The association of subjective and objective sleep measures with chronic tinnitus.

STUDY OBJECTIVES: Poor sleep is a prevalent complaint in the population with chronic tinnitus, but the relationship between the two is not well-characterized. The objective of this study was to understand how subjective and objective measures of sleep compare in patients with or without chronic tinnitus. METHODS: This prospective cohort study included consecutive adult patients who presented to a sleep laboratory between January 19, 2017, and January 10, 2020. All patients underwent an in-laboratory nocturnal polysomnogram and filled out questionnaires including the Pittsburgh Sleep Quality Index (PSQI), Tinnitus Screener, and Tinnitus Handicap Inventory, among others. RESULTS: The study included 1,968 participants, out of which 284 (14.4%) reported chronic tinnitus. Patients with chronic tinnitus were younger (51.6 years vs 54.1 years; P < .05) and more likely female (16.4% vs 11.7%; P < .005). They demonstrated worse subjective sleep quality (PSQI: 11.3 vs 9.5; P < .0005) and increased sleepiness (Epworth Sleepiness Scale: 9.8 vs 8.6; P < .005). In the objective sleep parameters only the total sleep time was increased in chronic tinnitus (311.5 vs 294.5 minutes; P < .05) and total arousals were decreased (41.7 vs 47; P < .005). Sleep stage N3 was higher in those with chronic tinnitus (14.9% vs 13.0%; P < .05). In multivariable analyses, as PSQI increases the odds of chronic tinnitus increases. This effect was modified by age: In those younger than 55 years of age, the odds of the presence of chronic tinnitus was 1.10 (95% confidence interval, 1.03, 1.17) times higher as PSQI increased. CONCLUSIONS: Chronic tinnitus is associated with significant changes in qualitative sleep (higher PSQI) but no major differences in quantitative sleep measures were observed. CITATION: Weingarten JA, Islam A, Dubrovsky B, Gharanei M, Coelho DH. The association of subjective and objective sleep measures with chronic tinnitus. J Clin Sleep Med. 2024;20(3):399-405.

Pulmonary hypertension predicts higher mortality in patients admitted with severe COVID-19 infection.

Objective: Patients with underlying conditions are predicted to have worse outcomes with COVID-19. A strong association between baseline cardiovascular disease and COVID-19-related mortality has been shown by a number of studies. In the current retrospective study, we aim to identify whether patients with pulmonary hypertension have worse outcomes compared with patients without pulmonary hypertension. Methods: Data from patients of ⩾18 years of age with COVID was retrospectively collected and analyzed (n = 679). Patients who underwent transthoracic echocardiography, at the discretion of the medical team, were identified and the transthoracic echocardiography was reviewed for the presence of pulmonary hypertension. Patient health parameters and outcomes were measured and statistically analyzed. Results: Of 679 consecutive patients identified with a diagnosis of COVID-19, 57 underwent transthoracic echocardiography, 32 of which were found to have pulmonary hypertension. Patients who underwent transthoracic echocardiography had a significantly higher intensive care unit admission rate (73.7% versus 25.4%, p < 0.001) and increased presence of acute respiratory distress syndrome (63.2% versus 21.6%, p > 0.001). These patients had longer intensive care unit length of stay, longer mechanical ventilation time, longer hospital length of stay, and a significantly higher mortality rate when compared to those not undergoing transthoracic echocardiography (59.7% versus 32.3%, p < 0.001). Among patients who underwent transthoracic echocardiography, those with pulmonary hypertension had significantly higher mortality compared to those without pulmonary hypertension (80% versus 43.8%, p < 0.01). Conclusion: COVID-19 in patients with pulmonary hypertension was associated with high in-hospital mortality even when adjusted for confounding factors. A number of mechanisms have been proposed for the worse outcomes in patients with pulmonary hypertension and right ventricular dysfunction, including right ventricle overload and indirect pro-inflammatory cytokine storm. Further, large-scale studies are required to evaluate the impact of right ventricular dysfunction in COVID-19 patients and to elucidate the associated mechanisms.

Metformin Protects Against Sunitinib-induced Cardiotoxicity: Investigating the Role of AMPK.

ABSTRACT: Sunitinib is associated with cardiotoxicity through inhibition of AMP-protein kinase (AMPK) signaling. By contrast, the common antidiabetic agent metformin has demonstrated cardioprotection through indirect AMPK activation. In this study, we investigate the effects of metformin during sunitinib-induced cytotoxicity. Left ventricular developed pressure, coronary flow, heart rate, and infarct size were measured in Langendorff-perfused rat hearts treated with 1 µM sunitinib ±50 µM metformin ±1 µM human equilibrative nucleoside transporter inhibitor S-(4-Nitrobenzyl)-6-thioinosine (NBTI). Western blot analysis was performed for p-AMPKα levels. Primary isolated cardiac myocytes from the left ventricular tissue were used to measure live cell population levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess adjunctive treatment of and metformin in human hepatoma G2 and promyelocytic leukemia (HL-60) cells treated with 0.1-100 µM sunitinib ±50 µM metformin. In the perfused hearts, coadministration of metformin attenuated the sunitinib-induced changes to left ventricular developed pressure, infarct size, and cardiac myocyte population. Western blot analysis revealed a significant decrease in p-AMPKα during sunitinib treatment, which was attenuated after coadministration with metformin. All metformin-induced effects were attenuated, and NBTI was coadministered. The MTT assay demonstrated an increase in the EC50 value during coadministration of metformin with sunitinib compared with sunitinib monotherapy in hepatoma G2 and HL-60 cell lines, demonstrating the impact and complexity of metformin coadministration and the possible role of AMPK signaling. This study highlights the novel cardioprotective properties of metformin and AMPK activation during sunitinib-induced cardiotoxicity when administered together in the Langendorff heart model.

Atrial-specific hiPSC-derived cardiomyocytes in drug discovery and disease modeling.

The discovery and application of human-induced pluripotent stem cells (hiPSCs) have been instrumental in the investigation of the pathophysiology of cardiovascular diseases. Patient-specific hiPSCs can now be generated, genome-edited, and subsequently differentiated into various cell types and used for regenerative medicine, disease modeling, drug testing, toxicity screening, and 3D tissue generation. Modulation of the retinoic acid signaling pathway has been shown to direct cardiomyocyte differentiation towards an atrial lineage. A variety of studies have successfully differentiated patient-specific atrial cardiac myocytes (hiPSC-aCM) and atrial engineered heart tissue (aEHT) that express atrial specific genes (e.g., sarcolipin and ANP) and exhibit atrial electrophysiological and contractility profiles. Identification of protocols to differentiate atrial cells from patients with atrial fibrillation and other inherited diseases or creating disease models using genetic mutation studies has shed light on the mechanisms of atrial-specific diseases and identified the efficacy of atrial-selective pharmacological compounds. hiPSC-aCMs and aEHTs can be used in drug discovery and drug screening studies to investigate the efficacy of atrial selective drugs on atrial fibrillation models. Furthermore, hiPSC-aCMs can be effective tools in studying the mechanism, pathophysiology and treatment options of atrial fibrillation and its genetic underpinnings. The main limitation of using hiPSC-CMs is their immature phenotype compared to adult CMs. A wide range of approaches and protocols are used by various laboratories to optimize and enhance CM maturation, including electrical stimulation, culture time, biophysical cues and changes in metabolic factors.

The cardiac work-loop technique: An in vitro model for identifying and profiling drug-induced changes in inotropy using rat papillary muscles.

The cardiac work-loop technique closely mimics the intrinsic in vivo movement and characteristics of cardiac muscle function. In this study, six known inotropes were profiled using the work-loop technique to evaluate the potential of this method to predict inotropy. Papillary muscles from male Sprague-Dawley rats were mounted onto an organ bath perfused with Krebs-Henseleit buffer. Following optimisation, work-loop contractions were performed that included an initial stabilisation period followed by vehicle control or drug administration. Six known inotropes were tested: digoxin, dobutamine, isoprenaline, flecainide, verapamil and atenolol. Muscle performance was evaluated by calculating power output during work-loop contraction. Digoxin, dobutamine and isoprenaline caused a significant increase in power output of muscles when compared to vehicle control. Flecainide, verapamil and atenolol significantly reduced power output of muscles. These changes in power output were reflected in alterations in work loop shapes. This is the first study in which changes in work-loop shape detailing for example the activation, shortening or passive re-lengthening have been linked to the mechanism of action of a compound. This study has demonstrated that the work-loop technique can provide an important novel method with which to assess detailed mechanisms of drug-induced effects on cardiac muscle contractility.

Predictivity of in vitro non-clinical cardiac contractility assays for inotropic effects in humans--A literature search.

Adverse drug effects on the cardiovascular system are a major cause of compound attrition throughout compound discovery and development. There are many ways by which drugs can affect the cardiovascular system, including effects on the electrocardiogram, vascular resistance, heart rate and the force of contraction of the heart (inotropy). Compounds that increase the force of contraction of the heart can be harmful in patients with ischemic heart disease, whilst negative inotropes can induce symptoms of heart failure. There is a range of non-clinical in vitro and in vivo assays used to detect inotropic effects of drugs. We have conducted a literature review of the in vitro assays and compared the findings from these with known effects on cardiac contractility in man. There was a wide variety of assays used, ranging from perfuse whole hearts to isolated regions of the heart (papillary muscle, ventricle and atria), which were removed from a number of species (cat, guinea pig, rabbit and rat). We conducted two analyses. The first was investigating the concordance of the findings from the in vitro assays at any concentration with those observed in man (an assessment of hazard identification) and the second was the concordance of the in vitro findings at concentrations tested up to 10-fold higher than those tested in the clinic. We found that when used as a hazard identification tool, the available assays had good sensitivity (88%), although the specificity was not so good (60%), but when used as a risk management tool the sensitivity was considerably reduced (sensitivity 58-70% and specificity 60%). These data would suggest that the available in vitro assays can be used as hazard identification tools for adverse drug effects on cardiac contractility, but there is a need for new assays to better predict the exposures in man that may cause a change in cardiac contractility and therefore better predict the likely therapeutic index of compounds prior to nomination of compounds for clinical development.

Investigation into the cardiotoxic effects of doxorubicin on contractile function and the protection afforded by cyclosporin A using the work-loop assay.

Doxorubicin is known to cause cardiotoxicity through multiple routes including the build-up of reactive oxygen species and disruption of the calcium homeostasis in cardiac myocytes, but the effect of drug treatment on the associated biomechanics of cardiac injury remains unclear. Detecting and understanding the adverse effects of drugs on cardiac contractility is becoming a priority in non-clinical safety pharmacology assessment. The work-loop technique enables the assessment of force-length work-loop contractions, which mimic those of the pressure-volume work-loops experienced by the heart in vivo. During this study we evaluated whether the work-loop technique could potentially provide improved insight into the biomechanics associated with drug-induced cardiac dysfunction. In order to do this we investigated the cardiotoxic effects of doxorubicin and characterised the protection afforded by the co-administration of cyclosporin A (CsA). This study provides detailed biomechanical in vitro insight into the cardiac dysfunction associated with Doxorubicin treatment, including reduction in peak force, force during shortening and power output. These effects were significantly abrogated in doxorubicin-CsA co-treatment studies. Closely mimicking the in vivo pressure-volume muscle mechanics, this assay provides a quick and easy technique to gain a better understanding of the detailed biomechanics of drug-induced cardiac dysfunction.

Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor.

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties.