A Murine Model of Pressure Overload-Induced Right Ventricular Hypertrophy and Failure by Pulmonary Trunk Banding.

Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The pathogenesis of RV failure is complex and remains inadequately understood. To identify new therapeutic strategies for the treatment of RV failure, robust and reproducible animal models are essential. Models of pulmonary trunk banding (PTB) have gained popularity, as RV function can be assessed independently of changes in the pulmonary vasculature. In this paper, we present a murine model of RV pressure overload induced by PTB in 5-week-old mice. The model can be used to induce different degrees of RV pathology, ranging from mild RV hypertrophy to decompensated RV failure. Detailed protocols for intubation, PTB surgery, and phenotyping by echocardiography are included in the paper. Furthermore, instructions for customizing instruments for intubation and PTB surgery are given, enabling fast and inexpensive reproduction of the PTB model. Titanium ligating clips were used to constrict the pulmonary trunk, ensuring a highly reproducible and operator-independent degree of pulmonary trunk constriction. The severity of PTB was graded by using different inner ligating clip diameters (mild: 450 µm and severe: 250 µm). This resulted in RV pathology ranging from hypertrophy with preserved RV function to decompensated RV failure with reduced cardiac output and extracardiac manifestations. RV function was assessed by echocardiography at 1 week and 3 weeks after surgery. Examples of echocardiographic images and results are presented here. Furthermore, results from right heart catheterization and histological analyses of cardiac tissue are shown.

Pneumonectomy combined with SU5416 or monocrotaline pyrrole does not cause severe pulmonary hypertension in mice.

In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with three weeks of hypoxia (Hx). Additionally, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared to Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared to PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.

Effects of empagliflozin on right ventricular adaptation to pressure overload.

Background: Right ventricular (RV) failure is the prime cause of death in patients with pulmonary arterial hypertension. Novel treatment strategies that protect the RV are needed. Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, shows cardioprotective effects on the left ventricle in clinical and preclinical studies, but its direct effects on RV remain elusive. We investigated the effects of empagliflozin on RV dysfunction induced by pulmonary trunk banding (PTB). Methods: Male Wistar rats (116 ± 10 g) were randomized to PTB or sham surgery. One week after surgery, PTB animals received empagliflozin mixed into the chow (300 mg empagliflozin/kg chow; PTB-empa, n = 10) or standard chow (PTB-control, n = 10). Sham rats (Sham, n = 6) received standard chow. After five weeks, RV function was evaluated by echocardiography, cardiac MRI, and invasive pressure-volume measurements. Results: PTB caused RV failure evident by decreased cardiac output compared with sham. PTB-empa rats had a 49% increase in water intake compared with PTB-control yet no differences in hematocrit or blood glucose. Treatment with empagliflozin decreased RV end-systolic pressures without any changes in RV cardiac output or ventricular-arterial coupling (Ees/Ea). The decrease in RV end-systolic pressure was complemented by a slight reduction in RV cross sectional area as a sign of reduced hypertrophy. Load-independent measures of RV systolic and diastolic function were not affected in PTB-empa rats compared with PTB-control. Conclusion: Empagliflozin treatment reduced RV end-systolic pressure in RV failure induced by pressure overload. Further studies are needed to elucidate whether this simply relates to a diuretic effect and/or additional independent beneficial RV effects.

Recovery rates and parosmia in olfactory loss during the COVID-19 era.

INTRODUCTION: Olfactory dysfunction (OD) is a common symptom of COVID-19. In some patients, OD persists for many months, fluctuates during recovery or parosmia may occur. Knowledge about the prognosis of these patients is insufficient. METHODS: Data on chemosensory function and possible prognostic factors were collected through a baseline questionnaire and six follow-up questionnaires answered at 2-3-month intervals. RESULTS: One year after onset of OD, 42.0% of the respondents reported sustained complete recovery, 41.7% reported partial recovery and 2.4% reported no improvement of olfaction. Follow-up was unavailable for 13.9%. Parosmia, high severity of OD and female sex were associated with lower rates of recovery. Subjects who reported that OD had a high impact on their quality of life were less likely to recover within one month. Smoking, alcohol habits, BMI and physical activity were not associated with persistence of OD. CONCLUSIONS: High recovery rates were reported within the first months. Recovery of sensory function after more than six months with no prior improvement was reported. After one year, 97.1% of participants with at least one year of follow-up had reported at least some recovery. Recurring OD after initial complete recovery was reported by 24.5% of participants. Parosmia and severity of OD were associated with prolonged recovery rates. FUNDING: AF received research funding from Velux Fonden. The sponsors had no say nor any responsibilities in relation to the study. TRIAL REGISTRATION: not relevant.

Sustained Chemosensory Dysfunction during the COVID-19 Pandemic.

INTRODUCTION: Chemosensory dysfunction (CD) has proven valuable in prediction of COVID-19, as it is a frequent and specific symptom of the disease. The aim of this study was to investigate the duration of CD in patients with sudden subjective olfactory and/or gustatory loss during the SARS-CoV-2 pandemic. The secondary aim was to identify possible prognostic factors for the duration of CD. METHODS: An online baseline questionnaire was designed to assess subjective CD. Three rounds of follow-up questionnaires were sent out to any participants with persistent CD in 6-week intervals, prospectively assessing subjective chemosensory function and extending the follow-up time of this cohort significantly. RESULTS: In total, 467 participants completed the baseline questionnaire. The most significant improvement and recovery of chemosensory function was observed within the first month after the initial loss. Rates became stagnant after about 2 months, and only little improvement and recovery was seen after 2-4 months. After a mean follow-up of 95.9 days (olfactory dysfunction) and 94.0 days (gustatory dysfunction), 86.7% of participants reported gustatory improvement and 82.6% reported olfactory improvement, while 55.0% reported full gustatory recovery and 43.8% reported full olfactory recovery. Female gender was associated with better improvement of gustatory function. High subjective severity of chemosensory loss was associated with lower rates of olfactory and gustatory recovery as well as improvement of olfactory function. Young age was not associated with a better prognosis. DISCUSSION/CONCLUSION: Rates of improvement and recovery of chemosensory function decreased after 2-4 months after initial chemosensory loss, possibly indicating that prolonged and perhaps permanent chemosensory loss may be a complication of SARS-CoV-2 infections. High subjective severity of CD may worsen the prognosis for improvement and recovery of chemosensory function.