In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p -cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

UA (uric acid) is the final product of purine metabolism in humans and is implicated in many disease conditions. Sustained hyperuricaemia has putative adverse roles in cardiovascular diseases. Despite strong evidence emerging from large epidemiological studies supporting the hypothesis that UA independently influences cardiovascular disease outcomes and mortality, a causal role is yet to be established. Serum UA is also considered as a useful biomarker for mortality in high-risk patients with acute coronary syndromes, heart failure and hypertension and in patients with Type 2 diabetes mellitus. Post-hoc analyses of clinical trial data suggest beneficial effects of reducing serum UA. However, these findings are inconclusive and are only hypothesis-generating. In the present issue of Clinical Science , Ndrepepa and co-workers have investigated the prognostic role of UA in high-risk Type 2 diabetic patients with established coronary artery disease in predicting 1-year survival and cardiovascular mortality. These results support the independent role of serum UA in predicting survival in Type 2 diabetic patients. However, long-term follow-up studies are required with serial UA measurement to establish the time-dependent association of UA with mortality outcomes.

Studies investigating the prognostic role of UA (uric acid) in patients with Type 2 diabetes mellitus have given conflicting findings. We undertook the present study to assess the association between UA and outcome in patients with Type 2 diabetes mellitus and CAD (coronary artery disease). The study included 3705 patients with diabetes mellitus and angiography-proven CAD. UA was measured before coronary angiography. The primary outcome was 1-year all-cause mortality. The UA concentration [median (25th–75th quartiles)] was 6.44 mg/dl (5.40–7.70 mg/dl). There were 264 deaths (7.1%) during follow-up: 45 deaths in patients of the first UA quartile, 43 deaths in patients of the second UA quartile, 51 deaths in patients of the third UA quartile and 125 deaths in patients of the fourth UA quartile {Kaplan–Meier estimates of mortality, 5.1, 4.8, 5.6 and 14.0% respectively; unadjusted HR (hazard ratio), 2.81 [95% CI (confidence interval), 2.21–3.58]; P <0.001 for fourth quartile compared with first–third quartiles combined}. In the multivariable analysis, UA predicted all-cause mortality with an adjusted HR of 1.29 (95% CI, 1.12–1.48; P <0.001), for each S.D. increase in the logarithmic scale of UA level. The inclusion of UA in the multivariable model alongside known cardiovascular risk factors and other relevant variables increased the discriminatory power of the model regarding prediction of all-cause mortality [absolute and relative IDI (integrated discrimination improvement) 0.034 and 20.5% respectively; P <0.001]. In conclusion, in patients with Type 2 diabetes mellitus and confirmed CAD, elevated levels of UA predict mortality independently of known cardiovascular risk factors.

Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and glutathione depletion an observational study was performed. The results were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months. Plasma glutamine concentration and whole blood glutathione status at admittance were analysed. The admission plasma glutamine concentrations were totally independent of the conventional risk scoring at admittance, and a subnormal concentration was an independent predictor of mortality. In addition, glutathione redox status was also an independent mortality predictor, but here a normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation post-ICU should be evaluated prospectively.

Sepsis and the severe systemic response syndrome are very common illnesses that are responsible for a great amount of morbidity and death. These closely related conditions are characterized by a remarkable increase in the prohormone ProCT (procalcitonin). ProCT is both a marker of sepsis and a harmful mediator of the disease. In the present issue of Clinical Science , in a study in rats with endotoxin shock, Tavares and Miñano used an antibody to a segment of N-ProCT (aminoprocalcitonin) that is part of the ProCT molecule, and confirmed that immunoneutralization of ProCT saves the animals from this severe illness. Furthermore, they extensively studied the epiphenomena associated with this immunoneutralization.

Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin LPS (lipopolysaccharide) and pro-inflammatory cytokines, particularly TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β. Severity and mortality of sepsis have also been associated with high concentrations of N-PCT (aminoprocalcitonin), a 57-amino-acid neuroendocrine peptide derived from ProCT (procalcitonin). Previous studies in a lethal model of porcine polymicrobial sepsis have revealed that immunoneutralization with IgG that is reactive to porcine N-PCT significantly improves short-term survival. To explore further the pathophysiological role of N-PCT in sepsis, we developed an antibody raised against a highly conserved amino acid sequence of human N-PCT [N-PCT-(44–57)]. This sequence differs by only one amino acid from rat N-PCT. First, we demonstrated the specificity of this antibody in a well-proven model of anorexia induced in rats by central administration of human N-PCT-(1–57). Next we explored further the therapeutic potential of anti-N-PCT-(44–57) in a rat model of lethal endotoxaemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We show that this specific antibody inhibited the LPS-induced early release of TNF-α and IL-1β and increased survival, even if treatment began after the cytokine response had occurred. In addition, anti-N-PCT-(44–57) may increase long-term survival in LPS-treated rats by up-regulating the late production of counter-regulatory anti-inflammatory mediators such as ACTH (adrenocorticotropic hormone) and IL-10. In conclusion, these results support N-PCT as a pro-inflammatory factor in both the early and the late stages of lethal endotoxaemia, and suggest anti-N-PCT as a candidate for septic shock therapy.

AHF (acute heart failure) causes significant morbidity and mortality. Recent studies have postulated that the expression of inflammatory mediators, such as cytokines and chemokines, plays an important role in the development and progression of heart failure. A pro-inflammatory state has been postulated as a key factor in triggering CMV (cytomegalovirus) reactivation. Therefore we sought to determine the prevalence of active CMV infection in immunocompetent patients admitted for AHF and to quantify the association with the risk of the combined end point of death or AHF readmission. A total of 132 consecutive patients admitted for AHF were enrolled in the present study. Plasma CMV DNAaemia was assessed by qRT-PCR (quantitative real-time PCR), and cytokine measurements in plasma were performed by ELISA. Clinical data were evaluated by personnel blinded to CMV results. The independent association between active CMV infection and the end point was determined by Cox regression analysis. During a median follow-up of 120 [IQR (interquartile range), 60–240] days, 23 (17.4%) deaths, 34 (24.2%) readmissions for AHF and 45 (34.1%) deaths/readmissions for AHF were identified. Plasma CMV DNAaemia occurred in 11 (8.3%) patients, albeit at a low level (<100 copies/ml). The cumulative rate of the composite end point was higher in patients with CMV DNAaemia (81.8 compared with 29.8%; P <0.001). After adjusting for established risk factors, the occurrence of CMV DNAaemia was strongly associated with the clinical end point [hazard ratio = 4.39 (95% confidence interval, 2.02–9.52); P <0.001]. In conclusion, active CMV infection occurs, although uncommonly, in patients with AHF, and may be a marker of disease severity.

After a long debate, due to conflicting data from clinical studies, homocysteine is now largely accepted as a risk factor for cardiovascular diseases including stroke. To date, the role of elevated homocysteine levels in stroke recurrences has not been evaluated. In the present issue of Clinical Science , Zhang and co-workers prove that Chinese patients with high homocysteine levels have an increased risk of stroke recurrence and of all-cause mortality with respect to patients with lower levels. Remarkably, in their study, high homocysteine levels were associated with an increased risk of stroke recurrence for atherothrombotic stroke and intracerebral haemorrhage, but not lacunar stroke. The study by Zhang and co-workers provides important information for clinical practice and represents the basis for further investigations, as it raises questions referring to the puzzling relationship between homocysteine and cardiovascular disease. Moreover, the results support the hypothesis that, for undisclosed reasons, the relationship between homocysteine and cardiovascular disease may not be homogeneous for all the conditions encompassed in the category of cardiovascular disease, being peculiar for stroke patients. The finding of an association between high homocysteine levels and a risk of recurrent stroke or all-cause mortality in patients with intracerebral haemorrhage should be taken with caution until this same result is confirmed in other case series with different ethnicity.

Plasma homocysteine concentrations have been associated with the risk of stroke, but its relevance to secondary vascular events and mortality after stroke remains unclear because of inconsistent results from clinical trials. The aim of the present study was to investigate whether plasma homocysteine levels and the MTHFR (methylenetetrahydrofolate reductase) variant C677T contributed to the risk of stroke recurrence and all-cause mortality in a large prospective cohort of stroke patients in a Chinese population. A total of 1823 stroke patients (age, 35–74 years) were recruited during 2000–2001 and prospectively followed-up for a median of 4.5 years. During the follow-up, 347 recurrent strokes and 323 deaths from all-causes were documented. After adjustment for age, gender and other cardiovascular risk factors, a high homocysteine concentration was associated with an increased risk of 1.74-fold for stroke recurrence {RR (relative risk), 1.74 [95% CI (confidence interval), 1.3–2.3]; P <0.0001} and 1.75-fold for all-cause mortality [RR, 1.75 (95% CI, 1.3–2.4); P <0.0001] when highest and lowest categories were compared. Spline regression analyses revealed a threshold level of homocysteine for stroke recurrence. By dichotomizing homocysteine concentrations, the RRs were 1.31 (95% CI, 1.10–1.61; P =0.016) for stroke recurrence and 1.47 (95% CI, 1.15–1.88; P <0.0001) for all-cause mortality in patients with homocysteine levels ≥16 μmol/l relative to those with levels <16 μmol/l. The association of elevated plasma homocysteine concentrations with all-cause mortality was mainly due to an increased risk of cardiovascular deaths. No significant association was found between MTHFR C677T and stroke recurrence or mortality. In conclusion, our findings suggest that elevated homocysteine concentrations can predict the risk of stroke recurrence and mortality in patients with stroke.

The efficacy of CRT (cardiac resynchronization therapy) can be affected by a number of factors; however, the prognostic significance of the LV (left ventricular) lead position has not been explored. The aim of the present study was to examine whether a PL (posterolateral) lead position has an additional value to systolic dyssynchrony in predicting a better survival after CRT. Patients ( n =134) who received CRT were followed-up for 39±24 months. The LV lead position was determined by cine fluoroscopy, and baseline dyssynchrony was assessed by TDI (tissue Doppler imaging). The relationship between the LV lead position/dyssynchrony and mortality was compared using Kaplan–Meier curves, followed by Cox regression analysis. The all-cause and cardiovascular mortalities were 38 and 31% respectively. The presence of dyssynchrony and a PL lead position predicted a lower all-cause mortality (29 compared with 47%; log-rank χ 2 =5.38, P =0.02) and cardiovascular mortality (21 compared with 41%; log-rank χ 2 =6.75, P =0.009) than when absent. The all-cause mortality was as high as 62% when patients had neither dyssynchrony nor a PL lead position, but was reduced to 29% when both criteria were present, and was between 45 and 46% when only one criterion was present (χ 2 =6.79, P =0.01). The corresponding values for cardiovascular mortality were 62% when patients had neither dyssynchrony nor a PL lead position, 36–38% when patients had either dyssynchrony or a PL lead position, and 21% when patients had both criteria present (χ 2 =9.54, P =0.004). Combining dyssynchrony and a PL lead position independently predicted a lower all-cause morality {HR (hazard ratio), 0.496 [95% CI (confidence interval), 0.278–0.888]; P =0.018} and cardiovascular mortality [HR, 0.442 (95% CI, 0.232–0.844); P =0.013]. In conclusion, the placement of the LV lead at a PL position provides additional value to baseline dyssynchrony in predicting a lower all-cause and cardiovascular mortality during long-term follow-up after CRT.

Although an association between elevated leucocyte count and mortality in patients with ACS (acute coronary syndromes) has been established, the independence of this association from coronary risk factors and C-reactive protein has been inadequately studied. In the present study, this prospective registry included 4329 patients with ACS treated with PCI (percutaneous coronary intervention): 1059 patients with STEMI [ST-segment elevation MI (myocardial infarction)], 1753 patients with NSTEMI (non-STEMI) and 1517 patients with unstable angina. Blood samples were obtained before angiography for leucocyte count and C-reactive protein measurements. The primary outcome of this analysis was 1-year mortality. At 1 year, 345 patients (8%) had died: 45 patients in the 1st tertile, 93 patients in the 2nd tertile and 207 patients in the 3rd tertile of leucocyte count [Kaplan–Meier estimates of mortality, 3.2%, 6.4% and 14.1% with an OR (odds ratio)=2.42, 95% CI (confidence interval)1.78–3.12; P <0.001 for tertile 3 compared with tertile 2 and an OR=1.99, 95% CI 1.77–2.25; P <0.001 for tertile 2 compared with tertile 1]. The Cox proportional hazards model adjusting for coronary risk factors, ACS presentation, extent of coronary artery disease, C-reactive protein and other covariates identified leucocyte count with a HR (hazard ratio)=1.05 (95% CI 1.02–1.07; P <0.001 for 1000 cells/mm 3 increase in the leucocyte count), but not C-reactive protein (HR=1.13, 95% CI 0.95–1.34; P =0.15 for a 1 tertile increase in the C-reactive protein concentration) as an independent correlate of 1-year mortality. We conclude that elevated leucocyte count, but not C-reactive protein, predicts 1-year mortality independent of cardiovascular risk factors across the entire spectrum of patients with ACS treated with PCI.

HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) are well-established therapies in the prevention and treatment of cardiovascular disease, reducing all-cause mortality and cardiovascular events in many disease states. Studies have also suggested that statins given to patients after myocardial infarction improve event-free survival even in short time frames; however, evidence for the benefit of statins in established HF (heart failure) has not been demonstrated with the same rigour of a randomized clinical trial setting. In fact, clinical data examining the effect of statins in HF have been limited by the retrospective or observational nature of these analyses, examination of incompletely validated surrogate end points, small prospective studies in subgroups of HF subjects, and non-uniform doses and different statins being used. In this review, we examine the evidence for the effect of statins on mortality in HF, taking into account theoretical arguments, appropriateness of surrogate markers, animal data and analysis of the predominantly retrospective clinical data that is currently available.

In the present study, we investigated the potential of N-BNP (N-terminal B-type natriuretic peptide) as a prognostic marker for risk of CV (cardiovascular) events, overall mortality and progression to ESRD (end-stage renal disease) in a cohort of 83 pre-dialysis CKD (chronic kidney disease) patients without clinical evidence of heart failure. During the study, ten patients reached the combined end point of overall mortality and/or CV event. Univariate factors associated with the combined end point were plasma N-BNP ( P <0.0005), creatinine ( P <0.002), systolic blood pressure ( P <0.009) and age ( P <0.015). N-BNP levels were higher in patients with CV events ( P <0.0005). Cox model regression analysis yielded log 10 N-BNP (hazard ratio, 9.608; P <0.007) and pre-existing CV disease (hazard ratio, 4.571; P <0.029) as independent predictors of overall mortality or CV events. Kaplan–Meier analysis curves for the subgroup with supramedian creatinine levels (225 μmol/l) showed significant separation of the curves stratified for plasma N-BNP levels above and below the group median (291 pmol/l) for all end points. Receiver-operator-characteristic curves for N-BNP (355 pmol/l cut-off) demonstrated a specificity of 65.8% at a sensitivity of 100% for predicting CV events/overall mortality. The measurement of plasma N-BNP may aid in the risk stratification of pre-dialysis CKD patients. The high sensitivity and negative predictive value (100%) may enable the selection of patients who could safely be excluded from further investigations, resulting in better focusing of resources.

Patients with end-stage renal disease show disturbances of calcium metabolism, including calcification of arterial walls. Such patients show increased mortality, in particular due to increased cardiovascular-associated deaths. The association of calcium channel blockers and mortality in patients undergoing haemodialysis was investigated. A total of 188 patients who were receiving haemodialysis as of July 1998 were followed up for 30 months. Baseline characteristics, including age, sex, laboratory and clinical data, medication and dialysis prescription, were obtained. As of December 2000, 51 of the patients (27%) had died. In the deceased group, age was significantly higher, body mass index was significantly lower, and smoking was significantly more frequent compared with the survival group (each P <0.001). The percentage of patients taking calcium channel blockers was significantly higher in the survival group. Cox proportional hazard regression analysis showed that haemodialysis patients assigned calcium channel blocker therapy had a significantly lower risk of mortality [relative risk 0.33 (95% confidence interval 0.17–0.67); P <0.001]. Thus, in haemodialysis patients who were at high risk of cardiovascular events, administration of calcium channel blockers was associated with lower mortality.

1. This study includes 1038 patients (325 men and 713 women) who consulted the medical out-patient clinic, Rigshospitalet, Copenhagen, during the years 1932–38. All these patients had a blood pressure of 160/100 mmHg or 180 mmHg or more. 2. The average age at the first examination was 54 years; 97% were followed at intervals of 10 years until 1975, when sixty patients were still alive. Treatment was minimal until 1970. 3. Sixty per cent of the men and 76% of the women reached an age of 65 years or more. Nine per cent of the total patients lived to 85 years or more. Excess mortality was far higher in men than in women. 4. Causes of death were stroke in 17%, heart failure in 24%, coronary occlusion in 16%, uraemia in 4% and other diseases in 39%. At the first examination thirteen cases of malignant hypertension were registered, none at later sessions.

1. The National Blood Pressure Study (NBPS) is a single blind trial designed to test the efficacy of active drug treatment in reducing complications from mild hypertension (mean diastolic pressure = 95–109 mmHg). 2. Between 1973 and 1975, four centres screened about 104 000 subjects aged 30–69 years, yielding an estimated prevalence of hypertension (≥95 mmHg diastolic) of 16% and of moderate-to-severe hypertension (≥110 mmHg diastolic) of 1·3%. 3. Some 4000 subjects selected for untreated uncomplicated mild hypertension were randomized to either active treatment (chlorothiazide + α-methyldopa and/or a β-adrenoreceptor antagonist as required) or to matching placebos. 4. At 1 year mean pressures had fallen significantly below entry pressures in both groups but in the active group the fall was greater by a margin of 14·4±1·3 (sem) mmHg systolic and 71 ±0·7 mmHg diastolic. At 1 year 5% of subjects in the placebo group had been placed on active treatment on the ethical grounds that pressure had exceeded the mild hypertension limit. 5. Trial end-points (death, morbidity from stroke, hypertensive heart and renal disease, and ischaemic heart disease) number 106 (nine deaths) thus far, of which ischaemic heart disease accounts for 71% and stroke 19%. 6. The duration of trial may need to be extended beyond the original estimate of 5 years.

1. During the years 1968–69 a population study of 1462 women aged 38–60 years was carried out in Göteborg, Sweden. A total of 126 women were classified as hypertensive. 2. Hypertensive women reported a history of albuminuria and hypertension during pregnancy more often than women in the general population. Albuminuria, alterations of the eye-ground vessels and ECG changes indicating left ventricular strain were more often found in hypertensive women. Hypertensive women were on average heavier. 3. The same population sample was re-studied 6 years later. Two of the 126 women classified as hypertensive had died during the 6 years interval since the first examination, both from myocardial infarction. The death rate was similar to the population sample as a whole.

1. The organization of a multi-centre randomized therapeutic trial for mild hypertension is described. 2. Particular attention will be paid to the effect of blood pressure lowering on susceptibility to myocardial infarction. 3. It is calculated that screening of around 180 000 subjects will be required, and that approx. 9000 men and 9000 women will eventually enter the treated group, and a similar number be randomly allocated to the control group. 4. Two separate hypotensive drugs, with different modes of action, will be employed in the treated group.