Hemodynamic Evaluation of Nonselective \u3b2-Blockers in Patients with Cirrhosis and Refractory Ascites

BACKGROUND:Nonselective \u3b2-blockers (NSBB) have been associated with increased incidence of paracentesis-induced circulatory dysfunction (PICD) and reduced survival in patients with cirrhosis and refractory ascites. AIM:To prospectively evaluate a hemodynamic response to NSBB in cirrhotics listed for liver transplantation with refractory ascites undergoing large volume paracentesis (LVP). METHODS:Patients with cirrhosis and refractory ascites, with an indication to start NSBB in primary prophylaxis for variceal bleeding, were enrolled. During two consecutive LVP, while being, respectively, off and on NSBB, cardiac output (CO), systemic vascular resistances (SVR), peripheral vascular resistances (PVR), and plasma renin activity (PRA) were noninvasively assessed. RESULTS:Seventeen patients were enrolled, and 10 completed the study. Before NSBB introduction, SVR (1896 to 1348\u2009dyn\ub7s\ub7cm-5; p = 0.028) and PVR (47 to 30\u2009mmHg\ub7min\ub7dl\ub7ml-1; p = 0.04) significantly decreased after LVP, while CO showed an increasing trend (3.9 to 4.5\u2009l/m; p = 0.06). After NSBB introduction, LVP was not associated with a significant increase in CO (3.4 to 3.8\u2009l/m; p = 0.13) nor with a significant decrease in SVR (2002 versus 1798\u2009dyn\ub7s\ub7cm-5; p = 0.1). Incidence of PICD was not increased after NSBB introduction. CONCLUSION:The negative inotropic effect of NSBB was counterbalanced by a smaller decrease of vascular resistances after LVP, probably due to splanchnic \u3b22-blockade. This pilot study showed that NSBB introduction may be void of detrimental hemodynamic effects after LVP in cirrhotics with refractory ascites

Serum uric acid and left ventricular mass index independently predict cardiovascular mortality: The uric acid right for heart health (URRAH) project

UNLABELLED A relationship between serum uric acid (SUA) and cardiovascular (CV) events has been documented in the Uric Acid Right for Heart Health (URRAH) study. AIM of this study was to investigate the association between SUA and left ventricular mass index (LVMI) and whether SUA and LVMI or their combination may predict the incidence of CV death. METHODS Subjects with echocardiographic measurement of LVMI included in the URRAH study (n=10733) were part of this analysis. LV hypertrophy (LVH) was defined as LVMI > 95 g/m2 in women and 115 g/m2 in men. RESULTS A significant association between SUA and LVMI was observed in multiple regression analysis in men: beta 0,095, F 5.47, P 5.6 mg/dl in men and 5.1 mg/dl in women) and LVH (log-rank chi-square 298.105; P<0.0001). At multivariate Cox regression analysis in women LVH alone and the combination of higher SUA and LVH but not hyperuricemia alone, were associated with a higher risk of CV death, while in men hyperuricemia without LVH, LVH without hyperuricemia and their combination were all associated with a higher incidence of CV death. CONCLUSIONS Our findings demonstrate that SUA is independently associated with LVMI and suggest that the combination of hyperuricemia with LVH is an independent and powerful predictor for CV death both in men and women

Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds

BACKGROUND: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. METHODS: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). RESULTS: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. CONCLUSIONS: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%

Serum uric acid and left ventricular mass index independently predict cardiovascular mortality: The uric acid right for heart health (URRAH) project

A relationship between serum uric acid (SUA) and cardiovascular (CV) events has been documented in the Uric Acid Right for Heart Health (URRAH) study. Aim: of this study was to investigate the association between SUA and left ventricular mass index (LVMI) and whether SUA and LVMI or their combination may predict the incidence of CV death. Methods: Subjects with echocardiographic measurement of LVMI included in the URRAH study (n=10733) were part of this analysis. LV hypertrophy (LVH) was defined as LVMI > 95 g/m2 in women and 115 g/m2 in men. Results: A significant association between SUA and LVMI was observed in multiple regression analysis in men: beta 0,095, F 5.47, P 5.6 mg/dl in men and 5.1 mg/dl in women) and LVH (log-rank chi-square 298.105; P<0.0001). At multivariate Cox regression analysis in women LVH alone and the combination of higher SUA and LVH but not hyperuricemia alone, were associated with a higher risk of CV death, while in men hyperuricemia without LVH, LVH without hyperuricemia and their combination were all associated with a higher incidence of CV death. Conclusions: Our findings demonstrate that SUA is independently associated with LVMI and suggest that the combination of hyperuricemia with LVH is an independent and powerful predictor for CV death both in men and women

Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study

High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mortality (CVM) were explored by the Kaplan-Meier estimator and Cox multivariable regression, adopting recently defined SUA cut-offs for ACM (&gt;= 4.7 mg/dL) and CVM (&gt;= 5.6 mg/dL). Exploratory analysis across cardiometabolic subgroups and a sensitivity analysis using SUA/serum creatinine were performed as validation. SUA predicted ACM (HR 1.25 [1.12-1.40], p &lt; 0.001) and CVM (1.31 [1.11-1.74], p &lt; 0.001) in the whole study population, and according to TG strata: ACM in normotriglyceridemia (HR 1.26 [1.12-1.43], p &lt; 0.001) and hypertriglyceridemia (1.31 [1.02-1.68], p = 0.033), and CVM in normotriglyceridemia (HR 1.46 [1.23-1.73], p &lt; 0.001) and hypertriglyceridemia (HR 1.31 [0.99-1.64], p = 0.060). Exploratory and sensitivity analyses confirmed our findings, suggesting a substantial role of SUA in normotriglyceridemia and hypertriglyceridemia. In conclusion, we report that SUA can predict ACM and CVM in cardiometabolic patients without established cardiovascular disease, independent of TG levels

World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

BACKGROUND: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. METHODS: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. FINDINGS: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629-0·741) to 0·833 (0·783-0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. INTERPRETATION: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. FUNDING: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research

Blood pressure and metabolic phenotypes in relation to SAH gene variants and ADRB1 Arg389Gly and ADRAB2 I/D polymorphisms in white family-based population samples

Objectives: Aim of the present doctoral dissertation is independent confirmation in family-based population samples, using strict appropriate statistical approach, of the associations, if any, between blood pressure (BP) and related metabolic phenotypes, analysed as continuous traits, and variations in candidate genes arising from experimental animal models [Spontaneously hypertensive rat-clone A-Hypertension-associated (SAH) gene], and from physiological cascades of the adrenergic system [alfa2B- (ADRAB2) and beta1- (ADRB1) adrenergic receptors]. Methods and Results: The SAH gene variants were evaluated in the frame of the European Project On Genes in Hypertension. In details, 2603 relatives from 560 families and 31 unrelated subjects (mean age 38.8?15.7 years; 52.1% women) were randomly recruited from six European populations. Systolic/diastolic BP, body mass index, triceps skinfold, waist-to-hip ratio, serum total and HDL cholesterol, serum triglycerides and blood glucose were measured. All subjects were genotyped for the G-1606A and -962 del/ins polymorphisms and the allele frequencies were 11.8% and 29.5% for -1606A and -962del, respectively. Lewontin’s D’ was 0.97 (p<0.0001). Haplotype frequencies were 58.8% for -1606G plus -962ins, 29.5% for -1606G plus -962del, and 11.7% for -1606A plus -962ins. Both before and after adjustment for covariates, none of the phenotype-genotype associations approached statistical significance. Family-based analyses did not reveal any population stratification (P?0.67) as a possible explanation of those negative results. The association studies between ADRB1 Arg389Gly and ADRA2B I/D polymorphisms of the beta1- and alfa2B-adrenergic receptors with BP and metabolic phenotypes, were conducted in a subsample of the EPOGH cohort. 1802 relatives from 175 families and 79 unrelated subjects (mean age 45.5?15.7 years; 51.1% women) were randomly recruited from a Caucasian population living in Northern Belgium. Systolic/diastolic BP, body mass index, waist-to-hip ratio, serum total and HDL cholesterol were measured. All subjects were genotyped for the ADRA2B I/D and ADRB1 Arg389Gly polymorphisms. The ADRA2B genotypes (II 45.7%, ID 41.7%, and DD 12.5%; P=0.05) and the ADRB1 genotypes (ArgArg 56.2%, ArgGly 36.9%, and GlyGly 6.9%; P=0.66) did not deviate from Hardy–Weinberg proportions. ADRB1 ArgArg homozygotes, compared with Gly allele carriers, had higher diastolic BP (79.4 vs 78.4 mmHg; P=0.012), and higher serum HDL cholesterol (1.33 vs 1.29 mmol/l; P=0.020). None of the other cardiovascular or metabolic phenotypes in relation to the two polymorphisms reached significance. The family-based analyses did not reveal population stratification (P?0.23). Conclusions: The present study gives evidence in favour of association of diastolic BP and HDL cholesterol with the ADRB1 Arg389Gly polymorphism in the absence of population stratification. However, the evidences supporting association of hypertension or hypertension-related phenotypes with the SAH gene remain equivocal in human studies

Metabolic syndrome: nothing more than a constellation?

In these last years, the scientific community made a considerable effort to understand the biology underlying cardiovascular disease (CVD), the major cause of morbidity and mortality in the developed world. From the very beginning it became apparent that several CVD risk factors were present in the same individual, and the concept of clustering risk factors was finally labelled in the 1980s by Reaven as \u2018Syndrome X\u2019. This author postulated that a set of metabolic and cardiovascular risk factors\u2014such as hypertension, hypertriglyceridaemia, low high-density lipoprotein (HDL)-cholesterol levels, and hyperinsulinaemia\u2014could have a common aetiology based on insulin resistance, this latter also playing per se a pivotal role on pathophysiology of CVD. Since then, several other features were taken into account to build the so-called \u2018metabolic syndrome\u2019 (MetS). The first operational definition of MetS was proposed in 1999 by the World Health Organization (WHO), with hyperglycaemia and/or insulin resistance as a central feature and other greater than or equal to two related abnormalities (hypertension, dyslipidaemia, central obesity, or microalbuminuria). In 2001, the National Cholesterol Education Program (NCEP) proposed a new definition of MetS, no longer requiring glucose impairment but rather treating glucose metabolism as of equal importance with the other components. Three over five criteria were sufficient, and no one mandatory. Up to date, six different definitions of MetS exist as described by Wang et al.4 in Table 1 which this editorial refers to. All include the same core criteria of central obesity, hyperglycaemia, dyslipidaemia, and hypertension, but differ as for cut-off, mandatory requirements (central obesity or insulin resistance) and inclusion of additional factors (e.g. microalbuminuria). As a consequence of uncertain criteria, a heated debate about MetS as fact or fiction came to the limelight.5Coexistence of many definitions leads to the feeling that MetS is nothing more than a container, where different criteria are clustered time-to-time. Not only, but such definitions even proceed from the activity of panels of experts, rather than from prospective epidemiological evidence, and are therefore arbitrary.6 Finally, it is quite difficult to compare the data published in the overabundance of studies, where different definitions have been used and different genetic background, lifestyle, and age were considered. The paper by Wang et al. has the merit to compare in the same non-diabetic population the prevalence of MetS coming from all the six current definitions. Their analysis demonstrates that each definition arbitrarily excludes subjects that are arbitrarily included in another one, so that the different sets of people are not congruent. MetS has increased in arbitrariness when in 2001 the NCEP decided to leave the glucocentric view that was the cornerstone of the previous criteria. Once left out any sine qua non criterion, the natural consequence was a certain degree of relativism, with all criteria rising to the same rank. The paper by Wang et al.4 simply originates from this deal. The decision to cluster equipollent criteria into a constellation called MetS is the concrete answer of epidemiologists to the wish of predicting outcome. The rational of this clustering is that subjects with more than two criteria should show higher cardiovascular mortality/morbidity than those having only two or one criteria. Unfortunately, the Wang\u2019s paper4 demonstrates this is not the case, as the predictive power of the constellation is shown not to be higher than that of its major components. Considering MetS as a risk predictor has therefore the meaningfulness of a fiction. We must be aware that, if one single criterion has the same prognostic value than greater than or equal to three aggregated criteria, using MetS is nothing more than a diversion of resources. Why does not the aggregation work better than single covariables? At a superficial analysis this is a little surprising. This phenomenon is probably due to the fact that, as already mentioned above, aggregation leads to restriction of the field of interest, with loss of subjects and increasing specificity to the detriment of sensitivity (excess false negatives). When we base the diagnosis on greater tha or equal to three criteria and we employ this definition for calculating relative risk, we actually compare subjects at very high risk (those having MetS) with a sub-population at low-to-intermediate-to-high risk represented by those having 0, 1, or 2 criteria considered as a whole. It is obvious that the relative risk of this subpopulation is more than one, thus reducing the power of the predictive analysis. Wang et al. took into consideration an elderly population, so stressing that in particular cohorts some criteria probably become too inclusive, creating problems. For example, as in western society, blood pressure increases with growing old while the \u2018130/85\u2019 criterion is fixed, it is only natural to find a very high prevalence of arterial hypertension in the elderly. When dealing with MetS in the elderly\u2014where about all subjects finish to be considered hypertensive\u2014the criterion \u2018arterial hypertension\u2019 is therefore emptied of any statistical power. Finally, a couple of words about cut-off values and continuous variables. It has been recently pointed out that all the items considered for labelling MetS are continuous, meaning that their relative risk increases linearly without any definite cut-off. Falsely dichotomizing continuously distributed variables are prone to error. If this is accompanied by fickleness of criteria, the result is misclassification of diseased subjects as healthy and viceversa. An example is represented by those criteria that, according to clinical guidelines, became more and more inclusive. For instance, when passing from the cut-off of hypertension \u2018140/90 mmHg\u2019 (WHO, 1998\u201399) to \u2018130/85 mmHg\u2019 (Updated NCEP, 2005),7 in our experience \ufe24% subjects have hypertension, and passing from \u20186.1 mmol/L\u2019 to \u20185.6 mmol/L\u2019 \ufe109% have glucose intolerance, and are therefore automatically incorporated in MetS. So, as criteria become more elastic, MetS becomes more prevalent in general population. It would be a better choice to employ variables showing curvilinear relation with cardiovascular risk, making possible the identification of clear and definit inflection points. As regards dyslipidaemia, we could suggest low-density lipoprotein (LDL) instead of HDL-cholesterol, as the former has, at least in the elderly, shows an inflection point that the latter has not. Any effort should be make in order to find similar inflection points for any possible variables implicates in the assessment of CVD risk

Hormonal regulation of human adipocytes at the cross-roads between obesity and hypertension

status: publishe

Evolving concepts of left ventricular hypertrophy

Adaptative left ventricular hypertrophy mainly derives from pressure or volume overload. Nevertheless, in the general population, about one-fifth of normotensives develop left ventricular hypertrophy despite a normal pressure load, while more than one-third of hypertensives do not develop it in response to pressure overload (Table 1). It is unclear why some subjects become hypertrophic while others do not. Hypoxic or ischaemic myocyte loss could account for a limited number of such cases. The natural history of left ventricular hypertrophy is also very different, with some subjects developing heart failure and premature death and others who seem to be free of these prognostic effects1. Both left ventricular hypertrophy and its consequences are complex integrating multigenic traits acting in the long term. It has been known since the 1990s that biochemical signalling events and changes in gene expression (including an increase of immediate early genes and re-expression of fetal genes) are important for the hypertrophic response. These phenomena lead to increased protein synthesis and cell size which are characteristic of a hypertrophic pattern. In recent years, several transcription factors have been identified as determinants modulating gene expression during hypertrophy in differentiated cells. The promoter region of specific genes involved in the hypertrophic response is a key point for signal integration. The complete mechanism describing development/decompensation of myocardial hypertrophy has not been fully clarified, but it is known that hypertrophy signalling occurs through multiple parallel pathways, including those linked with activation of the heterotrimeric G-protein Gq, encoded by the GNAQ gene. It is therefore clear that researchers involved in the field of cardiac hypertrophy have to deal with these complex signalling pathways that are under genetic control, not only to answer some unanswered questions about the pathophysiology of left ventricular hypertrophy but also from a prognostic and therapeutic viewpoint. Cardiologists are in general sceptical about genetics. Cardiovascular disease is multifactorial, and responds to a mosaic of genes that interact in common pathways to yield a synergistic mechanism of action, adding further experimental uncertainty to the merely probabilistic value of classical risk factors. Futhermore, association studies based on the analysis of several polymorphisms have often been disappointing for cardiologists. However, it must be emphasized that the study of Frey et al.8 discussed here is not a mere study of association, but rather a wide spectrum of research going \u2018from genetics, to molecular characterization, to a large clinical study\u2019. One of the principal candidate signalling pathways for cardiac hypertrophy is stimulation of the G protein Gq through its G-protein-coupled receptors. The aim of the study by Frey et al.8 was to investigate in humans the Gq protein overexpression encoded by the GNAQ gene and to identify Gq promoter polymorphism and specific transcription factors that regulate gene expression, as already observed in animal models. In a recent study by Clerk et al., they first characterized the GNAQ promoter looking for a possible polymorphism suspected to play a prominent role in disease susceptibility. They then identified the transcription factors and their binding sites, and clarified whether the Gq promoter was inducible by circulating stimuli, and whether the novel single polymorphism was really able to increase Gq expression resulting in enhanced activation of the Gq pathway and in enhanced cell growth in a signal-dependent manner. After identification of the promising GC(\u2013695/\u2013694)TT GNAQ polymorphism and in vitro experiments highlighting its functional expression, they checked in a population survey for its possible association with left ventricular mass. Finally, applying multiple regression models in subjects from the general population, the authors concluded that the GC allele was more common in individuals with than without left ventricular hypertrophy, and - more importantly\u2014that, in contrast, the above-mentioned polymorphism explained a significant part of the variance, really predicting left ventricular hypertrophy. Every effort was made to demonstrate that this polymorphism was important and functional, by reproducing step by step the entire pathway from identification of a novel polymorphism to its phenotypic expression, \u2018from genetics, to molecular characterization, to a large clinical study\u2019. The in vitro study was carried out on fresh human atria, as there are no well-established continuous cell lines that can be used to study cardiomyocyte development and growth. The investigation showed that this single-nucleotide polymorphism had functional implications, with the GC allele increasing Gq expression (contrasting findings shown by others could be attributable to the different setting14) and enhancing signal transduction via Gq-coupled receptors. In particular, in the GC allele carriers, Gq expression was found to be more inducible by stimulation with angiotensin II, which is of interest as there are higher circulating levels of this hormone in chronic disease, with increased workload leading to heart failure. The greatest merit of the study is to provide confirmation to the hypothesis that cardiomyocyte Gq signalling is both necessary for pressure overload hypertrophy3,4 and sufficient to produce overload-like hypertrophy even in the absence of haemodynamic stress,15 giving support to the pathological and physiological mass increase. In the population study, the effect of being GC allele carriers was more prominent (odds ratio 5.52) in women than in men, possibly explaining at the level of Gq mRNA expression why in populationbased studies women have on average higher left ventricular mass and higher prevalence of left ventricular hypertrophy than men. Although the study needs to be confirmed in further population cohorts respecting the criteria for internal validity of an association study, Frey et al. have opened a way through better knowledge of the onset and natural history of cardiac hypertrophy