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A 37-year-old athlete completed invasive endurance (90 km) bicycle exercise testing for right ventricular pressure-volume analysis. Increased right ventricular afterload caused declines in ventricular-arterial coupling and cardiac output, causing increased arteriovenous oxygen difference to maintain oxygen uptake. These findings demonstrate effects of changes in right ventricular performance on exercise capacity. (

Ischemic heart disease and stroke are the number 1 and number 2 causes of death worldwide, respectively. A lifelong commitment to exercise reduces the risk of these adverse events and is also associated with several cardiometabolic improvements, including reductions in blood pressure, cholesterol, and inflammatory markers, as well as improved glucose control. Routine exercise also reduces the risk of developing comorbidities that increase the risk of cardiovascular or cerebrovascular disease. While the benefits of a lifelong commitment to exercise are well documented, there is a complex interaction between exercise and stroke risk, such that the risk of ischemic or hemorrhagic stroke may increase acutely during or immediately following exercise. In this article, we discuss the physiological responses to different types of exercise, as well as the determinants of resting and exertional cerebrovascular perfusion, and explore the complex interaction between atrial fibrillation, exercise, and stroke risk. Finally, we highlight the increased risk of stroke during different types of exercise, as well as factors that may alleviate this risk.

Epicardial adipose (EA) tissue may limit effective radiofrequency ablation (RFA).We sought to evaluate the lesion formation of different ablation strategies on ventricular myocardium with overlying EA.Bovine myocardium with EA was placed in a circulating saline bath in an ex vivo model. Open-irrigated (OI) RFA was performed, parallel to the myocardium, over fat at 50 W for variable RF durations, variable contact force, catheter configurations (unipolar RF vs bipolar RF), and catheter irrigants (normal saline vs half-normal saline). Ablation was also performed with a needle-tipped ablation catheter (NTAC), perpendicular to the myocardium.Increasingly thick EA attenuated lesion size regardless of ablation strategy. RF applied with longer durations and increasing CF produced larger lesion volumes and deeper lesions with ablation over EA more than 3 mm but was unable to produce measurable lesions when EA less than 3 mm. Similarly, ablation with half normal saline irrigant created slightly deeper lesions than bipolar RF and unipolar RF with normal saline as EA thickness increased, but was unable to produce measurable lesions when EA more than 3 mm. Of all ablation strategies, only NTAC produced effective lesion volumes when ablating over thick (3 mm) EA.While EA attenuates lesion depth and size, relatively larger, and deeper lesions can be achieved with longer RFA duration, higher CF, half normal saline irrigant, and, to a greater extent, by utilizing bipolar RF or NTAC, but only over thin adipose (3 mm). Of those catheters/strategies tested, only NTAC was able to effectively deliver RF over thick (3 mm) EA with this model.

Since their inception, percutaneous epicardial approaches have become increasingly common in clinical practice with the advent of new technology and the growth of catheter ablation for both ventricular and supraventricular arrhythmias. In addition to identifying the arrhythmogenic foci, there remain challenges to successful epicardial ablation such as the choice of energy source, optimizing irrigation during ablation, and anatomic barriers such as epicardial fat and coronary vessels. The performance of continued translational studies to understand how each of these factors contribute to lesion formation will be essential to guide future advances in the field of epicardial ablation.

Epicardial catheter ablation is most commonly performed following unsuccessful endocardial ablation. Given the frequency of epicardial substrates in certain cardiomyopathic disease states, however, a combined endocardial-epicardial approach should be considered as a primary treatment strategy. Although epicardial ablation is primarily deployed in patients with ventricular arrhythmias, the role of epicardial approaches in supraventricular tachycardias (eg, atrial fibrillation, inappropriate sinus tachycardia, and-rarely-accessory pathways) is growing, with continued advances being made.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening form of pulmonary artery hypertension that is defined as a mean arterial pulmonary pressure greater than 25mmHg that persists for more than 6 months following anticoagulation therapy in the setting of pulmonary emboli. CTEPH is categorized by the World Health Organization as group IV pulmonary hypertension and is thought to be due to unresolved thromboemboli in the pulmonary artery circulation. Among the 5 classes of pulmonary hypertension, CTEPH is unique in that it is potentially curable with the use of pulmonary thromboendarterectomy surgery. Despite an increasing array of medical and surgical treatment options for patients with CTEPH over the past 2 decades, patients commonly present with advanced disease and carry a poor prognosis, thus, the need for early diagnosis and appropriate referral to an expert center. This review article first highlights the epidemiology, pathophysiology, and clinical presentation of CTEPH. The article then provides diagnostic and therapeutic algorithms for the management of the patient with suspected CTEPH.

Objectives The goal of this study was to determine the impact of catheter ablation in the region of papillary muscles (PMs) and valvular cusps (VC) on mitral, tricuspid, or aortic valve function. Background Ventricular arrhythmias arising from PMs and VCs often require extensive catheter ablation. Little is known regarding the risk of valve dysfunction after radiofrequency catheter ablation of such arrhythmias. Methods A retrospective analysis was completed for 149 PM and VC VT/premature ventricular contraction (PVC) ablations from 2008 to 2018 at our institution. Patient and procedural details were collected for VT and PVC ablation cases involving PMs and VCs with available echocardiographic data pre-ablation and post-ablation (within 6 months). Degree of valvular regurgitation (VR) was graded from 0 (none) to 4 (severe), and significant valvular dysfunction was defined as a 2+ change in VR. Results Of 149 radiofrequency catheter ablation cases, there were 84 (56%) aortic valve cusp ablations, 60 (40%) left ventricular PM ablations, and 5 (3%) right ventricular PM ablations. There were no statistically significant differences between pre-ablation and post-ablation VR severity (p = 0.33). No patients had a 2+ grade change in VR severity when pre-ablation and post-ablation echocardiograms were compared. There were no significant sequelae requiring intervention in the post-ablation period. On follow-up of 36 ± 9 months, for those with a change in VR, the severity had improved to baseline or remained stable. Conclusions Despite often-times extensive ablation on and around valvular networks, risk of longstanding or permanent valvular dysfunction after VT/PVC ablation is rare.

Case Presentation A man in his 50s presented to the ED with a 3-day history of small-volume hemoptysis and new-onset dyspnea. The patient did not have fevers, chills, chest pain, abdominal pain, or changes in urination. His medical history included hypertension, a 35-pack-year active smoking history, and occupational hydrocarbon exposure as a mechanic in the foresting industry. He reported no recent travels, and he denied sick contacts. His medications included amlodipine, hydrochlorothiazide, lisinopril, omeprazole, and nicotine replacement therapy.

Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3–4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders.

Defibrillation testing (DFT) has declined in recent years due to randomized data showing no difference in outcomes when used routinely. However, with low sensed R waves in sinus rhythm, DFT allows for the evaluation of sensing in ventricular fibrillation (VF), and if adequate, may obviate the need

BACKGROUND: Small studies have shown that adenosine is equivalent to regadenoson when obtaining coronary fractional flow reserve (FFR) measurements. A study that also evaluates time and safety of aminophylline reversal of regadenoson effects has not been presented. HYPOTHESIS: Reversal of regadenoson with aminophylline is safe and equivalent to adenosine for FFR measurements. METHODS: Forty‐six consecutive patients who underwent clinically indicated FFRs at the time of coronary angiography were enrolled between 4/2012 and 5/2014. Each patient had FFR measured using adenosine 140 mcg/kg/min IV, and following return to baseline, FFR was measured using regadenoson 400 mcg IV, which then was reversed with aminophylline 150 mg IV. Time to baseline hemodynamics was measured. Agreement between the two assessments was compared using linear regression. RESULTS: FFR results were similar with both agents (R (2) = 0.935, P < 0.0001). Also, using the 0.80 cutoff for significantly depressed FFR, there was no divergence regarding studies' significance. After aminophylline reversal of regadenoson, hemodynamics returned to baseline in 111 ± 71 seconds. There were no unexpected side effects or complications. CONCLUSIONS: For FFR measurement, regadenoson and adenosine are equivalent hyperemic agents. Regadenoson with aminophylline reversal may be considered as an alternative to adenosine for FFR measurements.

Hydrogen sulfide (H2S) is a biologically active endogenous gasotransmitter formed in penile tissue that has been shown to relax isolated cavernosal smooth muscle. In the present study, erectile responses to the H2S donors sodium sulfide (Na2S) and sodium hydrosulfide (NaHS) were investigated in the anesthetized rat. Intracavernosal injections of Na2S in doses of 0.03–1 mg/kg increased intracavernosal pressure and transiently decreased mean arterial pressure in a dose-dependent manner. Blood pressure responses to Na2S were rapid in onset and short in duration. Responses to Na2S and NaHS were similar at doses up to 0.3 mg/kg, after which a plateau in the erectile response to NaHS was reached. Increases in intracavernosal pressure in response to Na2S were attenuated by tetraethylammonium (K+ channel inhibitor) and iberiotoxin (large-conductance Ca2+-activated K+ channel inhibitor), whereas glybenclamide [ATP-sensitive K+ (KATP) channel inhibitor] and inhibitors of nitric oxide (NO) synthase, cyclooxygenase, and cytochrome P-450 epoxygenase had no effect. These data indicate that erectile responses to Na2S are mediated by a tetraethylammonium- and iberiotoxin-sensitive mechanism and that KATP channels, NO, or arachidonic acid metabolites are not involved. Na2S did not alter erectile responses to sodium nitroprusside (NO donor) or cavernosal nerve stimulation, indicating that neither NO nor cGMP metabolism are altered. Thus, Na2S has erectile activity mediated by large-conductance Ca2+-activated K+ channels. It is suggested that strategies that increase H2S formation in penile tissue may be useful in the treatment of erectile dysfunction when NO bioavailability, KATP channel function, or poor responses to PGE1 are present.

Hydrogen sulfide (H2S) is an endogenous gaseous molecule formed from L-cysteine in vascular tissue. In the present study, cardiovascular responses to the H2S donors Na2S and NaHS were investigated in the anesthetized rat. The intravenous injections of Na2S and NaHS 0.03–0.5 mg/kg produced dose-related decreases in systemic arterial pressure and heart rate, and at higher doses decreases in cardiac output, pulmonary arterial pressure, and systemic vascular resistance. H2S infusion studies show that decreases in systemic arterial pressure, heart rate, cardiac output, and systemic vascular resistance are well-maintained, and responses to Na2S are reversible. Decreases in heart rate were not blocked by atropine, suggesting that the bradycardia was independent of parasympathetic activation and was mediated by an effect on the sinus node. The decreases in systemic arterial pressure were not attenuated by hexamethonium, glybenclamide, Nw-nitro-l-arginine methyl ester hydrochloride, sodium meclofenamate, ODQ, miconazole, 5-hydroxydecanoate, or tetraethylammonium, suggesting that ATP-sensitive potassium channels, nitric oxide, arachidonic acid metabolites, cyclic GMP, p450 epoxygenase metabolites, or large conductance calcium-activated potassium channels are not involved in mediating hypotensive responses to the H2S donors in the rat and that responses are not centrally mediated. The present data indicate that decreases in systemic arterial pressure in response to the H2S donors can be mediated by decreases in vascular resistance and cardiac output and that the donors have an effect on the sinus node independent of the parasympathetic system. The present data indicate that the mechanism of the peripherally mediated hypotensive response to the H2S donors is uncertain in the intact rat.

As a subset of microangiopathic hemolytic anemia, thrombotic thrombocytopenic purpura can present with a constellation of symptoms similar to the hemolytic anemia attributed to severe vitamin B12 deficiency. There have been few case reports in the medical literature concerning the development of a clinical syndrome consistent with microangiopathic hemolytic anemia attributable to B12 deficiency. We report a case of B12 deficiency leading to microangiopathic hemolytic anemia that was corrected solely with a ten-day course of intramuscular cobalamin replacement. Prompt diagnostic and clinical evaluation utilizing specific exclusion parameters can promote accurate and safe treatment of the clinical syndrome of microangiopathic hemolytic anemia related to B12 deficiency.

Background New epithelial cells are generated through the proliferation and differentiation of resident progenitor cells in the nasal cavity. In several upper airway diseases, such as cystic fibrosis and chronic rhinosinusitis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance. Herein, we describe our early work to define and characterize a rare population of human nasal epithelial putative progenitors. Methods Single-cell suspensions of human ethmoid sinus tissues were prepared following endoscopic sinus surgery. Cell surface antibodies were analyzed as candidate markers for detecting progenitor cells. A panel of antibodies, including epithelial cell adhesion molecule (EpCAM, epithelial cells), CD45 (hematopoietic cells), nerve growth factor receptor (NGFR/CD271), intercellular adhesion molecule-1 (ICAM1/CD54), and integrin-α6 (ITGA6/CD49f) were used to resolve epithelial progenitor candidates by high-dimensional flow cytometry and the gating technique of fluorescence minus one (FMO) controls. Results A rare population of approximately 0.06% of total ethmoid cells was discriminated as EpCAM−CD45−NGFR+ICAM1+ by surface markers. Use of ITGA6 was excluded based on FMO control analysis. This lineage-negative population was purified to 99% homogeneity by cell sorting and analyzed by immunofluorescence microscopy. Sorted cells were subsequently confirmed to uniformly express the transcription factor p63. Upon in vitro culture, lineage-negative clonal cells were confirmed to spontaneously differentiate into epithelial lineage-positive cells. Conclusion Using the NGFR and ICAM1 cellular coordinates, we have identified a promising population of native human nasal epithelial progenitor cells that require more formal investigation for their role in upper airway regeneration.

Severe forms of chronic rhinosinusitis (CRS), a common upper airway inflammatory disorder, are associated with nasal polyps (NPs). NP disease is ameliorated by glucocorticoid (GC) treatment, whose cellular effects are poorly understood. We therefore assessed the influence of GC therapy on NPs in CRS patients, focusing on regulatory T (Treg) cells. Treg cell populations were analyzed by flow cytometry in NPs and control tissues from GC-treated CRS patients and controls. After GC exposure, selective expansion of Treg cells was seen within NPs, and not blood or adjacent ethmoid tissues. To confirm direct GC effects, NPs from the same patients were biopsied prior to, and following, 1week of oral GC exposure. Direct expansion of Tregs into the same NP bed was detected in 4/4 CRS patients following GC exposure. Treg cell spikes into NPs were secondary to cellular recruitment given limited Ki67 expression within these regulatory cells. Chemokine gene expression profiling identified several chemokines, notably CCL4, induced within NPs upon GC treatment. Neutralization of chemokine receptor/ligand interactions using CCR4 small molecule antagonists reduced Treg migration towards GC-treated NPs in an ex vivo migration assay. Our findings suggest that the common use of GCs in the treatment of NP disease leads to recruitment of Treg cells from peripheral sites into NP tissues, which may be critical to the anti-inflammatory effect of GCs. Mechanistically Treg expansion appears to be conferred, in part, by chemokine receptor/ligand interactions induced following corticosteroid therapy.

Background The airway epithelium generates reactive oxygen species (ROS) as a first line of defense. Dual oxidases (DUOX1 and DUOX2) are the H2O2-producing isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family in the airway epithelium. The purpose of this study was to explore the molecular expression, function, and regulation of DUOXs in chronic rhinosinusitis (CRS).

The ring-opening polymerization of substituted cyclic carbonates with 1-(3,5-bis-trifluoromethyl-phenyl)-3-cyclohexyl-thiourea (TU)/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) organocatalysts afford highly functionalized oligocarbonates. The fluorescent alkaloid quinine can be readily incorporated into the oligocarbonates either by initiation from quinine or by ring-opening polymerization of a quinine-functionalized cyclic carbonate (MTC-Q). Copolymerization of MTC-Q with a boc-protected guanidinium cyclic carbonate affords, after deprotection, highly water-soluble cationic copolymers functionalized with both quinine and pendant guanidinium groups. When multiple quinine groups are attached to the oligomers, they exhibit minimal fluorescence due to self-quenching. Upon hydrolysis, the fluorescence intensity increases, providing a potential strategy for monitoring the hydrolysis rates in real time.

The catalytic condensation of cis-2-butene-1,4-diol with CpRu(MQA)(C(3)H(5)) (Cp = cyclopentadienyl, MQA = 4-methoxyquinoline-2-carboxylate) generates poly(2-butenediol), an unsaturated telechelic polyether diol with molecular weights between 400 and 4600 g/mol. This Ru(IV) allyl catalyst enchains 2-butene-1,4-diol primarily as the linear trans-2-butenyl ether (92%) along with vinyl branches (8%). These telechelic oligomers are useful chain extenders and macromonomers, as demonstrated by their use in the synthesis of poly(lactide)-b-poly(butenediol)-b-poly(lactide) triblock copolymers. Model studies support a proposed mechanism involving the formation of Ru(IV) allyl intermediates from allylic alcohols and chain growth by selective nucleophilic displacement at the terminus of the Ru(IV) allyl to generate trans-2-butenyl ether linkages.

New epithelial cells are generated through the proliferation and differentiation of resident progenitor cells in the nasal cavity. In several upper airway diseases, such as cystic fibrosis and chronic rhinosinusitis, self-renewing progenitor cells may be functionally defective, or compromised in their ability, to regenerate cells that maintain normal mucociliary clearance. Herein, we describe our early work to define and characterize a rare population of human nasal epithelial putative progenitors.Single-cell suspensions of human ethmoid sinus tissues were prepared following endoscopic sinus surgery. Cell surface antibodies were analyzed as candidate markers for detecting progenitor cells. A panel of antibodies, including epithelial cell adhesion molecule (EpCAM, epithelial cells), CD45 (hematopoietic cells), nerve growth factor receptor (NGFR/CD271), intercellular adhesion molecule-1 (ICAM1/CD54), and integrin-α6 (ITGA6/CD49f) were used to resolve epithelial progenitor candidates by high-dimensional flow cytometry and the gating technique of fluorescence minus one (FMO) controls.A rare population of approximately 0.06% of total ethmoid cells was discriminated as EpCAM(-) CD45(-) NGFR(+) ICAM1(+) by surface markers. Use of ITGA6 was excluded based on FMO control analysis. This lineage-negative population was purified to 99% homogeneity by cell sorting and analyzed by immunofluorescence microscopy. Sorted cells were subsequently confirmed to uniformly express the transcription factor p63. Upon in vitro culture, lineage-negative clonal cells were confirmed to spontaneously differentiate into epithelial lineage-positive cells.Using the NGFR and ICAM1 cellular coordinates, we have identified a promising population of native human nasal epithelial progenitor cells that require more formal investigation for their role in upper airway regeneration.

Nasal polyps (NPs) are hallmark inflammatory lesions of sinusitis. Despite the spectrum of NP conditions, cellular differences between NPs from patients with chronic rhinosinusitis with NPs (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) are poorly understood. NPs are associated with abundant eosinophils; the contributions of neutrophil and basophil granulocytes are less defined. We therefore sought to assess granulocyte subpopulations, and differential effects following prednisone pretreatment, within NPs of CRSwNP and AERD patients.NPs, adjacent ethmoid sinus tissue, and peripheral blood mononuclear cells (PBMCs) were obtained from patients undergoing endoscopic sinus surgery. Samples from 5 cohorts: CRSwNP ± prednisone (n = 6 each), AERD ± prednisone (n = 6 each), and controls (n = 9), were analyzed by high-dimensional flow cytometry to gate granulocyte populations. Specimens were also assessed using immunohistochemistry (IHC) staining.Systemic prednisone administration was associated with a lower frequency of eosinophils (p0.0001, n = 6) in NPs in both CRSwNP and AERD patients, whereas a decrease in neutrophils (p = 0.0070, n = 6) in NPs was only observed in CRSwNP patients after prednisone treatment. In contrast, steroids do not alter basophil proportions (p = 0.48, n = 6) within NPs from either group. No significant shift in granulocyte subsets after steroid treatment was identified in the adjacent ethmoid mucosa or PBMCs from the same patients. Immunohistochemistry (IHC) staining supported these findings.Granulocyte subpopulations are focally affected within NPs by systemic steroid exposure, without notable granulocyte alterations in the surrounding regional tissues. These data provide direct insights into the cellular effects of routine prednisone exposure in CRS patients, and highlight a unique microenvironment present within NP lesions.

The airway epithelium generates reactive oxygen species (ROS) as a first line of defense. Dual oxidases (DUOX1 and DUOX2) are the H2 O2 -producing isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family in the airway epithelium. The purpose of this study was to explore the molecular expression, function, and regulation of DUOXs in chronic rhinosinusitis (CRS).Human nasal tissue samples and nasal secretions were collected from 3 groups of patients undergoing sinus surgery (normal, n = 7; CRS with polyposis [CRSwP], n = 6; CRS without polyposis [CRSsP], n = 6). Nasal secretions were studied for cytokine and H2 O2 content. Tissue samples were used to determine DUOX mRNA and protein expression.DUOX1 mRNA level (80.7 ± 60.5) was significantly increased in CRSwP compared to normal (2.7 ± 1.2) and CRSsP (2.3 ± 0.5, p = 0.042). DUOX2 mRNA levels were increased in both CRSwP (18.6 ± 9.9) and CRSsP (4.0 ± 1.3) compared to normal (1.1 ± 0.3; p = 0.008). DUOX protein was found in the apical portion of the nasal epithelium and protein expression was increased in CRSwP and CRSsP. H2 O2 production was significantly higher in CRSwP (160.9 ± 59.4 nM) and CRSsP (81.7 ± 5.6 nM) compared to normal (53.5 ± 11.5 nM, p = 0.032). H2 O2 content of nasal secretions correlated tightly with DUOX expression (p0.001). Cytokines (eotaxin, monokine-induced by interferon γ [MIG], tumor necrosis factor [TNF]-α, interleukin [IL]-8) showed significantly higher levels in nasal secretions from CRSwP compared to normal (p0.05). Levels of eotaxin, MIG, and TNF-α correlated closely with DUOX expression.DUOX1 and DUOX2 were identified as factors upregulated in CRS. Close correlations between DUOX expression and H2 O2 release, and correlation between key inflammatory cytokines and DUOX expression, indicate DUOX in the inflammatory response in CRS.

The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.