CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data?

OBJECTIVE: Concerns about differences in registration practices across countries have limited the use of routine data for international very preterm birth (VPT) rate comparisons. DESIGN: Population-based study. SETTING: Twenty-seven European countries, the United States, Canada and Japan in 2010. POPULATION: A total of 9 376 252 singleton births. METHOD: We requested aggregated gestational age data on live births, stillbirths and terminations of pregnancy (TOP) before 32 weeks of gestation, and information on registration practices for these births. We compared VPT rates and assessed the impact of births at 22-23 weeks of gestation, and different criteria for inclusion of stillbirths and TOP on country rates and rankings. MAIN OUTCOME MEASURES: Singleton very preterm birth rate, defined as singleton stillbirths and live births before 32 completed weeks of gestation per 1000 total births, excluding TOP if identifiable in the data source. RESULTS: Rates varied from 5.7 to 15.7 per 1000 total births and 4.0 to 11.9 per 1000 live births. Country registration practices were related to percentage of births at 22-23 weeks of gestation (between 1% and 23% of very preterm births) and stillbirths (between 6% and 40% of very preterm births). After excluding births at 22-23 weeks, rate variations remained high and with a few exceptions, country rankings were unchanged. CONCLUSIONS: International comparisons of very preterm birth rates using routine data should exclude births at 22-23 weeks of gestation and terminations of pregnancy. The persistent large rate variations after these exclusions warrant continued surveillance of VPT rates at 24 weeks and over in high-income countries. TWEETABLE ABSTRACT: International comparisons of VPT rates should exclude births at 22-23 weeks of gestation and terminations of pregnancy.

Renocardiac syndromes: physiopathology and treatment stratagems.

PURPOSE OF REVIEW: Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. SOURCES OF INFORMATION: Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. FINDINGS: The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. LIMITATIONS: Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. IMPLICATIONS: Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes.

OBJECTIFS DE LA RÉVISION: Les interactions bidirectionnelles entre organes adjacents sont essentielles au bon fonctionnement du corps humain mais sont aussi susceptibles de provoquer des conditions adverses sur des organes plus éloignés. Cette revue offre un compte rendu sommaire de l'épidémiologie, des mécanismes physiopathologiques et du traitement clinique des patients atteints à la fois d'insuffisance rénale et de cardiopathie, ou tel que récemment désignés, atteints du syndrome cardiorénal de type 3 ou de type 4. La revue examine également des résultats obtenus en recherche fondamentale en utilisant des modèles animaux présentant des cas similaires de comorbidité. SOURCES: Les articles pertinents ont été répertoriés à la suite d'une recherche dans la littérature sur PubMed, MEDLINE et « Google Scholar ¼. Des données complémentaires provenant  d'études du laboratoire de recherche de l'auteur ont aussi été consultées. CONSTATATIONS: Le vieillissement de la population en plus de facteurs de risque incluant l'hypertension, le diabète et la dyslipidémie augmente en partie la prévalence du syndrome cardiorénal à travers le monde. La pathogenèse de ce désordre implique de multiples interactions bidirectionnelles entre le cœur et les reins; cependant, la participation d'organes périphériques n'est tout de même pas à exclure. Nos travaux soutiennent l'hypothèse selon laquelle l'environnement urémique résultant de la dysfonction rénale serait responsable d'altérations majeures dans la régulation de la pression, particulièrement au niveau des microvaisseaux. En résultent une perfusion sanguine altérée et une distribution insuffisante d'oxygène vers les organes. LIMITES DE L'ÉTUDE: La littérature clinique récente comporte de nombreux articles traitant de la nécessité d'identifier et de caractériser de façon plus élaborée les causes du syndrome cardiorénal dans la perspective d'améliorer le traitement clinique des patients qui en sont atteints. Par contre, puisqu'il existe encore très peu d'informations sur l'étiologie du syndrome cardiorénal, les patients ne sont pris en charge qu'après son apparition. Qui plus est, la compréhension des mécanismes impliqués dans la pathogenèse résultant des interactions entre organes demeure un objectif difficile à atteindre, en partie parce que la recherche fondamentale est limitée étant donné la rareté des modèles animaux pour cette pathologie. CONSÉQUENCES: À la lumière des données disponibles à ce jour, il apparait que la préservation de l'intégrité du système vasculaire, particulièrement au niveau des microvaisseaux, est un facteur-clé pour restreindre le développement de désordres impliquant plusieurs organes tel le syndrome cardiorénal. Davantage d'études en recherche fondamentale sont requises pour faire la lumière sur les mécanismes physiopathologiques de ce syndrome et développer des traitements efficaces pour en améliorer les résultats cliniques.

Impact of pre-pregnancy diabetes mellitus on congenital anomalies, Canada, 2002-2012.

OBJECTIVE: To examine the impact of pre-pregnancy diabetes mellitus (DM) on the population birth prevalence of congenital anomalies in Canada. METHODS: We carried out a population-based study of all women who delivered in Canadian hospitals (except those in the province of Quebec) between April 2002 and March 2013 and their live-born infants with a birth weight of 500 grams or more and/or a gestational age of 22 weeks or more. Pre-pregnancy type 1 or type 2 DM was identified using ICD-10 diagnostic codes. The association between DM and all congenital anomalies as well as specific congenital anomaly categories was estimated using adjusted odds ratios; the impact was calculated as a population attributable risk percent (PAR%). RESULTS: There were 118,892 infants with a congenital anomaly among 2,839,680 live births (41.9 per 1000). While the prevalence of any congenital anomaly declined from 50.7 per 1000 live births in 2002/03 to 41.5 per 1000 in 2012/13, the corresponding PAR% for a congenital anomaly related to pre-pregnancy DM rose from 0.6% (95% confidence interval [CI]: 0.4-0.8) to 1.2% (95% CI: 0.9-1.4). Specifically, the PAR% for congenital cardiovascular defects increased from 2.3% (95% CI: 1.7-2.9) to 4.2% (95% CI: 3.5-4.9) and for gastrointestinal defects from 0.8% (95% CI: 0.2-1.9) to 1.4% (95% CI: 0.7-2.6) over the study period. CONCLUSION: Although there has been a relative decline in the prevalence of congenital anomalies in Canada, the proportion of congenital anomalies due to maternal pre-pregnancy DM has increased. Enhancement of preconception care initiatives for women with DM is recommended.

TITRE: Influence du diabète antérieur à la grossesse sur les anomalies congénitales au Canada entre 2002 et 2012. OBJECTIF: Examiner l'influence du diabète antérieur à la grossesse sur la prévalence à la naissance des anomalies congénitales au Canada. MÉTHODOLOGIE: Nous avons réalisé une étude en population chez l'ensemble des femmes ayant accouché à l'hôpital au Canada (hors Québec) entre avril 2002 et mars 2013, ainsi que chez leurs enfants nés vivants ayant un poids à la naissance d'au moins 500 grammes ou un âge gestationnel d'au moins 22 semaines. On a attribué les codes de diagnostic de la CIM-10 au diabète de type 1 ou de type 2 antérieur à la grossesse. L'association entre le diabète et l'ensemble des anomalies congénitales ainsi qu'avec les diverses catégories prises séparément a été estimée à l'aide des rapports de cotes ajustés et son influence a été calculée sous forme de pourcentage de risque attribuable dans la population (%RAP). RÉSULTATS: Sur les 2 839 680 naissances vivantes, 118 892 nouveau-nés étaient atteints d'anomalies congénitales (41,9 pour 1 000). Même si la prévalence des anomalies congénitales est passée de 50,7 pour 1 000 naissances vivantes en 2002­2003 à 41,5 pour 1 000 en 2012­2013, le %RAP d'une anomalie congénitale liée au diabète antérieur à la grossesse est passé de 0,6 % (intervalle de confiance [IC] à 95 % : 0,4 à 0,8) à 1,2 % (IC à 95 % : 0,9 à 1,4). Plus précisément, le %RAP des cardiopathies congénitales est passé de 2,3 % (IC à 95 % : 1,7 à 2,9) à 4,2 % (IC à 95 % : 3,5 à 4,9) et celui des anomalies gastrointestinales de 0,8 % (IC à 95 % : 0,2 à 1,9) à 1,4 % (IC à 95 % : 0,7 à 2,6) au cours de la période étudiée. CONCLUSION: En dépit de la diminution relative de la prévalence des anomalies congénitales au Canada, la proportion d'anomalies congénitales pouvant être attribuées au diabète maternel antérieur à la grossesse a augmenté. On recommande l'amélioration des initiatives en matière de soins préconceptionnels destinées aux femmes diabétiques.

Nitric oxide bioavailability affects cardiovascular regulation dependent on cardiac nerve status.

The sympathetic nervous system and nitric oxide (NO) contribute to regulation of vascular tone, blood flow regulation and cardiac function. Intrinsic cardiac neurons are tonically influenced by locally released NO and exogenous NO donors; however, the role of intact central neural connections remains controversial. We investigated the effects of S-nitroso-N-acetylpenicillamine (SNAP) administered into an intracoronary artery near the ventral interventricular ganglionated plexus (VIVGP) to evaluate distribution of myocardial blood flow (MBF) and ventricular function in normal and acute cardiac decentralized dogs. MBF was measured with microspheres during infusion of SNAP (100µM, IC) after systemic administration of 7-nitroindazole (nNOS blocker) followed by N(ω)-nitro-L-arginine methyl ester (LN; non-selective NOS blocker). Cardiac dynamics were not significantly affected by cardiac decentralization; several of these parameters (aortic systolic and diastolic pressures) were significantly increased after systemic administration of LN. Overall SNAP administered to the VIVGP increased blood flow in the anterior LV wall (vs. posterior LV wall) without affecting other cardiodynamic factors. In cardiac decentralized dogs subepicardial blood flow to the anterior LV wall during LN+SNAP was diminished resulting in a significantly higher inner:outer blood flow ratio (index of blood flow uniformity across the LV wall). LV function was not affected by acute cardiac decentralization; however, LV ejection fraction decreased markedly after LN (reduced NO bioavailability). These results validate earlier claims that reduced NO bioavailability imposes an upper limit on myocardial blood flow regulation and its transmural distribution. These effects are exacerbated after disconnection of intrinsic cardiac neurons from intact central neuron connections.

Opinions, hopes and concerns regarding pharmacogenomics: a comparison of healthy individuals, heart failure patients and heart transplant recipients.

It is not yet known whether healthy individuals and patients with a chronic disease have similar attitudes towards pharmacogenomics. Thus we conducted a survey of 175 healthy volunteers, 175 heart failure (HF) patients and 100 heart transplant recipients to compare their opinions on this subject. Most participants (>90%) stated that they would accept pharmacogenomic testing and expressed high hopes regarding its potential applications. Overall, interest for pharmacogenomics was shared equally among the three groups. In contrast, after adjusting for age, gender, education and income, healthy individuals were more likely to voice concerns about potential employment (P=0.008 vs HF, odds ratio (OR)=2.93, confidence interval (CI)=1.33-6.47; P=0.010 vs Transplant, OR=2.46, CI=1.24-4.90) and insurance discrimination (P=0.001 vs HF, OR=5.58, CI=2.01-15.48; P<0.001 vs Transplant, OR=4.98, CI=2.03-12.21) and were possibly more worried by confidentiality issues. These findings highlight the need for strict legislation and proper educational strategies directed at the general population to facilitate the clinical implementation of pharmacogenomics.

Amniotic fluid embolism: incidence, risk factors, and impact on perinatal outcome.

OBJECTIVE: To extend our previous work on AFE in Canada by including stricter criteria for case identification and by examining risks for stillbirth, neonatal mortality and serious maternal and neonatal morbidity. DESIGN: Population-based cohort study. SETTING: Canada. POPULATION OR SAMPLE: In all, 4,508,462 hospital deliveries from fiscal year 1991/92 to 2008/09. METHODS: To reduce false-positive diagnoses, we restricted our analysis to AFE cases with cardiac arrest, shock or severe hypertension, respiratory distress, mechanical ventilation, coma, seizure, or coagulation disorder. Linkage of maternal and neonatal records, available since 2001/02, enabled us to examine the effects of AFE on neonatal outcomes. Detailed demographic and clinical data facilitated control for a broad array of potential confounding variables. MAIN OUTCOME MEASURES: Amniotic fluid embolism, in-hospital neonatal death, asphyxia, mechanical ventilation, bacterial sepsis, seizure, nonimmune haemolytic or traumatic jaundice and length of hospital stay. RESULTS: A total of 292 AFE cases were identified, of which only 120 (40%) were confirmed after applying our additional diagnostic criteria, yielding an AFE incidence of 2.5 per 100,000 deliveries. Of the 120 confirmed cases, 33 (27%) were fatal. Significant modifiable risk factors included medical induction, caesarean delivery, instrumental vaginal delivery, and uterine or cervical trauma. Amniotic fluid embolism was associated with significantly increased risks of stillbirth and neonatal asphyxia, mechanical ventilation, sepsis, seizures and prolonged length of hospital stay. CONCLUSIONS: Amniotic fluid embolism remains a rare but serious obstetric outcome, with several important modifiable risk factors and major implications for maternal, fetal and neonatal health.

Modulation of nitric oxide affects myocardial perfusion-contraction matching in anaesthetized dogs with recurrent no-flow ischaemia.

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Investigation of an increase in postpartum haemorrhage in Canada.

OBJECTIVE: To investigate the cause of a recent increase in hysterectomies for postpartum haemorrhage in Canada. DESIGN: Retrospective cohort study. SETTING: Canada between 1991 and 2004. POPULATION: All hospital deliveries in Canada as documented in the database of the Canadian Institute for Health Information (excluding incomplete data from Quebec, Manitoba and Nova Scotia). METHODS: Deliveries with postpartum haemorrhage by subtype were identified using International Classification of Diseases codes, while hysterectomies were identified using procedure codes. Changes in determinants of postpartum haemorrhage (all postpartum haemorrhage and that requiring hysterectomy) were examined, and crude and adjusted period changes were assessed using logistic models. MAIN OUTCOME MEASURES: Postpartum haemorrhage, postpartum haemorrhage with hysterectomy, postpartum haemorrhage with blood transfusion and postpartum haemorrhage by subtype. RESULTS: Rates of postpartum haemorrhage increased from 4.1% in 1991 to 5.1% in 2004 (23% increase, 95% CI 20-26%), while rates of postpartum haemorrhage with hysterectomy increased from 24.0 in 1991 to 41.7 per 100,000 deliveries in 2004 (73% increase, 95% CI 27-137%). These increases were because of an increase in atonic postpartum haemorrhage, from 29.4 per 1000 deliveries in 1991 to 39.5 per 1000 deliveries in 2004 (34% increase, 95% CI 31-38%). Adjustment for temporal changes in risk factors did not explain the increase in atonic postpartum haemorrhage but attenuated the increase in atonic postpartum haemorrhage with hysterectomy. CONCLUSIONS: There has been a recent, unexplained increase in the frequency, and possibly the severity, of atonic postpartum haemorrhage in Canada.

Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine.

OBJECTIVES: The purpose of this study was to assess the effects of amlodipine on neurohormones and oxidative stress in nonischemic cardiomyopathy, and determine the relationship between baseline and posttreatment levels of these markers with survival. BACKGROUND: Neurohormones and oxidative stress are important in the pathophysiology of heart failure. Calcium-channel blockers are associated with poor outcomes in patients with heart failure, in part due to neurohormonal activation. In contrast, amlodipine, a second-generation dihydropyridine, has a more favorable clinical profile. METHODS: In the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) trial, a subset of 181 patients with nonischemic cardiomyopathy were randomized to amlodipine (10 mg/day) or placebo. Blood samples were evaluated at baseline, 2 weeks and 26 weeks for norepinephrine, epinephrine, angiotensin II, dopamine, N-terminal pro-atrial natriuretic peptide (Nt-pro-ANP), brain natriuretic peptide (BNP), adrenolutin and malondialdehyde. RESULTS: There was no difference in levels of neurohormones or oxidative stress markers between the amlodipine and placebo groups at the different times. Both Nt-pro-ANP and BNP decreased at 2 weeks and at 26 weeks. Baseline Nt-pro-ANP correlated with survival in multivariate analysis (P =.001). A strong relationship was found between a reduction in BNP at 26 weeks and survival, with a hazard ratio of 0.153 (95% CI 0.051-0.461, P =.017). No relationship was found between markers of oxidative stress and survival. CONCLUSIONS: We conclude that amlodipine does not affect circulating neurohormones and oxidative stress markers in patients with nonischemic cardiomyopathy treated with angiotensin-converting enzyme inhibitors, digoxin and diuretics. In addition, low circulating Nt-pro-ANP and a reduction in BNP over time confers a good prognosis.

Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with severe heart failure.

OBJECTIVES: The purpose of this study was to assess whether adrenolutin, the inert product of the highly reactive molecules aminochromes, is increased in severe chronic heart failure and whether it is associated with a poor prognosis. BACKGROUND: Experimental evidence suggests that oxidative products of catecholamines, aminochromes, are more cardiotoxic than unoxidized catecholamines and may be increased in heart failure. METHODS: Adrenolutin was measured at baseline and at 1 and 3 months in 263 patients with chronic New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 22% +/- 7%. Adrenolutin levels were compared with normal levels, and their relation to prognosis was evaluated. RESULTS: Baseline adrenolutin was increased (55 +/- 90 pg/mL vs 8.4 +/- 9.1 pg/mL for control, P <.02) and remained increased at 1 month (49 +/- 65 pg/mL). During a mean follow-up of 309 +/- 148 days (22-609 days), 57 patients died. Baseline adrenolutin levels correlated with mortality rates by univariate and multivariate analyses (relative risk 1.06, 95% CI 1.01-1.10 for each 17.9-pg/mL rise, P =.032). Left ventricular ejection fraction (P =.013) and New York Heart Association class (P =.009) were the only other variables associated with survival. Age, sex, plasma creatinine, plasma N-terminal atrial natriuretic peptide, and plasma norepinephrine levels were not retained in our model. Adrenolutin levels 1 month after random assignment were not significantly correlated with total mortality rate (P =.061) but were correlated with mortality rate from low output (relative risk 1.14, 95% CI 1.06-1.22, P =.002). CONCLUSIONS: Plasma adrenolutin is increased in patients with heart failure and correlates with a poor prognosis independent of other important predictors of survival. This finding has potentially important pathophysiologic, prognostic, and therapeutic implications.

The importance of microalbuminuria as a cardiovascular risk indicator: A review.

The present review describes the knowledge of microalbuminuria as a cardiovascular risk indicator. Microalbuminuria is usually defined as a urinary albumin excretion rate of 30 to 300 mg in a 24 h urine collection, or as a urinary albumin excretion rate of 20 to 200 mg/min in a timed overnight urine collection, although microalbuminuria was demonstrated to be a predictor for cardiovascular events at levels below these conventional cut-off values. More than one consecutive urine collection is preferred given the high day to day variability of urinary albumin excretion. Microalbuminuria is frequently present and a known cardiovascular risk indicator in diabetic populations. Also, in hypertensive and general populations, microalbuminuria is common and has been associated with an adverse atherogenic risk profile and a higher prevalence of cardiovascular disease. Moreover, evidence strongly suggests that microalbuminuria is also an independent predictor of cardiovascular disease in these populations. However, more prospective studies are needed to elucidate fully the value of microalbuminuria as a cardiovascular risk indicator in hypertensive and general populations. Generalized endothelial dysfunction has been hypothesized to be the underlying factor for microalbuminuria on one hand and the underlying factor for increased cardiovascular risk on the other. In this respect, the loss of the glycosaminoglycan heparin sulphate might be an important pathophysiological mechanism. This hypothesis needs further clarification, especially in nondiabetic populations.

Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril.

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Changes in vasoconstrictive hormones, natriuretic peptides, and left ventricular remodeling soon after anterior myocardial infarction.

OBJECTIVE: Our purpose was to study the changes in vasoconstrictive neurohormones, N-terminal proatrial natriuretic peptide (Nt-proANP), and brain natriuretic peptide (BNP) and their relationship with left ventricular (LV) remodeling soon after anterior myocardial infarction (MI). BACKGROUND: The Healing and Afterload Reducing Therapy (HEART) trial has shown that early use of ramipril improves left ventricular ejection fraction (LVEF) and attenuates LV remodeling when initiated soon after MI. This neurohumoral substudy of HEART investigates the changes in vasoconstrictive and natriuretic peptides and their relationship with LV remodeling. METHODS: One hundred twenty-two patients had blood drawn for the measurement of catecholamines, endothelin-I, angiotensin II, Nt-proANP and BNP, and prostacyclins within 24 hours of an MI, and at 3, 14, and 90 days after the MI. Quantitative echocardiograms were performed at baseline and at 14 days. RESULTS: All neurohormones except angiotensin II (P =.12) and prostaglandins were significantly elevated at baseline. Vasoconstrictive neurohormones decreased significantly over time but remained elevated at 14 days. Both Nt-proANP and BNP were elevated within the first 14 days. BNP decreased significantly by 90 days, whereas Nt-proANP exhibited no change between 14 and 90 days. Ramipril decreased plasma levels of angiotensin II at 3 days but had no effect on the other neurohormones. CONCLUSIONS: Neurohumoral activation occurs and persists in patients with anterior MI and overall preserved LV function. Ramipril had only a modest impact on neurohormones despite its significant benefits on LV remodeling soon after MI.

Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.