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Introduction The evolution of patients with obstructive sleep apnea (OSA) non-eligible for PAP-therapy at diagnosis is unknown. Currently, the severity of OSA is based on the apnea-hypopnea index (AHI), but its prognostic relevance has raised concerns. The Baveno classification may allow a better stratification of severity and therapeutic guidance in OSA. Methods Patients with AHI≥5/h in 2015, classified into Baveno groups A and B and non-eligible for PAP therapy at diagnosis and over 5 years, were analyzed. Patients were reclassified into Baveno groups (A-D) and changes in groups over 5 years were explored. Patients in Baveno groups C and D, who developed major cardiovascular comorbidities (CVC) or end-organ damage (EOD group), were compared with patients in Baveno groups A and B (non-EOD group). To identify predictors of the development of major CVC or EOD, a logistic regression analysis was performed. Results There were 76 patients, 58% male, mean age 51.9 ± 10.1 years, mean body mass index (BMI) of 30.3 ± 5.0 kg/m2 and median AHI of 8.9 (5.9–12.0) events/h. At diagnosis, 46% and 54% of patients were classified into Baveno group A and group B, respectively. In total, 21% of patients developed major CVC or EOD (Baveno group C or D); higher age (p = 0.011) and BMI (p = 0.004) and a higher percentage of central apneas (p = 0.012) at diagnosis significantly predicted it, while sex, sleepiness, insomnia, AHI, ODI and T90 were not. Conclusions A significant percentage of patients non-eligible for PAP-therapy at diagnosis of OSA developed CVC or EOD; higher age and BMI and a higher percentage of central apneas were significant predictors.

Cardiovascular complications are the leading cause of death, and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2, and showed better endothelium-dependent relaxation. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.NEW & NOTEWORTHY We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.

The COVID-19 pandemic has highlighted racial health disparities within the United States. Although social determinants of health are the most likely drivers of this disparity, it is possible that genetic traits enriched in the black population like sickle cell trait (SCT) could worsen the morbidity and mortality of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients admitted for SARS-CoV-2 infection who identified as black or African American were included in the study (n = 166). Blood remnants were tested for SCT, and clinical data were abstracted from the chart. There was no difference in mortality between those with SCT and those without. There was no difference in respiratory complications between groups, but those without SCT had a much higher burden of chronic lung disease (P = .004). Those with SCT had higher creatinine on admission (P = .004), but no difference in in-hospital renal complications (P = .532). Notably, 12% of the cohort had SCT, which is higher than the expected 7.31% (P = .025). Our study did not show any evidence of increased end organ damage, morbidity, or mortality from SARS-CoV-2 infection among patients with SCT but did show differences in admission creatinine and preexisting lung disease., Key Points • There is no impact of SCT on respiratory, renal, or circulatory complications or mortality in patients with SARS-CoV-2 infection. • The prevalence of SCT in the hospitalized cohort was significantly higher than the prevalence in the community (12% vs 7.31%).

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Introduction BRAF V600 E mutation is present in 50% cases of LCH and is associated with aggressive forms of disease-particularly liver dysfunction in infants and younger children. It is associated with increased mortality due to poorer response to chemotherapy and higher rate of relapse. Though targeted therapy with Vemurafenib shows rapid clinical response and prevents end organ related mortality, optimal duration of therapy and combination of chemotherapy needs further studies. Material & methods We discuss here follow up of 3 patients with Relapse/Refractory LCH and BRAF mutation who were salvaged with Vemurafinib. Results Three patients with Relapse/Refractory MS LCH were treated in our centre with Vemurafenib. All 3 patients showed dramatic response to Vemurafenib at initiation as well as subsequent relapse on stopping. On PET scan, 2 patients had CR at 6 weeks and 3rd patient had PR on 6 and 12th week. We then used slow taper of vemurafenib with/without addition of oral chemotherapeutic agents and continued a minimal dose successfully in all the 3 patients to prevent recurrences. Conclusion Vemurafenib is a safe and effective salvage option to be used early in refractory/relapsed disease to prevent end organ damage. Gradual taper and maintaining a minimal dose with/without addition of oral chemotherapeutic agents may help in preventing recurrences.

BACKGROUND Blood pressure variability (BPV) is associated with end organ damage and cardiovascular outcomes in hypertensive patients. Prehypertensive patients frequently develop hypertension (HT). The purpose of the present study was to evaluate the effect of BPV on the development of HT. METHODS Two hundred and seven prehypertensive patients from the Cappadocia cohort were monitored over 2 years, and 24-hour ambulatory blood pressure monitoring (ABPM), office BP, and home BP measurements were subsequently performed at 4- to 6-month intervals. BPV was calculated as average real variability (ARV) from 24-h ABPM data, home BP, and office BP measurements at first visit. The relationship was evaluated between baseline ARV and the development of HT. RESULTS HT was diagnosed in 25.60% of subjects. Baseline 24-hour ABPM systolic blood pressure (SBP)ARV and diastolic blood pressure (DBP)ARV and home SBPARV were significantly higher in patients who developed HT than the other patients (P 0.006, 0.001 and 0.006, respectively). Baseline 24-hour ABPM SBPARV and home SBPARV exceeding the 90th percentile were identified as parameters affecting development of HT at logistic regression analysis. CONCLUSION In conclusion, our prospective observational cohort study showed that short-term BPV in particular can predict the development of HT in the prehypertensive population.

To accomplish a successful cardiac surgery, cardiopulmonary bypass (CPB) is often utilized to give the surgeon a bloodless field while keeping the patient hemodynamically stable. The perfusionist is responsible for running the heart-lung machine and other devices such as: cell savers, anticoagulation and blood gas management or mechanical circulatory support. Critical times during CPB include going on, cross clamp on and off, cardioplegia delivery, and termination. Troubleshooting is a component that is often overlooked but can be detrimental to delivering the best patient care. To help eliminate these errors, checklists and protocols are put into place to make sure standardized measures are taken pre/intra/post CPB. Safety techniques like deep hypothermic circulatory arrest is performed for certain cardiac surgeries to prevent end organ damage. Perfusion technology is constantly evolving; however, this chapter looks to help build a solid foundation for understanding CPB and supporting devices.

Background The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and SGLT2 inhibitors have demonstrated clinical benefits in HFrEF and CKD patients with T2D. Cardiovascular protection with finerenone and the SGLT2 inhibitor empagliflozin in combination in hypertensive cardiorenal disease is unknown. Purpose To test the hypothesis that the combination of finerenone with empagliflozin provides cardiovascular protection in preclinical hypertension-induced end-organ damage. Methods Cardiovascular morbidity and mortality was studied in hypertensive L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10–11 weeks old female, n=13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Blood pressure (week 1, 3 and 5), urinary (week 2 and 6) and plasma parameters (week 6 and at the end of the study) were determined during the course of the study, while cardiac histology and left ventricular gene expression analysis were performed after study end. Results Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone co-administration in the combination arm. Treatment with 3 mg/kg finerenone and the low dose combination significantly decreased systolic blood pressure (SBP) after 3 and 5 weeks as well as plasma uric acid after 6 weeks. SBP was significantly more reduced in the combination arm vs. the individual monotherapies after 3 weeks. Plasma NT-proBNP was reduced by empagliflozin, finerenone and the combination with similar efficacy. There was a dose-dependent protection from cardiac vasculopathy, cardiac and vascular fibrosis with both agents while low dose combination therapy was more efficient than the respective monotherapy dosages on these cardiac histology parameters. Placebo-treated rats demonstrated a ca. 50% survival rate over the course of 7 weeks while low dose combination provided the most prominent survival benefit (93%). Conclusion Non-steroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer cardiovascular protection in preclinical hypertensive-induced cardiorenal disease. Combination of these two modes of action at low dosages revealed efficacious reduction in blood pressure, cardiac lesions and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Introduction Peripheral eosinophilia with absolute eosinophil count more than 1.500 cells/uL and eosinophilic tissue and end-organ damage are typical features in hypereosinophilic syndrome. In the present study it was hypothesized that hypereosinophilic syndrome-related atrial and ventricular abnormalities are associated with changes in size and function of mitral and/or tricuspid annuli. Methods The study comprised 17 patients with hypereosinophilic syndrome who were recruited, prospectively, 2 patients had to be excluded due to suboptimal image quality (mean age: 61.7±11.2 years, 10 males). The control group consisted of 24 healthy volunteers (mean age: 55.2±7.9 years, 12 males). Complete two-dimensional Doppler echocardiography was performed, mitral and tricuspid annuli were measured by three-dimensional speckle-tracking echocardiography. Results Only interventricular septum proved to be significantly thickened in patients with hypereosinophilic syndrome, other parameters did not differ between the groups examined. Increased end-diastolic and end-systolic mitral annular diameter (2.6±0.3 cm vs. 2.4±0.3 cm, p Conclusion Mitral annular dilation is more pronounced compared to that of tricuspid annulus in hypereosinophilic syndrome. Mitral annular functional impairment is present in hypereosinophilic syndrome. Funding Acknowledgement Type of funding sources: None.