Age is not a sole predictor of outcomes in octogenarians undergoing complex endovascular aortic repair.

OBJECTIVE: To examine the perioperative, postoperative, and long-term outcomes of fenestrated/branched endovascular aneurysm repair (F/BEVAR) in octogenarians compared with nonoctogenarians. METHODS: A multicenter, retrospective cohort study was conducted using the Vascular Quality Improvement database, which prospectively captures information on patients who undergo vascular surgery across 1021 academic and community hospitals in North America. All patients who underwent F/BEVAR endovascular aortic repair from 2012 to 2022 were included. Patients were stratified into two groups: those aged <80 years and those aged ≥80 years at the time of the procedure. The preoperative, intraoperative, and postoperative factors were compared between the two groups. The primary outcome was long-term all-cause mortality; secondary outcomes included aortic-specific mortality and aortic-specific reintervention. RESULTS: A total of 6007 patients (aged <80 years, n = 4860; aged ≥80 years, n = 1147) who had undergone F/BEVAR procedures were included. No significant difference was found in technical success, postoperative length of stay, length of intensive care unit stay, postoperative bowel ischemia, and spinal cord ischemia. After adjustment for baseline covariates, octogenarians were more likely to suffer from a postoperative complication (odds ratio [OR]: 1.16; [95% confidence interval (CI): 0.98-1.37], P < .001) and be discharged to a rehabilitation center (OR: 1.60; [95% CI: 1.27-2.00], P < .001) or nursing home (OR: 2.23; [95% CI: 1.64-3.01], P < .001). Five-year survival was lower in octogenarians (83% vs 71%, hazard ratio [HR]: 1.70; [95% CI: 1.46-2.0], P < .0001). Multivariate Cox proportional hazard analysis demonstrated that age was associated with increased all-cause mortality (HR: 1.72, [95% CI: 1.39-2.12], P < .001) and aortic-specific mortality (HR: 1.92, [95% CI: 1.04-3.68], P = .038). Crawford extent II aortic disease was associated with an increase in all-cause mortality (HR 1.49; [95% CI: 1.01-2.19], P < .001), aortic-specific mortality (HR: 5.05; [95% CI: 1.35-18.9], P = .016), and aortic-specific reintervention (HR: 1.91; [95% CI: 1.24-2.93], P = .003). Functional dependence was associated with increased all-cause mortality (HR: 2.90; [95% CI: 1.87-4.51], P < .001) and aortic-specific mortality (HR: 4.93; [95% CI: 1.69-14.4], P = .004). CONCLUSIONS: Our findings suggest that octogenarians do have a mildly increased mortality rate and rate of adverse events after F/BEVAR procedures. Despite this, when adjusted for other risk factors, age is on par with other medical comorbidities and therefore should not be a strict exclusion criterion for F/BEVAR procedures, rather considered in the global context of patient's aortic anatomy, health, and functional status.

Evaluating the influence of altered cerebral hemodynamics on cognitive performance in asymptomatic carotid artery stenosis: A systematic review.

OBJECTIVE: Substantial controversy exists regarding asymptomatic carotid stenosis (ACS) and its potential role in the pathophysiology of cognitive impairment. If proven, this hypothesis may suggest an additional definition for symptomatic carotid disease that would alter current management. This study aimed to synthesize the literature evaluating the relationship between impaired cerebral hemodynamics and cognition in patients with ACS. METHODS: A literature search was performed using MEDLINE, Embase, and EBM Reviews through May 2022. We included prospective case-control studies that used validated, objective measure(s) of either global cognition or one or more domains of cognitive function and assessed cerebrovascular reserve (CVR). RESULTS: Five studies were included, comprising a total of 782 patients with moderate (50%-69%) to severe (70%-99%) ACS. Patients with ACS and impaired ipsilateral CVR demonstrated significant cognitive impairment compared with controls. Patients with unilateral or bilateral ACS and normal CVR had cognitive scores similar to controls. Those with bilateral CVR impairment demonstrated the lowest cognitive scores. CONCLUSIONS: This review lends support to the claim that cognitive impairment, likely the result of impaired cerebral hemodynamics, is an under-recognized morbidity in patients with ACS. CVR may serve as an additional tool to determine whether patients are in fact symptomatic from their carotid stenosis and warrant consideration for intervention.

Assessing the robustness of positive vascular surgery randomized controlled trials using their fragility index.

OBJECTIVE: The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. METHODS: In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. RESULTS: Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P = .035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P = .01, respectively). The FI did not vary between disease states (P = .285) or between index and follow-up trials (P = .147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). CONCLUSIONS: A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery.

The Impact of Heparin on Mortality Following Open Ruptured Abdominal Aortic Aneurysm Repair.

BACKGROUND: Systemic administration of heparin is widely used in patients undergoing open elective abdominal aortic aneurysm (AAA) repair. However, no clear consensus exists in the use of intraoperative heparin during open ruptured AAA (rAAA) repair. In this study, we assessed the safety of intravenous heparin administration in patients undergoing open rAAA repair. METHODS: A retrospective cohort study comparing patients who received and did not receive heparin during open rAAA repair in the Vascular Quality Initiative database between 2003 and 2020 was conducted. The primary outcomes were 30-day and 10-year mortality. The secondary outcomes included estimated blood loss, number of packed red blood cells transfused, early postoperative transfusions, and postsurgical complications. Propensity score matching was used to adjust for potentially confounding variables. The outcomes were compared between the 2 groups using relative risk for binary outcomes and paired t-test and the Wilcoxon rank-sum test for normally and non-normally distributed continuous variables, respectively. Survival was examined using Kaplan-Meier curves and compared using a Cox proportional hazards model. RESULTS: A total of 2,410 patients who underwent open rAAA repair between 2003 and 2020 were studied. Of the 2,410 patients, 1,853 patients received intraoperative heparin and 557 did not. Propensity score matching on 25 variables yielded 519 pairs for the heparin to no heparin comparison. Thirty-day mortality was lower in the heparin group (risk ratio: 0.74; 95% confidence interval [CI]: 0.66-0.84) and in-hospital was also lower in the heparin group (risk ratio: 0.68; 95% CI: 0.60-0.77). Furthermore, estimated blood loss was 910 mL (95% CI: 230 mL to 1,590 mL) lower in the heparin group and the mean number of packed red blood cells transfused intraoperatively and postoperatively were 17 units lower in the heparin group (95% CI: 8-42). Ten-year survival was higher for patients who received heparin, and their rate of survival was approximately 40% higher than those who did not receive heparin (hazard ratio: 0.62; 95% CI, 0.53-0.72; P < 0.0001). CONCLUSIONS: In patients who received systemic heparin administration at the time of open rAAA repair, there were significant short-term and long-term survival benefits within 30 days and at 10 years. Heparin administration may have afforded a mortality benefit or been a surrogate for healthier and less moribund patients at the time of the procedure.

Racial and ethnic differences in presentation severity and postoperative outcomes in vascular surgery.

BACKGROUND: We assessed the effect of race and ethnicity on presentation severity and postoperative outcomes in those with abdominal aortic aneurysms (AAAs), carotid artery stenosis (CAS), peripheral arterial disease (PAD), and type B aortic dissection (TBAD). METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception until December 2020. Two reviewers independently selected randomized controlled trials and observational studies reporting race and/or ethnicity and presentation severity and/or postoperative outcomes for adult patients who had undergone major vascular procedures. They independently extracted the study data and assessed the risk of bias using the Newcastle-Ottawa scale. The meta-analysis used random effects models to derive the odds ratios (ORs) and risk ratios (RRs) and their corresponding 95% confidence intervals (CIs). The primary outcome was presentation severity stratified by the proportion of patients with advanced disease, including ruptured vs nonruptured AAA, symptomatic vs asymptomatic CAS, chronic limb-threatening ischemia vs claudication, and complicated vs uncomplicated TBAD. The secondary outcomes included postoperative all-cause mortality and disease-specific outcomes. RESULTS: A total of 81 studies met the inclusion criteria. Black (OR, 4.18; 95% CI, 1.31-13.26), Hispanic (OR, 2.01; 95% CI, 1.85-2.19), and Indigenous (OR, 1.97; 95% CI, 1.39-2.80) patients were more likely to present with ruptured AAAs than were White patients. Black and Hispanic patients had had higher symptomatic CAS (Black: OR, 1.20; 95% CI, 1.04-1.38; Hispanic: OR, 1.32; 95% CI, 1.20-1.45) and chronic limb-threatening ischemia (Black: OR, 1.67; 95% CI, 1.14-2.43; Hispanic: OR, 1.73; 95% CI 1.13-2.65) presentation rates. No study had evaluated the effect of race or ethnicity on complicated TBAD. All-cause mortality was higher for Black (RR, 1.23; 95% CI, 1.01-1.51), Hispanic (RR, 1.90; 95% CI, 1.57-2.31), and Indigenous (RR, 1.24; 95% CI, 1.12-1.37) patients after AAA repair. Postoperatively, Black (RR, 1.54; 95% CI, 1.19-2.00) and Hispanic (RR, 1.54; 95% CI, 1.31-1.81) patients were associated with stroke/transient ischemic attack after carotid revascularization and lower extremity amputation (RR, 1.90; 95% CI, 1.76-2.06; and RR, 1.69; 95% CI, 1.48-1.94, respectively). CONCLUSIONS: Certain visible minorities were associated with higher morbidity and mortality across various vascular surgery presentations. Further research to understand the underpinnings is required.

Plasma complement component C2: a potential biomarker for predicting abdominal aortic aneurysm related complications.

Blood-based adjunctive measures that can reliably predict abdominal aortic aneurysm (AAA)-related complications hold promise for mitigating the AAA disease burden. In this pilot study, we sought to evaluate the prognostic performance of complement factors in predicting AAA-related clinical outcomes. We recruited consecutive AAA patients (n = 75) and non-AAA patients (n = 75) presenting to St. Michael's Hospital. Plasma levels of complement proteins were assessed at baseline, as well as prospectively measured regularly over a period of 2 years. The primary outcome was the incidence of rapidly progressing AAA (i.e. aortic expansion), defined as change in AAA diameter by either 0.5 cm in 6 months, or 1 cm in 12 months. Secondary outcomes included incidence of major adverse aortic events (MAAE) and major adverse cardiovascular events (MACE). All study outcomes (AAA diameter, MACE and MAAE) were obtained during follow-up. Multivariable adjusted Cox regression analyses were performed to assess the prognostic value of plasma C2 levels in patients with AAA regarding rapid aortic expansion and MAAE and MACE. Event-free survival rates of both groups were also compared. Compared to non-AAA patients, patients with AAA demonstrated significantly higher plasma concentrations of C1q, C4, Factor B, Factor H and Factor D, and significantly lower plasma concentrations of C2, C3, and C4b (p = 0.001). After a median of 24 months from initial baseline measurements, C2 was determined as the strongest predictor of rapid aortic expansion (HR 0.10, p = 0.040), MAAE (HR 0.09, p = 0.001) and MACE (HR 0.14, p = 0.011). Based on the data from the survival analysis, higher levels of C2 at admission in patients with AAA predicted greater risk for rapid aortic expansion and MAAE (not MACE). Plasma C2 has the potential to be a biomarker for predicting rapid aortic expansion, MAAE, and the eventual need for an aortic intervention in AAA patients.

A systematic review and meta-analysis of sex- and gender-based differences in presentation severity and outcomes in adults undergoing major vascular surgery.

BACKGROUND: Studies have investigated the effects of gender on vascular surgery care. However, to the best of our knowledge, no comprehensive synthesis of the literature has been performed on the presentation severity and postoperative outcomes for abdominal aortic aneurysms (AAAs), carotid artery stenosis (CAS), peripheral artery disease (PAD), and type B aortic dissection (TBAD). We conducted a systematic review and meta-analysis of the sex and gender differences in the presentation severity and outcomes for patients who had undergone major vascular surgery. METHODS: The MEDLINE, Embase, and Cochrane CENTRAL databases were searched from their inception to December 2020. All observational studies and randomized controlled trials that had evaluated the gender differences in presentation severity or outcomes for patients who had undergone open or endovascular AAA or TBAD repair, carotid endarterectomy or stenting, or lower extremity bypass or angioplasty were included. The presentation severity was defined as follows: AAA (symptomatic or ruptured vs asymptomatic), carotid artery disease (symptomatic vs asymptomatic), PAD (chronic limb-threatening ischemia [CLTI] vs claudication), and TBAD (complicated vs uncomplicated). The postoperative outcomes included long-term mortality, stroke, amputation, revascularization, and graft and/or stent thrombosis. A random effects model was used to derive the odds ratios (ORs), risk ratios (RRs), and 95% confidence intervals (CIs). RESULTS: A total of 236 studies met the inclusion criteria for our systematic review. Of the 236 studies, 86 (n = 2,099,534 patients), 62 (n = 2,300,888 patients), 28 (n = 2,394,143 patients), and 4 (n = 4525 patients) had evaluated the effects of gender on the outcomes for patients with AAA, CAS, PAD, and TBAD, respectively. The female patients were more likely to have presented with a ruptured AAA (OR, 1.18; 95% CI, 1.09-1.28) and CLTI (OR, 1.10; 95% CI, 1.02-1.19) than were the male patients. The all-cause mortality for those with an AAA (RR, 1.35; 95% CI, 1.20-1.52) and those with PAD (RR, 1.14; 95% CI, 1.05-1.23) was higher for the women. However, the female patients with CAS had had lower all-cause mortality (RR, 0.85; 95% CI, 0.76-0.94). No sex differences were found in the TBAD outcomes. CONCLUSIONS: We found that female patients who had undergone vascular surgery were associated with more severe disease at presentation, with a greater proportion of ruptured AAAs and CLTI. This potentially contributes to the higher mortality rates for female patients with AAAs and PAD compared with male patients. Future studies are needed to evaluate the reasons for these disparities, and greater efforts are required to support women in receiving more timely vascular surgical care.

A mouse model of inherited choline kinase ß-deficiency presents with specific cardiac abnormalities and a predisposition to arrhythmia.

The CHKB gene encodes choline kinase ß, which catalyzes the first step in the biosynthetic pathway for the major phospholipid phosphatidylcholine. Homozygous loss-of-function variants in human CHKB are associated with a congenital muscular dystrophy. Dilated cardiomyopathy is present in some CHKB patients and can cause heart failure and death. Mechanisms underlying a cardiac phenotype due to decreased CHKB levels are not well characterized. We determined that there is cardiac hypertrophy in Chkb-/- mice along with a decrease in left ventricle size, internal diameter, and stroke volume compared with wildtype and Chkb+/- mice. Unlike wildtype mice, 60% of the Chkb+/- and all Chkb-/- mice tested displayed arrhythmic events when challenged with isoproterenol. Lipidomic analysis revealed that the major change in lipid level in Chkb+/- and Chkb-/- hearts was an increase in the arrhythmogenic lipid acylcarnitine. An increase in acylcarnitine level is also associated with a defect in the ability of mitochondria to use fatty acids for energy and we observed that mitochondria from Chkb-/- hearts had abnormal cristae and inefficient electron transport chain activity. Atrial natriuretic peptide (ANP) is a hormone produced by the heart that protects against the development of heart failure including ventricular conduction defects. We determined that there was a decrease in expression of ANP, its receptor NPRA, as well as ventricular conduction system markers in Chkb+/- and Chkb-/- mice.

Machine learning in vascular surgery: a systematic review and critical appraisal.

Machine learning (ML) is a rapidly advancing field with increasing utility in health care. We conducted a systematic review and critical appraisal of ML applications in vascular surgery. MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to March 1, 2021. Study screening, data extraction, and quality assessment were performed by two independent reviewers, with a third author resolving discrepancies. All original studies reporting ML applications in vascular surgery were included. Publication trends, disease conditions, methodologies, and outcomes were summarized. Critical appraisal was conducted using the PROBAST risk-of-bias and TRIPOD reporting adherence tools. We included 212 studies from a pool of 2235 unique articles. ML techniques were used for diagnosis, prognosis, and image segmentation in carotid stenosis, aortic aneurysm/dissection, peripheral artery disease, diabetic foot ulcer, venous disease, and renal artery stenosis. The number of publications on ML in vascular surgery increased from 1 (1991-1996) to 118 (2016-2021). Most studies were retrospective and single center, with no randomized controlled trials. The median area under the receiver operating characteristic curve (AUROC) was 0.88 (range 0.61-1.00), with 79.5% [62/78] studies reporting AUROC ≥ 0.80. Out of 22 studies comparing ML techniques to existing prediction tools, clinicians, or traditional regression models, 20 performed better and 2 performed similarly. Overall, 94.8% (201/212) studies had high risk-of-bias and adherence to reporting standards was poor with a rate of 41.4%. Despite improvements over time, study quality and reporting remain inadequate. Future studies should consider standardized tools such as PROBAST and TRIPOD to improve study quality and clinical applicability.

Regulation of Transplanted Cell Homing by FGF1 and PDGFB after Doxorubicin Myocardial Injury.

There is no effective treatment for the total recovery of myocardial injury caused by an anticancer drug, doxorubicin (Dox). In this study, using a Dox-induced cardiac injury model, we compared the cardioprotective effects of ventricular cells harvested from 11.5-day old embryonic mice (E11.5) with those from E14.5 embryos. Our results indicate that tail-vein-infused E11.5 ventricular cells are more efficient at homing into the injured adult myocardium, and are more angiogenic, than E14.5 ventricular cells. In addition, E11.5 cells were shown to mitigate the cardiomyopathic effects of Dox. In vitro, E11.5 ventricular cells were more migratory than E14.5 cells, and RT-qPCR analysis revealed that they express significantly higher levels of cytokine receptors Fgfr1, Fgfr2, Pdgfra, Pdgfrb and Kit. Remarkably, mRNA levels for Fgf1, Fgf2, Pdgfa and Pdgfb were also found to be elevated in the Dox-injured adult heart, as were the FGF1 and PDGFB protein levels. Addition of exogenous FGF1 or PDGFB was able to enhance E11.5 ventricular cell migration in vitro, and, whereas their neutralizing antibodies decreased cell migration. These results indicate that therapies raising the levels of FGF1 and PDGFB receptors in donor cells and or corresponding ligands in an injured heart could improve the efficacy of cell-based interventions for myocardial repair.

Fractionation of embryonic cardiac progenitor cells and evaluation of their differentiation potential.

Mid-gestation mouse ventricles (E11.5) contain a larger number of Nkx2.5+ cardiac progenitor cells (CPCs). The proliferation rates are consistently higher in CPCs compared to myocyte population of developing ventricles. Recent studies suggested that CPCs are an ideal donor cell type for replacing damaged tissue in diseased hearts. Thus, the ability to isolate and expand CPCs from embryos or stem cell cultures could be useful for cell fate studies and regenerative therapies. Since embryonic CPCs possess fewer mitochondria compared to cardiomyocytes, we reasoned that CPCs can be fractionated using a fluorescent mitochondrial membrane potential dye (TMRM) and these cells may retain cardiomyogenic potential even in the absence of cardiomyocytes (CMs). FACS sorting of TMRM stained embryonic ventricular cells indicated that over 99% of cells in TMRM high fraction stained positive for sarcomeric myosin (MF20) and all of them expressed Nkx2.5. Although majority of cells present in TMRM low fraction expressed Nkx2.5, very few cells (~1%) stained positive for MF20. Further culturing of TMRM low cells over a period of 48 h showed a progressive increase in MF20 positive cells. Additional analyses revealed that MF20 negative cells in TMRM low fraction do not express markers for endothelial cells (vWF, CD31) or smooth muscle cells (SM myosin). Treatment of TMRM low cells with known cardiogenic factors DMSO and dynorphin B significantly increased the percentage of MF20+ cells compared to untreated cultures. Collectively, these studies suggest that embryonic CPCs can be separated as a TMRM low fraction and their differentiation potential can be enhanced by exogenous addition of known cardiomyogenic factors.

Erratum: New insights and new hope for pulmonary arterial hypertension: natriuretic peptides clearance receptor as a novel therapeutic target for a complex disease.

[This corrects the article on p. 112 in vol. 9, PMID: 28951773.].

New insights and new hope for pulmonary arterial hypertension: natriuretic peptides clearance receptor as a novel therapeutic target for a complex disease.

BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a deadly and disabling disease for which there is no marketed drug that addresses the underlying disease mechanism and targets to cure patients. The lack of understanding of the disease mechanism represents the main challenges in developing curative therapies. We here report, for the first time, that mice lacking natriuretic peptides clearance receptor develop PAH. METHODS AND RESULTS: Initial studies assessed cardiac structure and function in NPR-C+/+ (wild type) and age matched, littermate NPR-C-/- mice by echocardiography. Mice lacking NPR-C had right atrial dilation, tricuspid regurgitation as well as echocardiographic signs of right ventricular pressure overload, including flattening and paradoxical bulging of the septum into the left ventricle during systole, and hypertrophy of the right ventricular free wall. Among the 10 NPR-C-/- mice aged between 12 and 20 weeks studied, 8 showed the above typical echocardiographic features of PAH [80%, 95% CI: (0.4439-0.9748)], and only one had pericardial effusion [10%, 95% CI: (0.0025-0.4450)], finding that has a prognostic significance in subjects affected by this clinical entity. To confirm the presence of increased right ventricular systolic pressure (RVSP) among NPR-C-/- mice, right heart catheterization was performed. Strikingly, RVSP was significantly elevated in NPR-C-/- mice compared to their age matched, littermate NPR-C+/+ mice, at baseline (21.95±0.56 mmHg vs. 5.3±0.6 mmHg, respectively (P<0.001)). CONCLUSION: The above results suggest that NPR-C-mediated signalling pathways play a critical role in the development of PAH, indicating that NPR-C is an important protective receptor in the heart rather than just being a clearance receptor.

A natriuretic peptides clearance receptor's agonist reduces pulmonary artery pressures and enhances cardiac performance in preclinical models: New hope for patients with pulmonary hypertension due to left ventricular heart failure.

BACKGROUND: In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) is common and represents a strong predictor of death. Despite recent advances in the pathophysiological understanding there is as yet no prospect of cure of this deadly clinical entity and the majority of patients continue to progress to right ventricular failure and die. Furthermore, there is no single medical treatment currently approved for PH related to HF. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent the progressive increased or reverse the elevated pulmonary arterial pressures while enhancing cardiac performance in HF. METHOD AND RESULTS: We here reported, for the first time, using a pressure-loop (P-V) conductance catheter system, that a specific natriuretic peptides clearance receptors' agonist, the ring-deleted atrial natriuretic peptide analogue, cANF4-23 (cANF) reduces pulmonary artery pressures. Strikingly, the administration of the cANF in these mice decreased the RVSP by 50% (n=5, F 25.687, DF 14, p<0.001) and heart rate (HR) by 11% (n=5, F 25.69, DF 14, p<0.001) as well as enhancing cardiac performance including left ventricular contractility in mice. Most strikingly, mice lacking NPR-C were much more susceptible to develop HF, indicating that NPR-C is a critical protective receptor in the heart. CONCLUSION: Natriuretic peptides clearance receptors' agonists may, therefore represent a novel and attractive therapeutic strategy for PH related to HF, and ultimately improves the life expectancy and quality for millions of people around the planet.

Effects of ß-adrenergic receptor drugs on embryonic ventricular cell proliferation and differentiation and their impact on donor cell transplantation.

ß-Adrenergic receptors (ß-ARs) and catecholamines are present in rodents as early as embryonic day (E)10.5. However, it is not known whether ß-AR signaling plays any role in the proliferation and differentiation of ventricular cells in the embryonic heart. Here, we characterized expression profiles of ß-AR subtypes and established dose-response curves for the nonselective ß-AR agonist isoproterenol (ISO) in the developing mouse ventricular cells. Furthermore, we investigated the effects of ISO on cell cycle activity and differentiation of cultured E11.5 ventricular cells. ISO treatment significantly reduced tritiated thymidine incorporation and cell proliferation rates in both cardiac progenitor cell and cardiomyocyte populations. The ISO-mediated effects on DNA synthesis could be abolished by cotreatment of E11.5 cultures with either metoprolol (a ß1-AR antagonist) or ICI-118,551 (a ß2-AR antagonist). In contrast, ISO-mediated effects on cell proliferation could be abolished only by metoprolol. Furthermore, ISO treatment significantly increased the percentage of differentiated cardiomyocytes compared with that in control cultures. Additional experiments revealed that ß-AR stimulation leads to downregulation of Erk and Akt phosphorylation followed by significant decreases in cyclin D1 and cyclin-dependent kinase 4 levels in E11.5 ventricular cells. Consistent with in vitro results, we found that chronic stimulation of recipient mice with ISO after intracardiac cell transplantation significantly decreased graft size, whereas metoprolol protected grafts from the inhibitory effects of systemic catecholamines. Collectively, these results underscore the effects of ß-AR signaling in cardiac development as well as graft expansion after cell transplantation.NEW & NOTEWORTHY ß-Adrenergic receptor (ß-AR) stimulation can decrease the proliferation of embryonic ventricular cells in vitro and reduce the graft size after intracardiac cell transplantation. In contrast, ß1-AR antagonists can abrogate the antiproliferative effects mediated by ß-AR stimulation and increase graft size. These results highlight potential interactions between adrenergic drugs and cell transplantation.

Mechanisms of renal hyporesponsiveness to BNP in heart failure.

The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, is a potent natriuretic, diuretic, and vasodilatory peptide that contributes to blood pressure and volume homeostasis. These attributes make BNP an ideal drug that could aid in diuresing a fluid-overloaded patient who had poor or worsening renal function. Despite the potential benefits of BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily increase natriuresis in patients with heart failure (HF). Moreover, despite high BNP levels, natriuresis falls when HF progresses from a compensated to a decompensated state, suggesting the emergence of renal resistance to BNP. Although likely multifactorial, several mechanisms have been proposed to explain renal hyporesponsiveness in HF, including, but not limited to, decreased renal BNP availability, down-regulation of natriuretic peptide receptors, and altered BNP intracellular signal transduction pathways. Thus, a better understanding of renal hyporesponsiveness in HF is required to devise strategies to develop novel agents and technologies that directly restore renal BNP efficiency. It is hoped that development of these new therapeutic approaches will serve to limit sodium retention in patients with HF, which may ultimately delay the progression to overt HF.

Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis.

The biological effects of atrial natriuretic peptide (ANP) are mediated by natriuretic peptide receptors (NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptor-specific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/cGMP-mediated signaling pathways.

Divergent cell cycle kinetics of midgestation ventricular cells entail a higher engraftment efficiency after cell transplantation.

Cardiac progenitor cells (CPCs) in the primary and secondary heart fields contribute to the formation of all major cell types in the mammalian heart. While some CPCs remain undifferentiated in midgestation and postnatal hearts, very little is known about their proliferation and differentiation potential. In this study, using an Nkx2.5 cell lineage-restricted reporter mouse model, we provide evidence that Nkx2.5(+) CPCs and cardiomyocytes can be readily distinguished from nonmyocyte population using a combination of Nkx2.5 and sarcomeric myosin staining of dispersed ventricular cell preparations. Assessment of cell number and G1/S transit rates during ventricular development indicates that the proliferative capacity of Nkx2.5(+) cell lineage gradually decreases despite a progressive increase in Nkx2.5(+) cell number. Notably, midgestation ventricles (E11.5) contain a larger number of CPCs (∼2-fold) compared with E14.5 ventricles, and the embryonic CPCs retain cardiomyogenic differentiation potential. The proliferation rates are consistently higher in embryonic CPCs compared with myocyte population in both E11.5 and E14.5 ventricles. Results from two independent cell transplantation models revealed that E11.5 ventricular cells with a higher percentage of proliferating CPCs can form larger grafts compared with E14.5 ventricular cells. Furthermore, transplantation of embryonic ventricular cells did not cause any undesirable side effects such as arrhythmias. These data underscore the benefits of donor cell developmental staging in myocardial repair.

Drug-eluting nasal implants: formulation, characterization, clinical applications and challenges.

Chronic inflammation and infection of the nasal sinuses, also referred to as Chronic Rhinosinusitis (CRS), severely affects patients' quality of life. Adhesions, ostial stenosis, infection and inflammation relapses complicate chronic sinusitis treatment strategies. Drug-eluting stents, packings or implants have been suggested as reasonable alternatives for addressing these concerns. This article reviewed potential drug candidates for nasal implants, formulation methods/optimization and characterization methods. Clinical applications and important considerations were also addressed. Clinically-approved implants (Propel™ implant, the Relieva stratus™ MicroFlow spacer, and the Sinu-Foam™ spacer) for CRS treatment was an important focus. The advantages and limitations, as well as future considerations, challenges and the need for additional research in the field of nasal drug implant development, were discussed.