Impact of COVID-19 pandemic on the management of nonculprit lesions in patients presenting with ST-elevation myocardial infarction: Outcomes from the pan-London heart attack centers.

BACKGROUND: The impact of COVID-19 on the diagnosis and management of nonculprit lesions remains unclear. OBJECTIVES: This study sought to evaluate the management and outcomes of patients with nonculprit lesions during the COVID-19 pandemic. METHODS: We conducted a retrospective observational analysis of consecutive primary percutaneous coronary intervention (PPCI) pathway activations across the heart attack center network in London, UK. Data from the study period in 2020 were compared with prepandemic data in 2019. The primary outcome was the rate of nonculprit lesion percutaneous coronary intervention (PCI) and secondary outcomes included major adverse cardiovascular events. RESULTS: A total of 788 patients undergoing PPCI were identified, 209 (60%) in 2020 cohort and 263 (60%) in 2019 cohort had nonculprit lesions (p = .89). There was less functional assessment of the significance of nonculprit lesions in the 2020 cohort compared to 2019 cohort; in 8% 2020 cohort versus 15% 2019 cohort (p = .01). There was no difference in rates of PCI for nonculprit disease in the 2019 and 2020 cohorts (31% vs 30%, p = .11). Patients in 2020 cohort underwent nonculprit lesion PCI sooner than the 2019 cohort (p < .001). At 6 months there was higher rates of unplanned revascularization (4% vs. 2%, p = .05) and repeat myocardial infarction (4% vs. 1%, p = .02) in the 2019 cohort compared to 2020 cohort. CONCLUSION: Changes to clinical practice during the COVID-19 pandemic were associated with reduced rates of unplanned revascularization and myocardial infarction at 6-months follow-up, and despite the pandemic, there was no difference in mortality, suggesting that it is not only safe but maybe more efficacious.

Role of reactive oxygen species and sulfide-quinone oxoreductase in hydrogen sulfide-induced contraction of rat pulmonary arteries.

Application of H2S ("sulfide") elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 µM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 µM) and by 50 µM ryanodine; the Ca2+ channel blocker nifedipine (1 µM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 µM), the NADPH oxidase (NOX) blocker VAS2870 (10 µM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 µM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 µM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production.

Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension.

Objectives: SSc-pulmonary arterial hypertension (SSc-PAH) is associated with worse response to therapy and survival when compared with idiopathic PAH. It is suggested that the vasculopathy in SSc may involve postcapillary pulmonary venules resulting in pulmonary veno-occlusive disease (PVOD). This may underlie the lower gas transfer and worse outcome on therapy. We sought to test whether CT signs of PVOD (CTS-PVOD) were frequent in SSc-PAH and whether they were associated with pulmonary oedema on therapy and worse survival. Methods: CT thorax of 66 SSc patients with precapillary pulmonary hypertension (PH) were blindly scored by two radiologists for CTS-PVOD (⩽1 or ⩾ 2). Case note and radiograph review determined the presence of pulmonary oedema on therapy. Results: Fifty-nine patients (89%) had ⩽1 CTS-PVOD and only 7 (11%) had ⩾2 CTS-PVOD. Pulmonary oedema on therapy was relatively common in those with ⩾2 CTS-PVOD. On univariate analysis ⩾2 CTS-PVOD were associated with a trend towards worse survival. Conclusion: CTS-PVOD were less frequent in this SSc-PAH cohort than in previous reports but the presence of at least two of these signs is associated with pulmonary oedema on therapy and a trend towards worse survival on univariate analysis.

Hypoxic pulmonary vasoconstriction in the absence of pretone: essential role for intracellular Ca2+ release.

Hypoxic pulmonary vasoconstriction (HPV) maintains blood oxygenation during acute hypoxia but contributes to pulmonary hypertension during chronic hypoxia. The mechanisms of HPV remain controversial, in part because HPV is usually studied in the presence of agonist-induced preconstriction ('pretone'). This potentiates HPV but may obscure and distort its underlying mechanisms. We therefore carried out an extensive assessment of proposed mechanisms contributing to HPV in isolated intrapulmonary arteries (IPAs) in the absence of pretone by using a conventional small vessel myograph. Hypoxia elicited a biphasic constriction consisting of a small transient (phase 1) superimposed upon a sustained (phase 2) component. Neither phase was affected by the L-type Ca2+ channel antagonists diltiazem (10 and 30 µm) or nifedipine (3 µm). Application of the store-operated Ca2+ entry (SOCE) blockers BTP2 (10 µm) or SKF96365 (50 µm) attenuated phase 2 but not phase 1, whereas a lengthy (30 min) incubation in Ca2+-free physiological saline solution similarly reduced phase 2 but abolished phase 1. No further effect of inhibition of HPV was observed if the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid (30 µm) was also applied during the 30 min incubation in Ca2+-free physiological saline solution. Pretreatment with 10 µm ryanodine and 15 mm caffeine abolished both phases, whereas treatment with 100 µm ryanodine attenuated both phases. The two-pore channel blocker NED-19 (1 µm) and the nicotinic acid adenine dinucleotide phosphate (NAADP) antagonist BZ194 (200 µm) had no effect on either phase of HPV. The lysosomal Ca2+-depleting agent concanamycin (1 µm) enhanced HPV if applied during hypoxia, but had no effect on HPV during a subsequent hypoxic challenge. The cyclic ADP ribose antagonist 8-bromo-cyclic ADP ribose (30 µm) had no effect on either phase of HPV. Neither the Ca2+-sensing receptor (CaSR) blocker NPS2390 (0.1 and 10 µm) nor FK506 (10 µm), a drug which displaces FKBP12.6 from ryanodine receptor 2 (RyR2), had any effect on HPV. HPV was virtually abolished by the rho kinase blocker Y-27632 (1 µm) and attenuated by the protein kinase C inhibitor Gö6983 (3 µm). Hypoxia for 45 min caused a significant increase in the ratio of oxidised to reduced glutathione (GSSG/GSH). HPV was unaffected by the NADPH oxidase inhibitor VAS2870 (10 µm), whereas phase 2 was inhibited but phase 1 was unaffected by the antioxidants ebselen (100 µm) and TEMPOL (3 mm). We conclude that both phases of HPV in this model are mainly dependent on [Ca2+]i release from the sarcoplasmic reticulum. Neither phase of HPV requires voltage-gated Ca2+ entry, but SOCE contributes to phase 2. We can detect no requirement for cyclic ADP ribose, NAADP-dependent lysosomal Ca2+ release, activation of the CaSR, or displacement of FKBP12.6 from RyR2 for either phase of HPV. Sustained HPV is associated with an oxidising shift in the GSSG/GSH redox potential and is inhibited by the antioxidants ebselen and TEMPOL, consistent with the concept that it requires an oxidising shift in the cell redox state or the generation of reactive oxygen species.

Time to internal fixation of femoral neck fractures in patients under sixty years--does this matter in the development of osteonecrosis of femoral head?

PURPOSE: Osteonecrosis of femoral head remains a major complication of femoral neck fractures. It has been postulated that early internal fixation drastically reduces the incidence of osteonecrosis of the femoral head. However, there is a paucity of literature looking at the effect of time delay to internal fixation on the development of this late complication. In this study, we aim to assess the effect of time delay and method of internal fixation on the development of osteonecrosis in those less than 60 years of age. METHODS: We retrospectively analysed 92 patients less than 60 years of age who presented with intracapsular neck of femur fractures that underwent internal fixation between 1999 and 2009. RESULTS: Of the 92 intracapsular fractures, 50 underwent fixation using cannulated screws, 32 using a dynamic hip screw, and ten using a dynamic hip screw with a derotation screw. In total, 13 patients (14.1 %) developed osteonecrosis of the femoral head, the highest incidence being in the cannulated screw fixation group with an osteonecrosis rate of 24 %. We did not find the time delay to internal fixation to be a significant predictor of the development of osteonecrosis. CONCLUSION: Our study demonstrated that the method of internal fixation rather than delay in internal fixation was more predictive of osteonecrosis of the femoral head. We did not find support to the current belief that early surgical fixation of neck of femur fractures reduces the risk of osteonecrosis in patients less than 60 years.

Key role of the RhoA/Rho kinase system in pulmonary hypertension.

Pulmonary hypertension (PH) is a general term comprising a spectrum of pulmonary hypertensive disorders which have in common an elevation of mean pulmonary arterial pressure (mPAP). The prototypical form of the disease, termed pulmonary arterial hypertension (PAH), is a rare but lethal syndrome with a complex aetiology characterised by increased pulmonary vascular resistance (PVR) and progressive elevation of mPAP; patients generally die from heart failure. Current therapies are inadequate and median survival is less than three years. PH due to chronic hypoxia (CH) is a condition separate from PAH and is strongly associated with chronic obstructive pulmonary disease (COPD). An early event in the pathogenesis of this form of PH is hypoxic pulmonary vasoconstriction (HPV), an acute homeostatic process that maintains the ventilation-perfusion ratio during alveolar hypoxia. The mechanisms underlying HPV remain controversial, but RhoA/Rho kinase (ROK)-mediated Ca²+-sensitisation is considered important. Increasing evidence also implicates RhoA/ROK in PASMC proliferation, inflammatory cell recruitment and the regulation of cell motility, all of which are involved in the pulmonary vascular remodelling occurring in all forms of PH. ROK is therefore a potential therapeutic target in treating PH of various aetiologies. Here, we examine current concepts regarding the aetiology of PAH and also PH due to CH, focusing on the contribution that RhoA/ROK-mediated processes may make to their development and on ROK inhibitors as potential therapies.

Cardiac arrest, chronic total occlusion, and occluded stent in a 16-year-old boy with Kawasaki disease: a case report.

BACKGROUND: Kawasaki disease is the leading cause of premature coronary artery disease in developed countries. As such, patients may require revascularisation as children. However, there are no randomized data guiding treatment so this must be individualized. This case report describes the decision-making in a young patient requiring revascularization who had already suffered stent occlusion. CASE SUMMARY: Our patient, a 16-year-old boy with Kawasaki disease, presented with cardiac arrest during exercise. Coronary angiography showed that a proximal left anterior descending artery stent implanted at the age of 8 years had occluded some time ago and his right coronary artery was also chronically occluded. He has discussed in several Heart Team meetings and with international colleagues and a consensus reached to revascularize him surgically. DISCUSSION: It is vital that young patients with complex coronary disease are discussed in an extensive multidisciplinary setting to determine the most suitable means of treatment. The previously occluded stent was crucial in the individualized decision-making in this patient.

Pulmonary hypertension in systemic lupus erythematosus.

Systemic lupus erythematosus is associated with several forms of pulmonary hypertension. It can cause pulmonary hypertension through pulmonary thromboembolic disease, left heart disease and lung disease as well as causing an isolated pulmonary vasculopathy called pulmonary arterial hypertension. The true prevalence of pulmonary arterial hypertension in patients with lupus is not known but probably is no more than 1%. Currently, treatment for lupus-associated pulmonary arterial hypertension is with pulmonary vasodilators including phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostacyclin analogues, as it is for other causes of pulmonary arterial hypertension. Case series suggest there may be a special role for immunosuppression in this rare group of patients. We present two brief case histories and summarise our experience over 15 years. Prognosis is better in lupus-associated pulmonary arterial hypertension than in systemic sclerosis-associated pulmonary arterial hypertension, but unfortunately it remains a fatal condition in most patients.

Cell redox state and hypoxic pulmonary vasoconstriction: recent evidence and possible mechanisms.

During alveolar hypoxia, hypoxic pulmonary vasoconstriction (HPV) maintains blood oxygenation near optimum via incompletely defined mechanisms. It is proposed that a hypoxia-induced rise in the intracellular concentration of reactive oxygen species (ROS) or an oxidising shift in the cytoplasmic redox state provides the signal which initiates the constriction of pulmonary arteries (PA), although this is controversial. Here, we review recent investigations demonstrating that hypoxia causes a rise in [ROS] in PA smooth muscle, and that ROS and antioxidants have effects on PA which would be predicted if cell oxidation causes contraction. We argue that intracellular Ca2+ release and Ca2+-sensitisation are the key effector mechanisms causing HPV, and discuss evidence that both processes are promoted by ROS or oxidative protein modifications. We conclude that while it is plausible that an increase in cytoplasmic [ROS] activates HPV effector mechanisms, proving this link will require the determination of whether hypoxia causes oxidative modifications of proteins involved in Ca2+ homeostasis and sensitisation.