Exertional Cardiac and Pulmonary Vascular Hemodynamics in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Exertional dyspnea is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF), but quantitative data regarding exertional hemodynamics are lacking. OBJECTIVES: We sought to characterize exertional cardiopulmonary hemodynamics in patients with HFrEF. METHODS: We studied 35 patients with HFrEF (59 ± 12 years old, 30 males) who completed invasive cardiopulmonary exercise testing. Data were collected at rest, at submaximal exercise and at peak effort on upright cycle ergometry. Cardiovascular and pulmonary vascular hemodynamics were recorded. Fick cardiac output (Qc) was determined. Hemodynamic predictors of peak oxygen uptake (VO2) were identified. RESULTS: Left ventricular ejection fraction and cardiac index were 23% ± 8% and 2.9 ± 1.1 L/min/m2, respectively. Peak VO2 was 11.8 ± 3.3 mL/kg/min, and the ventilatory efficiency slope was 53 ± 13. Right atrial pressure increased from rest to peak exercise (4 ± 5 vs 7 ± 6 mmHg,). Mean pulmonary arterial pressure increased from rest to peak exercise (27 ± 13 vs 38 ± 14 mmHg). Pulmonary artery pulsatility index increased from rest to peak exercise, while pulmonary arterial capacitance and pulmonary vascular resistance declined. CONCLUSIONS: Patients with HFrEF suffer from marked increases in filling pressures during exercise. These findings provide new insight into cardiopulmonary abnormalities contributing to impairments in exercise capacity in this population. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03078972.

Impact of Exercise on Cerebrovascular Physiology and Risk of Stroke.

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.

Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis.

BACKGROUND: Evidence to guide type 2 diabetes treatment individualization is limited. We evaluated heterogeneous treatment effects (HTE) of intensive glycemic control in type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT). METHODS: Causal forests machine learning analysis was performed using pooled individual data from two randomized trials (n = 12,042) to identify HTE of intensive versus standard glycemic control on MACE in patients with type 2 diabetes. We used variable prioritization from causal forests to build a summary decision tree and examined the risk difference of MACE between treatment arms in the resulting subgroups. RESULTS: A summary decision tree used five variables (hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index) to define eight subgroups in which risk differences of MACE ranged from - 5.1% (95% CI - 8.7, - 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control). Intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (- 4.2% [95% CI - 8.1, - 1.0]), intermediate (- 5.1% [95% CI - 8.7, - 1.5]), and high (- 4.3% [95% CI - 7.7, - 1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone. CONCLUSIONS: This data-driven analysis provides evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk and additionally suggests potential benefits of intensive glycemic control in some individuals at higher cardiovascular risk.

Impact of epicardial adipose tissue and catheter ablation strategy on biophysical parameters and ablation lesion characteristics.

BACKGROUND: Epicardial adipose (EA) tissue may limit effective radiofrequency ablation (RFA). OBJECTIVES: We sought to evaluate the lesion formation of different ablation strategies on ventricular myocardium with overlying EA. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids.

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.

Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension.

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 ß1 adrenergic receptor-blocking agent reported to increase NO production and stimulate ß3 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 ß3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with ß3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that ß3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating ß1 receptor antagonist that stimulates ß3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders.

Pseudo-Thrombotic Thrombocytopenic Purpura due to Severe Vitamin B12 Deficiency.

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.

Analysis of cardiovascular responses to the H2S donors Na2S and NaHS in the rat.

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, N(w)-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.

Analysis of erectile responses to H2S donors in the anesthetized rat.

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 Ca(2+)-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 Ca(2+)-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.

Analysis of erectile responses to bradykinin in the anesthetized rat.

The kallikrein-kinin system is expressed in the corpus cavernosa, and bradykinin (BK) relaxes isolated corpora cavernosal strips. However, erectile responses to BK in the rat have not been investigated in vivo. In the present study, responses to intracorporal (ic) injections of BK were investigated in the anesthetized rat. BK, in doses of 1-100 µg/kg ic, produced dose-related increases in intracavernosal pressure (ICP) and dose-related deceases in mean arterial pressure (MAP). When decreases in MAP were prevented by intravenous injections of angiotensin II (Ang II), increases in ICP, in response to BK, were enhanced. Increases in ICP, ICP/MAP ratio, and area under the curve and decreases in MAP in response to BK were inhibited by the kinin B2 receptor antagonist HOE-140 and enhanced by the angiotensin-converting enzyme (ACE) inhibitor captopril and by Ang-(1-7). Increases in ICP, in response to BK, were not attenuated by the nitric oxide (NO) synthase inhibitor (N(ω)-nitro-L-arginine methyl ester) or the soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but were attenuated by the cyclooxygenase inhibitor, sodium meclofenamate. Decreases in MAP were not attenuated by either inhibitor. These data suggest that erectile responses are mediated by kinin B2 receptors and modulated by decreases in MAP. These data indicate that ACE is important in the inactivation of BK and that erectile and hypotensive responses are independent of NO in the penis or the systemic vascular bed. Erectile responses to cavernosal nerve stimulation are not altered by BK or HOE-140, suggesting that BK and B2 receptors do not modulate nerve-mediated erectile responses under physiologic conditions. These data suggest that erectile responses to BK are mediated, in part, by the release of cyclooxygenase products.

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells.

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.

Characteristics and Treatment of Exercise Intolerance in Patients With Long COVID.

The post-acute sequalae of SARS-CoV-2, also known as "Long COVID," is characterized by profound fatigue, impaired functional capacity with post-exertional malaise, orthostatic intolerance, and tachycardia. At least 25-30% of individuals impacted by SARS-CoV-2 will go on to experience the Long COVID syndrome, underscoring the detrimental impact this condition has on society. Although efforts are underway to further understand risk factors for Long COVID and identify strategies to prevent disease development entirely, implementation of treatment strategies is warranted to alleviate symptom burden among those affected. This review provides a rationale for exercise prescriptions tailored to the Long COVID patient based on the pathophysiology underlying this syndrome, as well as the previously demonstrated benefits of exercise training in other similar populations whose clinical manifestations result from cardiac deconditioning. Herein, we discuss methods to tailor exercise protocols, accommodating exercise intolerance and post-exertional malaise that may otherwise limit the ability to participate in a training protocol, as well as data demonstrating that a focused exercise prescription may effectively alleviate symptom burden in these patients. Long COVID results, in large part, from deconditioning, which may result from as little as 20 hr of inactivity. Exercise prescriptions tailored to patients with Long COVID may effectively alleviate symptom burden associated with this condition and in the absence of overt contraindications should be considered in management.

Organocatalytic synthesis of quinine-functionalized poly(carbonate)s.

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.

Esophago-Pericardial Fistula as a Rare and Life-Threatening Complication of Epicardial Ventricular Tachycardia Ablation.

We describe a rare complication of esophago-pericardial fistula after epicardial ventricular tachycardia ablation. Echocardiogram revealed evidence of pneumopericardium and additional imaging studies confirmed esophageal leak with evidence of fistula formation requiring prompt surgical repair. (Level of Difficulty: Intermediate.).

Right Ventricular Dysfunction During Endurance Exercise as Determined by Pressure-Volume Analysis.

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. (Level of Difficulty: Intermediate.).

Polycondensation of butenediol: synthesis of telechelic 2-butene-1,4-diol oligomers.

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.

Patient Selection for Epicardial Ablation-Part I: The Role of Epicardial Ablation in Various Cardiac Disease States.

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.

Patient Selection for Epicardial Ablation-Part II: The Epicardial Approach and Current Challenges Associated with Epicardial Ablation.

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.

A Man in His 50s With Hemoptysis, Dyspnea, and Bilateral Patchy Ground-Glass Opacities.

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.

Follow-Up After Catheter Ablation of Papillary Muscles and Valve Cusps.

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.