The influence of comorbidities on achieving an N-terminal pro-b-type natriuretic peptide target: a secondary analysis of the GUIDE-IT trial.

AIMS: N-terminal pro-b-type natriuretic peptide (NT-proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT-proBNP targets and clinical outcomes. METHODS: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment trial. NT-proBNP was analysed every 3 months. RESULTS: Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43-76], and median BMI was 29 kg/m2 (IQR 25-34). Patients with AF, eGFR < 60 mL/min/1.73 m2 , or a BMI < 29 kg/m2 had a higher level of NT-proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT-proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2 , P < 0.001). The rate of change of NT-proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT-proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT-proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). CONCLUSIONS: Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT-proBNP. Clinicians should be aware of these factors both when interpreting NT-proBNP levels and making therapeutic decisions about heart failure therapies.

CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction.

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a ß-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.

Intrarenal Doppler Ultrasound Renal Venous Stasis Index Correlates With Acute Cardiorenal Syndrome in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Acute cardiorenal syndrome (ACRS) is associated with adverse outcomes in patients with acute decompensated heart failure (ADHF). Intrarenal venous blood flow can be assessed using Doppler ultrasound and has prognostic significance in ADHF. Although intrarenal Doppler (IRD) may be sensitive to renal congestion, an association between IRD parameters and ACRS has not been demonstrated in an ADHF population. METHODS: Hospitalized patients with ADHF (n = 21) or acute coronary syndrome (ACS; n = 21) were prospectively enrolled. Patients underwent echocardiography, including IRD, using a standard cardiac ultrasound transducer. Intrarenal venous flow was quantified with the renal venous stasis index (RVSI), defined as the duration of absent venous flow time divided by cardiac cycle duration. The primary outcome was acute kidney injury (AKI) as assessed using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: ADHF patients had a similar cardiac index (2.0 ± 0.6 vs 2.1 ± 0.4 L/min per m2, P = 0.91) but higher estimated central venous pressure (13.0 ± 3.2 vs 4.6 ± 2.4 mm Hg, P < 0.001) measured using echocardiography, compared with ACS patients. IRD was abnormal in all ADHF patients and normal in all ACS patients (RVSI 0.62 ± 0.20 vs 0.0 ± 0, P < 0.001). AKI stage II/III occurred in 10 of 21 ADHF patients (48%) vs 0 of 21 ACS patients (P < 0.001), with a mean rise in serum creatinine of 97.7 ± 79.3 vs 16.8 ± 10.9 µmol/L (P < 0.001), respectively. RVSI was correlated with AKI severity in ADHF patients (r = 0.57; P = 0.004). CONCLUSIONS: RVSI is associated with AKI among ADHF patients and may be a useful diagnostic biomarker for ACRS in this setting. Further studies are needed to validate this finding and evaluate the potential efficacy of IRD-guided decongestive therapy in this setting.

INTRODUCTION: Le syndrome cardiorénal aigu (SCRA) est associé à des résultats défavorables chez les patients atteints d'une insuffisance cardiaque en décompensation aiguë (ICDA). Le flux veineux intrarénal qui peut être évalué à l'aide de l'échographie Doppler a une importance pronostique lors d'ICDA. Bien que la Doppler intrarénale (DIR) puisse être sensible à la congestion rénale, l'association entre les paramètres de la DIR et le SCRA n'a pas été démontrée au sein d'une population atteinte d'ICDA. MÉTHODES: Nous avons inscrit de façon prospective les patients hospitalisés atteints d'une ICDA (n = 1) ou d'un syndrome coronarien aigu (SCA; n = 21). Les patients ont subi une échocardiographie, à savoir la DIR, à l'aide d'un transducteur d'échographie cardiaque standard. Le flux veineux intrarénal a été quantifié à l'aide de l'indice de stase veineuse rénale (ISVR), défini par la durée de l'absence du débit veineux divisée par la durée du cycle cardiaque. Le critère d'évaluation principal était l'insuffisance rénale aiguë (IRA) selon les critères de KDIGO (Kidney Disease: Improving Global Outcomes). RÉSULTATS: Les patients atteints d'ICDA avaient un indice cardiaque similaire (2,0 ± 0,6 vs 2,1 ± 0,4 l/min par m2, P = 0,91), mais une estimation plus élevée de la pression veineuse centrale (13,0 ± 3,2 vs 4,6 ± 2,4 mmHg, P < 0,001) selon les mesures obtenues à l'échocardiographie, comparativement aux patients atteints d'un SCA. La DIR était anormale chez les patients atteints d'une ICDA et normale chez les patients atteints d'un SCA (ISVR 0,62 ± 0,20 vs 0,0 ± 0, P < 0,001). L'IRA de stade II/III est apparue chez 10 des 21 patients atteints d'une ICDA (48 %) vs 0 des 21 patients atteints d'un SCA (P < 0,001), selon une augmentation moyenne respective des concentrations sériques de la créatinine de 97,7 ± 79,3 vs 16,8 ± 10,9 µmol/l (P < 0,001). L'ISVR corrélait à la gravité de l'IRA chez les patients atteints d'une ICDA (r = 0,57; P = 0,004). CONCLUSIONS: L'ISVR est associé à l'IRA chez les patients atteints d'une ICDA et peut être un biomarqueur diagnostique utile du SCRA dans ce contexte. Des études plus approfondies sont nécessaires pour valider ces conclusions et évaluer l'efficacité potentielle du traitement de décongestion guidé par DIR dans ce contexte.

Cost-Effectiveness of Earlier Transition to Angiotensin Receptor Neprilysin Inhibitor in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Angiotensin receptor neprilysin inhibitor (ARNi) therapy improves clinical outcomes in patients with heart failure and reduced left ventricular ejection fraction. However, ARNi therapy uptake remains modest, potentially in part due to perceived cost considerations of early transition from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy. METHODS: We constructed a decision-analytic Markov model to assess cost-effectiveness of 3 different ARNi initiation strategies according to timing of initiation: (1) de novo, or immediate initiation at baseline, (2) Early or after 3 months, or (3) Late, or after 9 months. Initiation strategies were compared with (4) current care, with utilization of ARNi derived from a large observational database. Total costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) were estimated over a 5-year time horizon in the base case analysis. RESULTS: Current care was associated with the lowest total cost (CAD$26,664) and accrued benefit (3.28 QALYs). The de novo strategy yielded an ICER of $34,727 per QALY gained, whereas Early and Late initiation strategies yielded a less favourable ICER per QALY gained of $35,871 and $40,234, respectively. The model was most sensitive to the cost of ARNi therapy. CONCLUSION: A strategy of de novo ARNi initiation is economically attractive and becomes less favourable as the delay of initiation increases. Our results suggest that ARNi therapy should be initiated as soon as possible for patients with heart failure and reduced left ventricular ejection fraction.

CONTEXTE: Le traitement par un antagoniste des récepteurs de l'angiotensine/inhibiteur de la néprilysine (ARNI) améliore les résultats cliniques chez les patients présentant une insuffisance cardiaque et une fraction d'éjection ventriculaire gauche réduite. L'adoption d'un tel traitement demeure toutefois modeste, peut-être en partie à cause des perceptions quant au coût associé à la substitution précoce d'un inhibiteur de l'enzyme de conversion de l'angiotensine ou d'un antagoniste des récepteurs de l'angiotensine. MÉTHODOLOGIE: Nous avons mis au point un modèle de Markov appliqué à l'analyse décisionnelle afin d'évaluer le rapport coût-efficacité de trois stratégies d'instauration d'un traitement par un ARNI, selon le moment de la mise en route : 1) instauration de novo, c'est-à-dire instauration immédiate dès le départ; 2) instauration précoce (après trois mois); ou 3) instauration tardive (après neuf mois). Les stratégies d'instauration ont été comparées à 4) la norme de soins actuelle, l'utilisation des ARNI étant dérivée d'une importante base de données observationnelles. Dans l'analyse du scénario de référence, les coûts totaux, les années de vie pondérées par la qualité (QALY pour quality-adjusted life-years) et le rapport coût-efficacité différentiel (RCED) ont été estimés sur une période de cinq ans. RÉSULTATS: La norme de soins actuelle était associée au coût le plus faible (26 664 $CAD) et à un bienfait cumulé (3,28 QALY). La stratégie de novo a donné lieu à un RCED de 34 727 $ par QALY gagnée, tandis que les RCED des stratégies d'instauration précoce et tardive étaient moins favorables et s'établissaient respectivement à 35 871 $ et à 40 234 $. Le modèle s'est révélé plus sensible au coût du traitement par un ARNI. CONCLUSION: La mise en route d'un traitement par un ARNI de novo est attrayante sur le plan financier, et devient de moins en moins intéressante à mesure que le temps passe. Nos résultats indiquent qu'il faudrait instaurer le traitement par un ARNI le plus rapidement possible chez les patients présentant une insuffisance cardiaque et une fraction d'éjection ventriculaire gauche réduite.

Percutaneous Left Ventricular Assist Device in Cardiogenic Shock: A Five-Year Single Canadian Center Initial Experience.

BACKGROUND: Mechanical circulatory support in cardiogenic shock (CS) with percutaneous left ventricular assist devices (PVADs) has expanded rapidly, but there is a paucity of Canadian data. Conflicting observational reports have emerged regarding the benefit of PVADs in CS. We describe a 5-year experience with Impella CP for CS at a single Canadian tertiary care centre. METHODS: Consecutive adult patients with CS supported with Impella CP were included. Comprehensive clinical data and outcomes were retrospectively assessed. We evaluated patient characteristics, patterns of care, in-hospital outcomes, 6-month survival, and predictors of survival. RESULTS: Thirty-four patients were supported with Impella CP for CS over 5 years. A majority had acute myocardial infarction (94%) with advanced CS (68% Society for Cardiovascular Angiography and Intervention [SCAI] stage D or E). Survival to discharge was 58%. In patients who survived to discharge, 6-month survival was 100% with excellent functional status. SCAI CS stage and initial serum lactate showed significant associations with survival. There was also a trend towards improved survival with shorter door-to-PVAD time. Clinically significant bleeding was common (26%), and 3 patients had device-related vascular complications. CONCLUSION: Impella CP may have a role in carefully selected patients with CS. The SCAI shock classification and serum lactate may facilitate patient selection, and minimizing door-to-support time as well as bleeding complications are important considerations. Further clinical investigations, particularly in a Canadian setting, will be necessary to establish the role of this new technology in CS.

CONTEXTE: L'assistance circulatoire mécanique en cas de choc cardiogénique (CC) avec des dispositifs d'assistance ventriculaire gauche percutanée s'est rapidement développée, mais les données canadiennes restent rares. Des rapports d'observation contradictoires ont émergé concernant les avantages des dispositifs d'assistance ventriculaire gauche percutanée en cas de CC. Nous décrivons une expérience de cinq ans avec l'Impella CP pour les CC dans un seul centre de soins tertiaires canadien. MÉTHODES: Des patients adultes assistés par l'Impella CP, consécutivement à un CC, ont été inclus. Les données et les conclusions cliniques détaillées ont été évaluées rétrospectivement. Nous avons évalué les caractéristiques des patients, les modèles de soins, les bilans en milieu hospitalier, la survie à six mois et les indicateurs de survie. RÉSULTATS: Trente-quatre patients ont été pris en charge avec l'Impella CP pour un CC sur une période de cinq ans. Une majorité d'entre eux ont subi un infarctus aigu du myocarde (94 %) avec un CC avancé (68 % au stade D ou E sur l'échelle de la Society for Cardiovascular Angiography and Intervention [SCAI]). La survie jusqu'au congé hospitalier était de 58 %. Chez les patients qui ont survécu jusqu'à leur congé de l'hôpital, la survie à six mois était de 100 % avec un excellent état fonctionnel. Le stade de leur CC selon la SCAI et le lactate sérique initial ont montré des associations significatives avec le taux de survie. On a également constaté une tendance à l'amélioration de la survie avec un temps de porte à dispositifs d'assistance ventriculaire gauche percutanée raccourci. Des hémorragies importantes étaient fréquentes (26 %) et trois patients présentaient des complications vasculaires liées au dispositif. CONCLUSION: L'Impella CP pourrait avoir un rôle chez des patients atteints de CC soigneusement sélectionnés. La classification du choc selon la SCAI et le niveau de lactate sérique peuvent faciliter la sélection des patients, et la réduction du temps de « porte à assistance ¼ ainsi que les complications hémorragiques constituent des considérations d'importance. D'autres investigations cliniques, en particulier dans un contexte canadien, seront nécessaires pour établir le rôle de cette nouvelle technologie dans le CC.

Comparative Prognostic Accuracy of Risk Prediction Models for Cardiogenic Shock.

OBJECTIVES: Despite advances in medical therapy, reperfusion, and mechanical support, cardiogenic shock remains associated with excess morbidity and mortality. Accurate risk stratification may improve patient management. We compared the accuracy of established risk scores for cardiogenic shock. METHODS: Patients admitted to tertiary care center cardiac care units in the province of Alberta in 2015 were assessed for cardiogenic shock. The Acute Physiology and Chronic Health Evaluation-II (APACHE-II), CardShock, intra-aortic balloon pump (IABP) Shock II, and sepsis-related organ failure assessment (SOFA) risk scores were compared. Receiver operating characteristic curves were used to assess discrimination of in-hospital mortality and compared using DeLong's method. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The study included 3021 patients, among whom 510 (16.9%) had cardiogenic shock. Patients with cardiogenic shock had longer median hospital stays (median 11.0 vs 4.1 days, P < .001) and were more likely to die (29.0% vs 2.5%, P < .001). All risk scores were adequately calibrated for predicting hospital morality except for the APACHE-II score (Hosmer-Lemeshow P < .001). Discrimination of in-hospital mortality with the APACHE-II (area under the curve [AUC]: 0.72, 95% confidence interval [CI]: 0.66-0.76) and IABP-Shock II (AUC: 0.73, 95% CI: 0.68-0.77) scores were similar, while the CardShock (AUC: 0.76, 95% CI: 0.72-0.81) and SOFA (AUC: 0.76, 95%CI: 0.72-0.81) scores had better discrimination for predicting in-hospital mortality. CONCLUSIONS: In a real-world population of patients with cardiogenic shock, existing risk scores had modest prognostic accuracy, with no clear superior score. Further investigation is required to improve the discriminative abilities of existing models or establish novel methods.

Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour.

Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH2 behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1-/- mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1-/- mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca2+]i following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1-/- mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.

Reliability of updated left ventricular diastolic function recommendations in predicting elevated left ventricular filling pressure and prognosis.

An updated 2016 echocardiographic algorithm for diagnosing left ventricular (LV) diastolic dysfunction (DD) was recently proposed. We aimed to assess the reliability of the 2016 echocardiographic LVDD grading algorithm in predicting elevated LV filling pressure and clinical outcomes compared to the 2009 version. METHODS: We retrospectively identified 460 consecutive patients without atrial fibrillation or significant mitral valve disease who underwent transthoracic echocardiography within 24 hours of elective heart catheterization. LV end-diastolic pressure (LVEDP) and the time constant of isovolumic pressure decay (Tau) were determined. The association between DD grading by 2009 LVDD Recommendations and 2016 Recommendations with hemodynamic parameters and all-cause mortality were compared. RESULTS: The 2009 LVDD Recommendations classified 55 patients (12%) as having normal, 132 (29%) as grade 1, 156 (34%) as grade 2, and 117 (25%) as grade 3 DD. Based on 2016 Recommendations, 177 patients (38%) were normal, 50 (11%) were indeterminate, 124 (27%) patients were grade 1, 75 (16%) were grade 2, 26 (6%) were grade 3 DD, and 8 (2%) were cannot determine. The 2016 Recommendations had superior discriminatory accuracy in predicting LVEDP (P<.001) but were not superior in predicting Tau. During median follow-up of 416 days (interquartile range: 5 to 2004 days), 54 patients (12%) died. Significant DD by 2016 Recommendations was associated with higher risk of mortality (P=.039, subdistribution HR1.85 [95% CI, 1.03-3.33]) in multivariable competing risk regression. CONCLUSIONS: The grading algorithm proposed by the 2016 LV diastolic dysfunction Recommendations detects elevated LVEDP and poor prognosis better than the 2009 Recommendations.

How important is the α1-adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of α1-adrenoceptor to urethral contractility.

Urethral smooth muscle (USM) contributes to urinary continence by contracting during the urine storage phase, which is mainly mediated by activation of postjunctional α1-adrenoceptors. Males and females show differences in the functioning of the lower urinary tract and the most common urinary tract symptoms (LUTS). LUTS in men typically occur in association with bladder outlet obstruction, whereas in women urinary urge-incontinence symptoms are more common. Therefore, this study aimed to evaluate sex differences in α1-adrenoceptor subtype expression and their importance in proximal urethra contraction in the mouse (C57BL6/J) and marmoset (Callithrix jacchus). Contractile responses to phenylephrine, norepinephrine, potassium chloride (KCl), and electrical-field stimulation (EFS) were evaluated. Phenylephrine, norepinephrine, KCl, and EFS produced markedly greater contractions in male mice and marmoset USM compared with females. The sex differences remained unchanged by Nω-nitro-l-arginine (l-NAME; nitric oxide synthase inhibitor), atropine (muscarinic receptor antagonist), and PPADS (P2X1-purinoceptor antagonist). Additionally, selective α1A (but not α1B- and α1D-)-adrenoceptor antagonists significantly reduced phenylephrine-induced USM contractions. qRT-PCR for α1A-, B-, and D-adrenoceptor subtypes revealed a marked presence of the α1A-adrenoceptor subtype in male USM, but not females. Male mouse urethra also exhibited a higher tyrosine hydroxylase mRNA expression. Histomorphometric analysis showed a greater USM area in male than female mice. In conclusion, male mouse and marmoset proximal USM shows strong α1A- adrenoceptor-induced contractions and abundant α1A-adrenoceptor expression, whereas α1A-adrenoceptor-mediated mechanisms are much less important in females. The differential expression of α1-adrenoceptors in the proximal urethra may contribute to the higher incidence of urinary incontinence in women and obstructed voiding in men.

The reservoir-wave approach to characterize pulmonary vascular-right ventricular interactions in humans.

Using the reservoir-wave approach (RWA) we previously characterized pulmonary vasculature mechanics in a normal canine model. We found reflected backward-traveling waves that decrease pressure and increase flow in the proximal pulmonary artery (PA). These waves decrease right ventricular (RV) afterload and facilitate RV ejection. With pathological alterations to the pulmonary vasculature, these waves may change and impact RV performance. Our objective in this study was to characterize PA wave reflection and the alterations in RV performance in cardiac patients, using the RWA. PA pressure, Doppler-flow velocity, and pulmonary arterial wedge pressure were measured in 11 patients with exertional dyspnea. The RWA was employed to analyze PA pressure and flow; wave intensity analysis characterized PA waves. Wave-related pressure was partitioned into two components: pressures due to forward-traveling and to backward-traveling waves. RV performance was assessed by examining the work done in raising reservoir pressure and that associated with the wave components of systolic PA pressure. Wave-related work, the mostly nonrecoverable energy expended by the RV to eject blood, tended to vary directly with mean PA pressure. Where PA pressures were lower, there were pressure-decreasing/flow-increasing backward waves that aided RV ejection. Where PA pressures were higher, there were pressure-increasing/flow-decreasing backward waves that impeded RV ejection. Pressure-increasing/flow-decreasing backward waves were responsible for systolic notches in the Doppler flow velocity profiles in patients with the highest PA pressure. Pulmonary hypertension is characterized by reflected waves that impede RV ejection and an increase in wave-related work. The RWA may facilitate the development of therapeutic strategies.

Blockade or deletion of transient receptor potential vanilloid 4 (TRPV4) is not protective in a murine model of sepsis.

Sepsis is a systemic inflammatory response triggered by microbial infection that can cause cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. The cation channel transient receptor potential vanilloid 4 (TRPV4) is expressed in vascular endothelium and causes vasodilatation, but excessive TRPV4 activation leads to profound hypotension and circulatory collapse - key features of sepsis pathogenesis. We hypothesised that loss of TRPV4 signaling would protect against cardiovascular dysfunction in a mouse model of sepsis (endotoxaemia). Multi-parameter monitoring of conscious systemic haemodynamics (by radiotelemetry probe), mesenteric microvascular blood flow (laser speckle contrast imaging) and blood biochemistry (iSTAT blood gas analysis) was carried out in wild type (WT) and TRPV4 knockout (KO) mice. Endotoxaemia was induced by a single intravenous injection of lipopolysaccharide (LPS; 12.5 mg/kg) and systemic haemodynamics monitored for 24 h. Blood flow recording was then conducted under terminal anaesthesia after which blood was obtained for haematological/biochemical analysis. No significant differences were observed in baseline haemodynamics or mesenteric blood flow. Naïve TRPV4 KO mice were significantly acidotic relative to WT counterparts. Following induction of sepsis, all mice became significantly hypotensive, though there was no significant difference in the degree of hypotension between TRPV4 WT and KO mice. TRPV4 KO mice exhibited a higher sepsis severity score. While septic WT mice became significantly hypernatraemic relative to the naïve state, this was not observed in septic KO mice. Mesenteric blood flow was inhibited by topical application of the TRPV4 agonist GSK1016790A in naïve WT mice, but enhanced 24 h following LPS injection. Contrary to the initial hypothesis, loss of TRPV4 signaling (either through gene deletion or pharmacological antagonism) did not attenuate sepsis-induced cardiovascular dysfunction: in fact, pathology appeared to be modestly exaggerated in mice lacking TRPV4. Local targeting of TRPV4 signalling may be more beneficial than global inhibition in sepsis treatment.

Grading diastolic function by echocardiography: hemodynamic validation of existing guidelines.

BACKGROUND: While echocardiographic grading of left ventricular (LV) diastolic dysfunction (DD) is used every day, the relationship between echocardiographic DD grade and hemodynamic abnormalities is uncertain. METHODS: We identified 460 consecutive patients who underwent transthoracic echocardiography within 24 h of elective left heart catheterization and had: normal sinus rhythm, no confounding structural heart disease, no change in medications between catheterization and echo, and complete echocardiographic data. Patients were grouped based on echocardiographic DD grade. Hemodynamic tracings were used to determine time constant of isovolumic pressure decay (Tau), LV end-diastolic pressure (LVEDP) and end-diastolic volume index at a pressure of 20 mmHg (EDVi20). RESULTS: Normal diastolic function was found in 55 (12.0%) patients, while 132 (28.7%) patients had grade 1, 156 (33.9%) grade 2 and 117 (25.4%) grade 3 DD. The median value for Tau was 46.9 ms for the overall population (interquartile range 38.6-58.1 ms), with a prevalence of a prolonged Tau (>48 ms) of 47.5%. While there was an association between DD grade and Tau (p = 0.003), LV dysfunction (ejection fraction <50%) was more strongly associated with increased Tau (p < 0.001) than was DD grade (p = 0.19). There was also an association between DD grade and LVEDP (p < 0.001), with both LV dysfunction (p = 0.029) and DD grade (p < 0.001) independently associated with LVEDP. Calculated EDVi20 was related to DD grade, but this relationship was driven by findings of paradoxically increased compliance in patients with severe DD. CONCLUSIONS: Although echocardiographic grading of DD was related to invasive hemodynamics in this population, the relationship was modest.

Baseline Functional Class and Therapeutic Efficacy of Common Heart Failure Interventions: A Systematic Review and Meta-analysis.

BACKGROUND: New York Heart Association (NYHA) functional class provides important prognostic information and is often used to select patients for cardiovascular therapies, yet, the effect of NYHA class on therapeutic efficacy has not been systematically studied. METHODS: In this systematic review and meta-analysis we compared the relative and absolute mortality benefit of 5 common heart failure interventions (angiotensin-converting enzyme [ACE] inhibitors, ß-blockers, mineralocorticoid receptor antagonists [MRAs], implantable cardioverter defibrillator [ICD], and cardiac resynchronization therapy [CRT]) across NYHA class. We included 26 randomized clinical trials of these interventions that reported all-cause mortality stratified according to baseline NYHA class in 36,406 patients. RESULTS: Pooled relative risk for NYHA I/II vs. III/IV strata were similar for ACE inhibitors (0.90 vs. 0.88), ß-blockers (0.72 vs. 0.79), MRA (0.79 vs. 0.75), and CRT (0.80 vs. 0.80), with all heterogeneity P > 0.8. Conversely, ICD efficacy was greater for class I/II (relative risk, 0.65 vs 0.86, heterogeneity P = 0.02). The pooled absolute risk difference was smaller for NYHA I/II vs III/IV with ACE inhibitors (-0.02 vs. -0.06, P = 0.12), ß-blockers (-0.02 vs. -0.05, P = 0.047), MRA (-0.03 vs. -0.11, P = 0.001), and CRT (-0.01 vs. -0.04, P = 0.036), but was similar across NYHA class for the ICD (-0.07 vs. -0.05; P = 0.27). CONCLUSIONS: Relative mortality reductions with most interventions were independent of baseline NYHA class. However, ICD efficacy was greater with NYHA I/II vs. III/IV limitation, and absolute benefit was greater with higher NYHA class. For interventions other than the ICD, there is little evidence supporting use of NYHA class as a rigid criterion for selecting heart failure therapies.

HDAC4 is required for inflammation-associated thermal hypersensitivity.

Transcriptional alterations are characteristic of persistent pain states, but the key regulators remain elusive. HDAC4 is a transcriptional corepressor that has been linked to synaptic plasticity and neuronal excitability, mechanisms that may be involved in peripheral and central sensitization. Using a conditional knockout (cKO) strategy in mice, we sought to determine whether the loss of HDAC4 would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely unnecessary for transcriptional regulation of naïve sensory neurons but was essential for appropriate transcriptional responses after injury, with Calca and Trpv1 expression consistently down-regulated in HDAC4 cKO compared to levels in the littermate controls (0.2-0.44-fold change, n = 4 in 2 separate experiments). This down-regulation corresponded to reduced sensitivity to 100 nM capsaicin in vitro (IC50 = 230 ± 20 nM, 76 ± 4.4% wild-type capsaicin responders vs. 56.9 ± 4.7% HDAC4 cKO responders) and to reduced thermal hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain (1.3-1.4-fold improvement over wild-type controls; n = 5-12, in 2 separate experiments). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors.

TRPA1 is essential for the vascular response to environmental cold exposure.

The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates α2C-adrenoceptors and Rho-kinase-mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates.

Development of a consensus algorithm to improve interobserver agreement and accuracy in the determination of tricuspid regurgitation severity.

BACKGROUND: Multiparametric scoring of valvular regurgitation may compromise interobserver agreement, as readers weight parameters differently. The aims of this study were to quantify interobserver variability in the grading of chronic tricuspid regurgitation (TR), develop an algorithm for grading TR, and assess the effect of this algorithm on concordance and accuracy. METHODS: On the basis of current guidelines, two experts graded the severity of TR by consensus in 40 patients with a spectrum of TR severity. A subgroup of patients (n = 18) also had TR severity assessed by cardiac magnetic resonance. Sixteen cardiologists independently graded the first 20 cases as severe or nonsevere TR. After group review, a grading algorithm to differentiate severe and nonsevere TR was devised by consensus. The same observers used the algorithm to grade the second set of cases. RESULTS: Baseline differentiation of severe from nonsevere TR showed modest reliability and accuracy compared with an expert read (multirater κ = 0.55; overall agreement, 78%; accuracy, 81%). The consensus algorithm for severe TR was a suggestive color jet and at least one of (1) right atrial area > 18 cm(2) and inferior vena cava diameter > 2.5 cm; (2) vena contracta width > 0.7 cm and jet area > 10 cm(2); (3) a dense, triangular TR Doppler profile; and (4) holosystolic reversal of hepatic vein flow. Application of this algorithm improved the multirater κ coefficient to 0.80, the level of agreement to 90% (P = .033), and mean reader accuracy to 92% (P = .001). CONCLUSIONS: Only modest baseline agreement was found between readers on the distinction of severe and nonsevere TR. An objective, structured grading algorithm improved both interrater agreement and accuracy.

Phenotype-independent effects of retroviral transduction in human dental pulp stem cells.

An immortalized human dental pulp stem cell (DPSC) line of an odontoblastic phenotype is established to circumvent the normal programmed senescence and to maintain the cell line's usefulness as a tool for further study of cellular activity. DPSCs are isolated from human dental pulp tissues and transfected using hTERT. The influence of this process on the DPSC phenotype and the mRNA expression of oncogenes involved in cellular senescence is investigated. The results reveal an absence of altered DPSC morphology and phenotype following the exogenous introduction of the hTERT gene, which is coupled with a significant reduction in p16 mRNA expression. This provides insight into how to circumvent in vitro dental pulp stem cell death following the exogenous introduction of hTERT.

Insulin relaxes bladder via PI3K/AKT/eNOS pathway activation in mucosa: unfolded protein response-dependent insulin resistance as a cause of obesity-associated overactive bladder.

We aimed to investigate the role of insulin in the bladder and its relevance for the development of overactive bladder (OAB) in insulin-resistant obese mice. Bladders from male individuals who were involved in multiple organ donations were used. C57BL6/J mice were fed with a high-fat diet for 10 weeks to induce insulin-resistant obesity. Concentration-response curves to insulin were performed in human and mouse isolated mucosa-intact and mucosa-denuded bladders. Cystometric study was performed in terminally anaesthetized mice. Western blot was performed in bladders to detect phosphorylated endothelial NO synthase (eNOS) (Ser1177) and the phosphorylated protein kinase AKT (Ser473), as well as the unfolded protein response (UPR) markers TRIB3, CHOP and ATF4. Insulin (1-100 nm) produced concentration-dependent mouse and human bladder relaxations that were markedly reduced by mucosal removal or inhibition of the PI3K/AKT/eNOS pathway. In mouse bladders, insulin produced a 3.0-fold increase in cGMP levels (P < 0.05) that was prevented by PI3K/AKT/eNOS pathway inhibition. Phosphoinositide 3-kinase (PI3K) inhibition abolished insulin-induced phosphorylation of AKT and eNOS in bladder mucosa. Obese mice showed greater voiding frequency and non-voiding contractions, indicating overactive detrusor smooth muscle. Insulin failed to relax the bladder or to increase cGMP in the obese group. Insulin-stimulated AKT and eNOS phosphorylation in mucosa was also impaired in obese mice. The UPR markers TRIB3, CHOP and ATF4 were increased in the mucosa of obese mice. The UPR inhibitor 4-phenyl butyric acid normalized all the functional and molecular parameters in obese mice. Our data show that insulin relaxes human and mouse bladder via activation of the PI3K/AKT/eNOS pathway in the bladder mucosa. Endoplasmic reticulum stress-dependent insulin resistance in bladder contributes to OAB in obese mice.