Collagen 18A1/Endostatin Expression in the Progression of Right Ventricular Remodeling and Dysfunction in Pulmonary Arterial Hypertension.

Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII alpha 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). Importantly, elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/Chronic hypoxic (SuHx) rat pulmonary hypertension (PH) model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricular (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance (CMR) imaging and advanced hemodynamic assessments with pressure-volume (PV) loops in patients with PAH to assess RV-pulmonary arterial (PA) coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index (VMI) were positively associated with ES while RV ejection fraction and RV-PA coupling were inversely associated with ES levels. Our animal data demonstrates that the development of PH is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared to the left ventricle (LV) and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increase early in disease development in the RV and implicate COL18A1/ES in pathologic RV dysfunction in PAH.

Poor Cardiac Output Reserve in Pulmonary Arterial Hypertension is Associated With Right Ventricular Stiffness and Impaired Interventricular Dependence.

BACKGROUND: Pulmonary arterial hypertension is characterized by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (p-V) loop analysis to characterize the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS: RV p-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance, Eed) and ventricular interdependence (left ventricular transmural pressure, LVTMP) were compared at matched exercise stages. RESULTS: Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 ml·m-2, p=0.0001), with higher associated exercise afterload (Ea 1.76 versus 0.90 mmHg·mL-1, p<0.0001), RV stiffness (Eed 0.68 versus 0.26 mmHg·mL-1, p=0.003), and right-sided pressures (RA 14 versus 8 mmHg, p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2 mmHg, p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS: Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness, and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiologic PAH differences unapparent at rest.

Occult right ventricular dysfunction and right ventricular-vascular uncoupling in left ventricular assist device recipients.

BACKGROUND: Detecting right heart failure post left ventricular assist device (LVAD) is challenging. Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction. METHODS: Thirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial coupling (ratio of Ees/Ea). RESULTS: LVAD patients had lower RV Ees (0.20 ± 0.08 vs 0.30 ± 0.15 mm Hg/ml, p = 0.01) and lower RV Ees/Ea (0.37 ± 0.14 vs 1.20 ± 0.54, p < 0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r = 0.68, p = 0.004) as well as the LVAD cohort itself (r = 0.78, p = 0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p = 0.048), driven by an inability to augment RV Ees (0.22 ± 0.11 vs 0.19 ± 0.02 mm Hg/ml, p = 0.95) to accommodate higher RV Ea (0.82 ± 0.38 vs 0.39 ± 0.08 mm Hg/ml, p = 0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients ((area under the curve) AUC = 0.80); during the ramp study, change in PAPi also correlated with change in RV Ees/Ea (r = 0.58, p = 0.04). CONCLUSIONS: LVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD left ventricular unloading, which reduces septal contractility.

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure With Pulmonary Hypertension.

BACKGROUND: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms. METHODS: Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls. RESULTS: Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure. CONCLUSIONS: Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.

Cardiovascular Disease in Patients with Diabetes: A Comparison of Professional Society Guidelines.

In this review, we compare major points given in the 2021 American Diabetes Association and the 2020 American Association of Clinical Endocrinologists/American College of Endocrinology guidelines, in particular, the assessment and management of cardiovascular risk in patients with diabetes with a focus on dyslipidemia, blood pressure, and pharmacotherapy in diabetes.

Beyond power amplification: latch-mediated spring actuation is an emerging framework for the study of diverse elastic systems.

Rapid biological movements, such as the extraordinary strikes of mantis shrimp and accelerations of jumping insects, have captivated generations of scientists and engineers. These organisms store energy in elastic structures (e.g. springs) and then rapidly release it using latches, such that movement is driven by the rapid conversion of stored elastic to kinetic energy using springs, with the dynamics of this conversion mediated by latches. Initially drawn to these systems by an interest in the muscle power limits of small jumping insects, biologists established the idea of power amplification, which refers both to a measurement technique and to a conceptual framework defined by the mechanical power output of a system exceeding muscle limits. However, the field of fast elastically driven movements has expanded to encompass diverse biological and synthetic systems that do not have muscles - such as the surface tension catapults of fungal spores and launches of plant seeds. Furthermore, while latches have been recognized as an essential part of many elastic systems, their role in mediating the storage and release of elastic energy from the spring is only now being elucidated. Here, we critically examine the metrics and concepts of power amplification and encourage a framework centered on latch-mediated spring actuation (LaMSA). We emphasize approaches and metrics of LaMSA systems that will forge a pathway toward a principled, interdisciplinary field.

Northern Territory perspectives on heart failure with comorbidities ­ understanding trial validity and exploring collaborative opportunities to broaden the evidence base.

Congestive Heart Failure (CHF) is an ambulatory care sensitive condition, associated with significant morbidity and mortality, rarely with cure. Outpatient based pharmacological management represents the main and most important aspect of care, and is usually lifelong. This narrative styled opinion review looks at the pharmacological agents recommended in the guidelines in context of the Northern Territory (NT) of Australia. We explore the concept of validity, a term used to describe the basis of standardising a particular trial or study and the population to which it is applicable. We aim to highlight the problems of the current guidelines based approach. We also present alternatives that could utilise the core principles from major trials, while incorporating regional considerations, which could benefit clients living in the NT and remote Australia.

The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE).

BACKGROUND: Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. METHODS: The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. CONCLUSION: The CONCORDANCE registry is a clinician-driven initiative describing clinical care for ACS patients admitted to Australian hospitals. The registry generates high quality data which is fed back to clinicians, and key stakeholders in ACS care. Using a CER approach, the registry describes the translation of randomised trial evidence into practice, and provides insights into strategies that could improve care and ultimately patient outcomes.

Measuring surface and bulk relaxation in glassy polymers.

We present a comprehensive study of gold nanoparticle embedding into polystyrene (PS) surfaces at temperatures ranging from T ( g ) + 8 K to T ( g ) - 83 K and times as long as 10(5) minutes. This range in times and temperatures allows the first concurrent observation of and differentiation between surface and bulk behavior in the 20 nm region nearest the free surface of the polymer film. Of particular importance is the temperature region near the bulk glass transition temperature where both surface and bulk processes can be measured. The results indicate that for the case of PS, enhanced surface mobility only exists at temperatures near or below the bulk T ( g ) value. The surface relaxation times are only weakly temperature dependent and near T ( g ), the enhanced mobility extends less than 10nm into the bulk of the film. The results suggest that both the concept of a "surface glass transition" and the use of glass transition temperatures to measure local mobility near interfaces may not universally apply to all polymers. The results can also be used to make a quantitative connection to molecular dynamics simulations of polymer films and surfaces.

Inhomogeneous magnetic-field response of YBa2Cu3Oy and La2-xSrxCuO4 persisting above the bulk superconducting transition temperature.

We report that in YBa2Cu3Oy and La2-xSrxCuO4 there is a spatially inhomogeneous response to the magnetic field for temperatures T extending well above the bulk-superconducting transition temperature Tc. An inhomogeneous magnetic response is observed above Tc even in ortho-II YBa2Cu3O6.50, which has highly ordered doping. The degree of the field inhomogeneity above Tc tracks the hole-doping dependences of both Tc and the density of the superconducting carriers below Tc, and therefore is apparently coupled to superconductivity.

Differential expression of neutrophil adhesion molecules during coronary artery surgery with cardiopulmonary bypass.

BACKGROUND: Activation of neutrophil adhesion molecules and subsequent neutrophil adhesion to vascular endothelium are key events initiating inflammatory organ dysfunction after cardiopulmonary bypass and ischemic reperfusion. OBJECTIVES: We sought to characterize neutrophil integrin CD11b and L-selectin activation associated with coronary artery bypass graft surgery and to determine whether neutrophil activation contributes to their sequestration on postbypass reperfusion. METHODS: Twenty patients undergoing routine coronary artery bypass were studied. Heparinized whole blood was simultaneously sampled from a central venous line, aorta, coronary sinus, and right and left atrium before, during, and up to 20 minutes after cardiopulmonary bypass. Neutrophil counts were obtained, and neutrophil CD11b and L-selectin expression was determined by flow cytometric analysis in whole blood. RESULTS: CD11b expression on circulating neutrophils increased during cardiopulmonary bypass, peaking at 145% of baseline level after release of the aortic clamp and then declined by 20 minutes after bypass (analysis of variance, P =.003). No change in neutrophil L-selectin expression was observed during cardiopulmonary bypass. Neutrophils responded to ex vivo stimulation by C5a and leukotriene B(4) during cardiopulmonary bypass but not at 24 hours after the operation. After reperfusion, neutrophil loss, but not local activation, was demonstrated in the coronary and pulmonary circulations. CONCLUSIONS: Upregulated CD11b expression on neutrophils is likely to contribute to neutrophil sequestration in the heart and lungs after bypass, but neutrophil activation may be limited by their reduced responsiveness to agonist stimulation. CD11b represents a potential therapeutic target for diminishing inflammation after cardiac operations.

Treatment of acute myocardial infarction in pregnancy with coronary artery balloon angioplasty and stenting.

Acute myocardial infarction in pregnancy is a rare condition with substantial risk of maternal and fetal mortality. We present a case of myocardial infarction during pregnancy which was treated by percutaneous coronary artery balloon angioplasty and stenting with excellent pregnancy outcome.

Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma.

Systemic cytokine therapy in cancer has major side effects, and we reasoned that the local infusion of cytokines into tumors could induce local immunologic responses with minimal toxicity and potentially strong systemic anticancer effects. This study investigated the toxicity and effectiveness of intralesional granulocyte/macrophage-colony-stimulating factor (GM-CSF) infusion in solid-tumor masses. We studied 14 patients (12 men, two women) with malignant mesothelioma (MM), aged 60 years (range, 46-70 years), with stage 2 disease, in whom the tumor was of sufficient size and accessibility for an intralesional catheter to be inserted. Recombinant human GM-CSF (Molgramostim; Schering Plough) was infused intralesionally for 8 weeks, by using a portable pump, at a dose of 2.5-10 micrograms/kg/day. One patient using GM-CSF developed histologically confirmed necrosis of tumor surrounding the distal catheter, one developed a marked lymphocytic infiltrate in the tumor and had a partial response measured by chest computed tomography (CT) scan, 10 progressed, and three had no response. Neutrophilia with morphologic evidence of neutrophil activation and clinical features suggestive of neutrophil plugging of blood vessels occurred at doses > 5 micrograms/kg/day. In vitro, GM-CSF doubled human neutrophil/CD11b/CD18 expression, suggesting that neutrophil clumping as seen in vivo might be due to integrin upregulation. Intralesional infusion of cytokines is feasible but can be associated with systemic toxicity and has considerable technical problems. It produces a localized immune reaction with tumor regression in a minority of patients.

The effect of aspirin on thrombin stimulated platelet adhesion receptor expression and the role of neutrophils.

AIMS: Aspirin has proven clinical efficacy in limiting the thrombotic complications of atherosclerotic vascular disease but its mechanism of action remains unclear. Recent evidence suggests the anti-platelet action of aspirin may be partly mediated by neutrophil derived nitric oxide (NO). The aim of the study was to determine the effects of aspirin on thrombin-induced platelet expression of the alpha-granule membrane protein, P-selectin, and the platelet surface glycoprotein required for aggregation, GPIIb-IIIa, and to assess whether this was enhanced by the presence of neutrophils. METHODS: Platelet P-selectin and GPIIb-IIIa receptor expression were assessed by flow cytometric analysis of washed platelets stimulated with thrombin (0.025 iu ml(-1), sub aggregatory concentration) alone or after pre-incubation with aspirin (0.05, 0.1, 0.5, 1.0 mg m1(-1) either in the presence or absence of neutrophils (100 platelets per neutrophil). NO release was determined by assay of nitrite in the supernatants from parallel samples. RESULTS: In preliminary aggregation studies, aspirin at all concentrations inhibited arachidonic acid but not thrombin-induced platelet aggregation. Similarly, aspirin at all concentrations failed to inhibit thrombin-induced platelet P-selectin or GPIIb-IIIa expression and this was not influenced by the presence of neutrophils. A reduction in P-selectin and GPIIb-IIIa receptor density on non-activated platelets co-incubated with unstimulated neutrophils was associated with NO release from neutrophils, but this was not enhanced by the addition of aspirin. CONCLUSIONS: These results confirm that thrombin-induced platelet alpha-granule release, with consequent P-selectin expression, and platelet GPIIb-IIIa expression, are not affected by aspirin inhibition of cyclo-oxygenase and suggest that the anti-thrombotic efficacy of aspirin in vivo may partly depend on other mechanisms. This study did not demonstrate an effect of neutrophils or neutrophil derived NO on aspirin inhibition of platelet adhesion receptor expression.

Neutrophil cathepsin G modulates platelet P-selectin expression and inhibits P-selectin-mediated platelet-neutrophil adhesion.

1. Close contact between platelets and neutrophils modulates their cellular interactions in thrombotic and inflammatory states, with stimulation of P-selectin expression on platelets by agonists such as thrombin and neutrophil-derived cathepsin G being critical in mediating platelet-neutrophil adhesion. This study compared the effects of thrombin and cathepsin G on platelet P-selectin expression and on P-selectin-mediated platelet-neutrophil adhesion. 2. Washed platelets and platelet-neutrophil mixed cell suspensions (platelet/neutrophil ratio, 10:1) were incubated with either the supernatant of activated neutrophils, purified cathepsin G or thrombin. Platelet P-selectin expression and platelet adhesion to neutrophils was quantified by flow fluorocytometric analysis. 3. The supernatant from activated neutrophils stimulated platelet P-selectin expression comparable to that produced by purified cathepsin G or thrombin. P-selectin expression induced by both activated neutrophil supernatant and purified cathepsin G was completely inhibited by alpha 1-antichymotrypsin, a specific inhibitor of cathepsin G. Unlike thrombin, which induced maximum platelet P-selectin expression by 10 min, sustained to 120 min, cathepsin G induced an initial large increase in platelet P-selectin expression, followed by a progressive reduction over 30-60 min to baseline levels. 4. Co-incubation of neutrophils with thrombin-stimulated platelets resulted in a significant increase in P-selectin-mediated platelet-neutrophil adhesion, which was completely inhibited by preincubation of neutrophils with anti-sialyl Lewis(x) monoclonal antibody. Thrombin produced maximum platelet-neutrophil adhesion by 10 min which remained stable over 120 min. In contrast, cathepsin G-stimulated platelets did not adhere to neutrophils over 120 min of co-incubation. Addition of cathepsin G to thrombin-stimulated platelets caused a progressive reduction over 30-60 min to baseline levels of platelet-neutrophil adhesion. 5. Neutrophil-derived cathepsin G is a potent platelet activator, but unlike thrombin it causes a time-dependent loss of platelet P-selectin expression and inhibits P-selectin-mediated platelet-neutrophil adhesion. Therefore, cathepsin G may modulate thrombin-mediated platelet-neutrophil adhesive interactions in inflammation and thrombosis.

Fatty acid synthetase activity in Mycobacterium phlei: regulation by polysaccharides.

The multienzyme complex from Mycobacterium phlei which catalyzes the synthesis of long chain fatty acids from acetyl-CoA and malonyl-CoA requires a heat-stable fraction (stimulating factor, SF) for activity. Fractionation of heat-treated M. phlei extracts affords two stimulatory subfractions, one of which (SF(2)) can be replaced by FMN. The other (SF(1)) is further separable into 3 polysaccharides (PS(I), PS(II), and PS(III)). PS(I) contains about 95% 3-O-methylmannose and 5% mannose; the sugar composition of PS(II) and PS(III) is about 55% 6-O-methylglucose and 45% glucose for both. Each of the three purified polysaccharides, in combination with FMN, substitutes for the crude stimulating factor. The polysaccharides exert their effect on the fatty acid synthetase by lowering the K(m) for acetyl-CoA about 50-fold.