Inhibition of phosphodiesterase 5 selectively reverses nitrate tolerance in the venous circulation

An important component of the antianginal efficacy of glyceryl trinitrate (GTN) is attributable to its selective venodilator effect, resulting in decreased cardiac preload and myocardial oxygen demand. Tolerance to nitrates occurs during chronic exposure, and the current study assessed whether this was due to increased phosphodiesterase (PDE) activity in the venous circulation. Tolerance was induced in rats by continuous exposure to 0.4 mg/h GTN for 48 h. Tension recordings of isolated femoral artery and vein indicated that tolerance was more pronounced in femoral vein. 4-[[3,4-(Methylenedioxy)benzyl]amino]-6-chloroquinazoline (MBCQ), a selective PDE5 inhibitor, significantly decreased the EC(50) values for GTN-induced relaxation in both tolerant and nontolerant tissues, but with the greatest relative shift occurring in tolerant veins. MBCQ also increased the vasodilator potency of 1,1-diethyl-2-hydroxy-2-nitrosohydrazine (DEA/NO), a nitric oxide donor; however, cross-tolerance between DEA/NO and GTN was not observed. A significant increase in cGMP PDE activity was observed in tolerant femoral vein, whereas PDE activity was unchanged in femoral artery. Conscious rats treated with hexamethonium (30 mg/kg) to induce ganglionic blockade exhibited blunted central venous pressure (CVP) and mean arterial pressure (MAP) responses to bolus i.v. doses of GTN in GTN-tolerant animals. The cGMP PDE inhibitor zaprinast (1 mg/kg) selectively reversed the blunted CVP response to GTN in tolerant animals but had no effect on the CVP response to GTN in nontolerant animals or on the MAP response in either group. These results suggest that increased PDE5 activity in the venous circulation contributes to the altered hemodynamic response to GTN following chronic GTN exposure.     

Canadian Consensus on cardiac transplantation in pediatric and adult congenital heart disease patients 2004: executive summary

Cardiac transplantation is an acceptable therapeutic option for the pediatric age group and for adult patients with congenital heart disease. There are a myriad of clinical diagnoses in these two patient populations. Survival has continued to improve, with graft half-lives of 14 years and greater in pediatric heart transplantation patients. There are issues unique to these patient populations in relation to heart transplantation for which the present document summarizes the relevant literature and presents management guidelines. Donor availability remains a major limiting factor in organ transplantation at present. Efforts need to be made to increase organ donor awareness, identify potential donors and aggressively manage marginal donors. Indications for transplantation and determination of timing of listing continue to be challenging due to a lack of evidence-based guidelines specifically for prognostic indices of outcome and pretransplant survival. The current status system for listing patients for transplantation does not necessarily reflect the typical clinical course of deterioration experienced by these two patient populations; therefore, consideration needs to be given to a parallel listing strategy. Evidence is accumulating pointing to an advantage to performing transplantations in patients in early infancy. ABO-incompatible heart transplantation has lead to a reduction in waiting time and waiting list mortality. Care of children after heart transplantation must take into consideration physical growth and multisystem development; stage of immunological maturation; intellectual, emotional and social maturation; educational activities; and other pediatric quality of life parameters. Post-transplantation issues are somewhat different, including rejection, coronary artery disease, malignancies and infections. Efforts need to be made to support multicentre trials to determine optimal treatment protocols.     

Improving nutritional status among urban poor children in sub‐Saharan Africa: An evidence‐informed Delphi‐based consultation

In sub‐Saharan Africa (SSA), rapid urbanisation coupled with the high prevalence of infant and young child (IYC) undernutrition in low‐income settings means that interventions to support IYC nutrition are a priority. Little is known about how urbanisation influences IYC feeding (IYCF) practices, and evidence‐based interventions to improve IYC health/nutrition in the urban poor are lacking. Therefore, this research aimed to (a) systematically review evidence on interventions for improving the nutritional status of IYC aged 6–23 months living in urban poor areas (PROSPERO CRD42018091265) and (b) engage stakeholders to identify the highest ranking evidence gaps for improving IYCF programmes/policies. First, a rapid systematic review was conducted. This focused on the literature published regarding nutrition‐specific and nutrition‐sensitive complementary feeding interventions in urban poor areas, specifically low‐income informal settlements, in low‐ and middle‐income countries (LMICs). Six intervention studies met the review inclusion criteria. Intervention adherence was generally high, and indicators of maternal knowledge and IYC nutritional intake typically increased because of the interventions, but the impact on anthropometric status was small. Second, stakeholders working across SSA were engaged via a Delphi‐based approach to identify priority areas for future intervention. Stakeholders reported that a situational analysis was required to better understand IYCF in urban poor areas, particularly the causes of IYC undernutrition, and highlighted the need to involve local communities in defining how future work should proceed. Together, these findings indicate a need for more evidence regarding IYCF and the factors that drive it in urban poor areas across LMIC settings, but particularly in SSA.     

Nutrition, total fluid and bladder cancer

Bladder cancer is a major health concern for older males in Western populations. About 30 years ago there was a suggestion that nutrition may have a role in the aetiology of the disease. Although the literature has been accumulating since then, owing to heterogeneity between studies results have often been inconsistent and unclear. The aim of this paper was to present an updated summary of the scientific evidence on the association between nutrition, total fluid intake and bladder cancer. A search of computerized databases, PubMed, ISI, Embase and Cochrane Library, was conducted to identify all epidemiological studies published between 1966 and October 2007. The level of scientific evidence for the various nutritional factors and total fluid intake was ranked according to the number of studies reporting a statistically significant association and the existence of mechanistic evidence. The levels of association were based on a ranking of statistically significant relative risks. Fruit and yellow-orange vegetables, particularly carrots and selenium, are probably associated with a moderately reduced risk of bladder cancer. Citrus fruits and cruciferous vegetables were also identified as having a possible protective effect. Possible risk factors are salted and barbecued meat, pork, total fat, pickled vegetables, salt, soy products, spices and artificial sweeteners. No clear association could be determined for beef, eggs, processed meats and total fluid intake. In conclusion, specific fruit and vegetables may act to reduce the risk of bladder cancer. Future studies on bladder cancer should investigate the effect of food categorization, amount and gender.     

Acute and chronic effects of continuous positive airway pressure therapy on left ventricular systolic and diastolic function in patients with obstructive sleep apnea and congestive heart failure

BACKGROUND:

Obstructive sleep apnea (OSA) may contribute to the pathogenesis of congestive heart failure (CHF). Nocturnal continuous positive airway pressure (CPAP) therapy can alleviate OSA and may have a role in the treatment of CHF patients.

OBJECTIVES:

To investigate the acute and chronic effects of CPAP therapy on left ventricular systolic function, diastolic function and filling pressures in CHF patients with OSA.

METHODS:

Twelve patients with stable CHF (New York Heart Association II or III, radionuclide ejection fraction lower than 40%) underwent overnight polysomnography to detect OSA. In patients with OSA (n=7), echocardiography was performed at baseline (awake, before and during acute CPAP administration) and after 6.9±3.3 weeks of nocturnal CPAP therapy. Patients without OSA (n=5) did not receive CPAP therapy, but underwent a baseline and follow-up echocardiogram.

RESULTS:

In CHF patients with OSA, acute CPAP administration resulted in a decrease in stroke volume (44±15 mL versus 50±14 mL, P=0.002) and left ventricular ejection fraction ([LVEF] 34.8±5.0% versus 38.4±3.3%, P=0.006) compared with baseline, but no change in diastolic function or filling pressures (peak early diastolic mitral annular velocity [Ea]: 6.0±1.6 cm/s versus 6.3±1.6 cm/s, P not significant; peak early filling velocity to peak late filling velocity [E/A] ratio: 1.05±0.74 versus 1.00±0.67, P not significant; E/Ea ratio: 10.9±4.1 versus 11.3±4.1, P not significant). In contrast, chronic CPAP therapy resulted in a trend to an increase in stroke volume (59±19 mL versus 50±14 mL, P=0.07) and a significant increase in LVEF (43.4±4.8% versus 38.4±3.3%, P=0.01) compared with baseline, but no change in diastolic function or filling pressures (Ea: 6.2±1.2 cm/s versus 6.3±1.6 cm/s, P not significant; E/A ratio: 1.13±0.61 versus 1.00±0.67, P not significant; E/Ea ratio: 12.1±2.7 versus 11.3±4.1, P not significant). There was no change in left ventricular systolic function, diastolic function or filling pressures at follow-up in CHF patients without OSA.

CONCLUSIONS:

Acute CPAP administration decreased stroke volume and LVEF in stable CHF patients with OSA. In contrast, chronic CPAP therapy for seven weeks improved left ventricular systolic function, but did not affect diastolic function or filling pressures. The potential clinical implications of the discrepant effects of CPAP therapy on left ventricular systolic and diastolic function in CHF patients with OSA warrant further study.     

Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knock out mice

Rationale

Obstructive sleep apnea results in nocturnal intermittent hypoxia (IH) as a main trigger for cardiovascular morbidity, including atherosclerosis. IH induces hemodynamic, hormono-metabolic and also immuno-inflammatory alterations that could differentially contribute to atherosclerosis. Our study aimed at examining their respective contribution to the proatherogenic role of IH in atherosclerosis-prone mice.

Methods

Fifteen-week-old male apolipoprotein E-deficient (ApoE^−/−) mice fed on a high-cholesterol diet (HCD) for 6 weeks and exposed for the last 14 days to IH (21–5% FiO₂, 60 s cycle, 8 h/day) or air, were investigated for aortic atherosclerosis and lipid alterations. Then IH proatherogenicity was assessed in 15- and 20-week-old ApoE^−/− mice fed on a standart-chow diet (SCD) exposed to IH or air for 14 days and assessed for atherosclerosis, lipid, hemodynamic and inflammation alterations.

Results

IH aggravated atherosclerosis in HCD-fed mice, whereas the extremely high cholesterol levels due to HCD were not different between normoxic and hypoxic animals. In SCD-fed mice, IH also aggravated atherosclerosis, more severely in 20 compared to 15-week-old animals. However, cholesterol levels that increased with IH were not different in the two SCD-fed groups. IH slightly elevated arterial blood pressure in 20-week-old animals only, and induced systemic and vascular inflammation, including increased splenocyte proliferation with decreased IL-10 secretion, and increased T-lymphocytes within atherosclerotic plaques.

Conclusions

A short IH exposure without HCD has proatherogenic effects. In contrast to blood pressure or plasma lipids which were slightly or inconstantly affected by IH, inflammation at systemic and vascular levels appears as a potential contributing factor to IH atherogenicity.     

DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. The exact nature of the breaks, and their location, has not been entirely clear, and it has not been evident how cells survive, replicate, and maintain genome integrity in environments like the renal inner medulla in which cells are constantly exposed to high NaCl concentration. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. Here, we confirm by specific comet assay and pulsed-field electrophoresis that cells adapted to high NaCl have increased levels of double-strand breaks. Importantly, γH2AX foci that occur during repair of the breaks are nonrandomly distributed in the mouse genome. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double-strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes ("gene deserts"), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation, and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes.     

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure. The aim of this study was to investigate the role of cardiac Fstl1 in the remodeling response to pressure overload. Cardiac myocyte-specific Fstl1-KO mice were constructed and subjected to pressure overload induced by transverse aortic constriction (TAC). Although Fstl1-KO mice displayed no detectable baseline phenotype, TAC led to enhanced cardiac hypertrophic growth and a pronounced loss in ventricular performance by 4 wk compared with control mice. Conversely, mice that acutely or chronically overexpressed Fstl1 were resistant to pressure overload-induced hypertrophy and cardiac failure. Fstl1-deficient mice displayed a reduction in TAC-induced AMP-activated protein kinase (AMPK) activation in heart, whereas Fstl1 overexpression led to increased myocardial AMPK activation under these conditions. In cultured neonatal cardiomyocytes, administration of Fstl1 promoted AMPK activation and antagonized phenylephrine-induced hypertrophy. Inhibition of AMPK attenuated the antihypertrophic effect of Fstl1 treatment. These results document that cardiac Fstl1 functions as an autocrine/paracrine regulatory factor that antagonizes myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload, possibly through a mechanism involving the activation of the AMPK signaling axis.     

Infant formula alters surfactant protein A (SP-A) and SP-B expression in pulmonary epithelial cells

Surfactant proteins A (SP-A) and SP-B are critical in the ability of pulmonary surfactant to reduce alveolar surface tension and provide innate immunity. Aspiration of infant milk formula can lead to lung dysfunction, but direct effects of aspirated formula on surfactant protein expression in pulmonary cells have not been described. The hypothesis that infant formula alters surfactant protein homeostasis was tested in vitro by assessing surfactant protein gene expression in cultured pulmonary epithelial cell lines expressing SP-A and SP-B that were transiently exposed (6 hr) to infant formula. Steady-state levels of SP-A protein and mRNA and SP-B mRNA in human bronchiolar (NCI-H441) and mouse alveolar (MLE15) epithelial cells were reduced in a dose-dependent manner 18 hr after exposure to infant formula. SP-A mRNA levels remained reduced 42 hr after exposure, but SP-B mRNA levels increased 10-fold. Neither soy formula nor non-fat dry milk affected steady-state SP-A and SP-B mRNA levels; suggesting a role of a component of infant formula derived from cow milk. These results indicate that infant formula has a direct, dose-dependent effect to reduce surfactant protein gene expression. Ultimately, milk aspiration may potentially result in a reduced capacity of the lung to defend against environmental insults.     

A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A

Background

Severe hemophilia requires life-long treatment with expensive clotting factor concentrates; studies comparing effects of different therapeutic strategies over decades are very difficult to perform. A simulation model was developed to evaluate the long-term outcome of on demand, prophylactic and mixed treatment strategies for patients with severe hemophilia A.

Design and Methods

A computer model was developed based on individual patients’ data from a Dutch cohort study in which intermediate dose prophylaxis was used and a French cohort study in which on demand treatment was used, and multivariate regression analyses. This model simulated individual patients’ life expectancy, onset of bleeding, life-time joint bleeds, radiological outcome and concentrate use according to the different treatment strategies.

Results

According to the model, life-time on demand treatment would result in an average of 1,494 joint bleeds during the hemophiliac’s life, and consumption of 4.9 million IU of factor VIII concentrate. In contrast, life-time intermediate dose prophylaxis resulted in a mean of 357 joint bleeds and factor consumption of 8.3 million IU. A multiple switch strategy (between prophylactic and on demand treatment based on bleeding pattern) resulted in a mean number of 395 joint bleeds and factor consumption of 6.6 million IU. The estimated proportion of patients with Pettersson scores over 28 points was 32% for both the prophylactic and the multiple switching strategies, compared to 76% for continuous on demand treatment.

Conclusions

The present model allows evaluation of the impact of various treatment strategies on patients’ joint bleeds and clotting factor consumption. It may be expanded with additional data to allow more precise estimates and include economic evaluations of treatment strategies.