema, severity of ventricular dysfunction, haemoglobin and creatinine and NT-proBNP) for all-cause mortality. Conclusions PCT is similarly elevated in all heart failure phenotypes studied and adds prognostic information to standard variables. Whether it is just a marker of risk or sits on an important pathway driving the progression of heart failure awaits further study.