Moyamoya disease (MMD) and posterior reversible encephalopathy syndrome (PRES) share similar pathophysiological characteristics of endothelial dysfunction and impaired cerebral autoregulation. However, there have never been any published studies to demonstrate the relationship between these 2 rare diseases.A 26-year-old Asian man presented with a throbbing headache, blurred vision, and extremely high blood pressure. We initially suspected acute cerebral infarction based on the cerebral computed tomography, underlying MMD, and prior ischemic stroke. However, the neurological symptoms deteriorated progressively.Cerebral magnetic resonance imaging indicated the presence of vasogenic edema rather than cerebral infarction.An appropriate blood pressure management prevents the patient from disastrous outcomes successfully. Cerebral magnetic resonance imaging at 2 months post treatment disclosed the complete resolution of cerebral edema. The patient's recovery from clinical symptoms and the neuroimaging changes supported the PRES diagnosis.This report suggests that patients with MMD may be susceptible to PRES. It highlights the importance of considering PRES as a differential diagnosis while providing care to MMD patients with concurrent acute neurological symptoms and a prompt intervention contributes to a favorable clinical prognosis. They facilitate the unique “puff of smoke” look on digital subtraction angiography, officially named MMD by Suzuki and Takaku in 1969. MMD is a rare disease and incidence rates are higher in East Asian populations than European and North American populations. The clinical presentations of MMD vary with age and have a bimodal distribution. Ischemic strokes and transient ischemic attacks are common in children, whereas hemorrhagic strokes are predominant in adult patients.Moyamoya disease (MMD) is an idiopathic, chronic cerebrovascular disease characterized by progressively steno-occlusive changes at the distal internal carotid artery, with occasional middle cerebral artery and anterior cerebral artery involvements. Clinical and radiological symptoms can be reversed with an appropriate diagnosis and management. Effective and early treatment is required for a favorable prognosis.Posterior reversible encephalopathy syndrome (PRES) is a heterogeneous clinical and neuroradiological syndrome characterized by a parieto-occipital predominant pattern of reversible vasogenic edema. Symptoms include altered consciousness, headache, visual disturbances, and seizures. Moreover, endothelial dysfunction and impaired cerebral autoregulation are reportedly pathophysiological characteristics of MMD.,8 However, to the best of our knowledge, there is no study reporting the relationship between MMD and PRES. Here, we report on the serial clinical investigations and neuroimaging changes of a unique case presenting with MMD and PRES.PRES has been reported to be associated with hypertension and endothelial dysfunction.2A 26-year-old male, with a history of hypertension, prior ischemic stroke, and MMD, Suzuki stage 4, was prescribed acetazolamide, clonidine, amlodipine, and valsartan for hypertension control along with aspirin for secondary prevention of stroke. He presented to the emergency room with a worsening throbbing headache and blurred vision in January 2021. On arrival, he was afebrile, with a normal heart rate (89 beats per minute) but an extremely high blood pressure (202/140 mm Hg). The white blood cell count and C-reactive protein were within normal limits, and his renal and hepatic functions were normal. Both autoimmune and coagulopathy profiles were unremarkable, and there was no exposure to cytotoxic substances and/or immunosuppressants. The neurological examination revealed no focal neurological deficits, except blurred vision. However, cerebral computed tomography identified a hypodense lesion in the left parieto-temporal lobe, and thus acute cerebral infarction was initially impressed (Fig. After we managed to control his hypertension for 1 week, the patient recovered consciousness, and intravenous nicardipine was replaced by oral medications. His clinical symptoms improved without neurological sequelae with a total hospitalization for 2 weeks. A follow-up cerebral MRI at 2 months posttreatment disclosed the complete resolution of cerebral edema without any newly developed intracranial lesion (Fig. 3 According to our critical literature review, MMD has not been reported as a risk factor for PRES.In this case study, we demonstrated a rare case of PRES predisposed by MMD, with a favorable outcome after opportune diagnosis and treatment. PRES could be triggered by acute hypertension and underlying endotheliopathy, which is associated with sepsis, pre-eclampsia, eclampsia, autoimmune disorders, and exposure to cytotoxic medications. MMD vasculopathy could contribute to endothelial dysfunction, disruption of the blood–brain barrier, and impaired cerebral autoregulation. Cerebral autoregulation is the intrinsic ability of the brain to maintain constant cerebral perfusion despite alterations in arterial blood pressure. Therefore, vasculopathy facilitates a lower limit of blood pressure in patients with MMD to overwhelm the cerebral autoregulation threshold. This results in cerebral hyperperfusion and vasogenic edema, 2 main pathophysiologies of PRES.The histopathological findings of MMD revealed intimal thickening, the undulation of the elastic lamina, and attenuation of media. However, patients with MMD have increased stroke risks, which may complicate the diagnosis and treatment for PRES. It is difficult to differentiate acute cerebral infarction and vasogenic edema from cerebral computed tomography. By contrast, MRI can differentiate PRES from early cerebral ischemia. As opposed to the hyperintense signal on diffusion-weighted imaging with a corresponding decreased signal on apparent diffusion coefficient in acute cerebral infarction, PRES usually presents with prominent vasogenic edema discernable in T2-weighted images and fluid-attenuated inversion recovery, with an isointense or hyperintense signal on diffusion-weighted imaging that is not accompanied by a corresponding decreased signal on apparent diffusion coefficient.PRES is generally considered clinically and neuroradiologically reversible with a favorable prognosis. However, the prognosis depends on the etiologies, the time available to control the causative factor, the presence of intracerebral hemorrhage, and restrictive diffusion on MRI. However, in patients with acute cerebral infarction, blood pressure should be maintained below 220/120 mm Hg. In our case, we suspected acute cerebral infarction initially because of the underlying MMD, the history of cerebral infarction, and the cerebral computed tomography. Therefore, we were not to control blood pressure intensively. However, neurological symptoms deteriorated progressively during the hospitalization period. Cerebral MRI suggested the presence of vasogenic edema rather than cerebral infarction. Consequently, we gradually reduced blood pressure and the patient managed to recover completely without sequelae. Due to the different goals of blood pressure control between acute cerebral infarction and PRES, an appropriate diagnostic tool to differentiate between these 2 conditions and prompt management of blood pressure plays a crucial role in preventing the development of neurological sequelae.In patients with MMD and acute hypertension, blood pressure must be lowered gradually to reach the mean arterial pressure to 105 to 125 mm Hg.In conclusion, this report suggests that patients with MMD could be susceptible to PRES due to the altered capacity for cerebral autoregulation. Also, we highlight the importance of considering PRES as a differential diagnosis while providing care to MMD patients with concurrent acute onset of neurological symptoms.Data curation: Meng-Ni Wu.Supervision: Ping-Song Chou.Visualization: I-Hsiao Yang.Writing – original draft: Chun-Hsin Teng.Writing – review & editing: Ping-Song Chou.


Contrast-induced nephropathy (CIN) is an impairment of renal function that occurs after the administration of an iodinated contrast medium (CM). Kidney dysfunction in CIN is considered transient and reversible in most cases. However, it is the third most common cause of hospital-acquired acute kidney injury and is associated with increased morbidity and mortality, especially in high-risk patients. Diagnostic and interventional procedures that require intravascular CM are being used with increasing frequency, especially among the elderly, who can be particularly susceptible to CIN due to multiple comorbidities. Therefore, identifying the exact mechanisms of CIN and its associated risk factors is crucial not only to provide optimal preventive management for at-risk patients, but also to increase the feasibility of diagnostic and interventional procedure that use CM. CM induces kidney injury by impairing renal hemodynamics and increasing the generation of reactive oxygen species, in addition to direct cytotoxicity. Periprocedural hydration is the most widely accepted preventive strategy to date. Here, we review the latest research results on the pathophysiology and management of CIN. Contrast-induced nephropathy (CIN) is an impairment of kidney function that occurs after the administration of iodinated contrast medium (CM). It is the third most common cause of hospital-acquired acute kidney injury (AKI) and is associated with prolonged hospital stay and increased morbidity and mortality ,2,3. TheThe term used to describe kidney injury following exposure to CM has changed over time. The most recent guidelines from the American College of Radiology (ACR) Committee on Drugs and Contrast Media suggested contrast-associated acute kidney injury (CA-AKI), formerly called post-contrast acute kidney injury (PC-AKI), as a general term to describe a decline in kidney function that occurs within 48 h after the intravascular administration of iodinated CM [However, it is difficult to identify the definite cause of AKI in patients who undergo a procedure using CM because various patient- and procedure-related factors can influence kidney function, such as hemodynamic instability or atheroembolism caused by catheter manipulation. The terms used in previous clinical studies have been inconsistent, and it is difficult to differentiate CI-AKI from CA-AKI in most studies, mainly due to the lack of a suitable control group. The incidence of CI-AKI might have included cases of CA-AKI, although CI-AKI is a subgroup of CA-AKI. We use the traditional term CIN in this article because we discuss the pathophysiology and management of kidney injury caused by CM.Kidney dysfunction in CIN is usually reversible; the decline in kidney function occurs 2–3 days after exposure to CM and returns to the baseline level within 1–2 weeks ,10. The Diverse definitions of kidney injury after CM administration have been used in clinical studies: an absolute increase in sCr ≥0.3–0.5 mg/dL or a relative increase in sCr ≥ 25–50% from baseline values. A relative increase ≥25% is the most sensitive indicator, and an absolute increase ≥0.5 mg/dL is the least sensitive ,13,14. TAlthough AKI is defined as a change in sCr, the elevation of sCr might not be a sensitive marker for assessing changes in glomerular filtration rate (GFR). SCr increases slowly after a reduction in GFR because creatinine is distributed in the total body water. Furthermore, creatinine is secreted by kidney tubular cells, and the sCr value is affected by multiple factors such as muscle mass, age, sex, and hydration status ,16. BecaBecause no definite treatment to ameliorate CIN has been established, the importance of preventive measures has been highlighted, and identifying patients at high risk for CIN is the first step in prevention. A variety of risk factors has been reported and can be divided into patient-related and procedure-related risk factors, as summarized in Impaired kidney function, diabetes, advanced age, and preexisting intravascular volume depletion before CM administration are frequently reported patient-related risk factors ,21. Fema2 , but not in patients with an eGFR greater than 45 mL/min/1.73 m2 [2, 7.4% for eGFR 30–45 mL/min/1.73 m2, and 16.7% for eGFR < 30 mL/min/1.73 m2 [Patients with CKD, particularly diabetic kidney disease, are most susceptible to CIN ,25,26. C/1.73 m2 . Similar/1.73 m2 . Though /1.73 m2 . The imm/1.73 m2 ,32. DecrAlthough those patient-related factors are generally accepted as risk factors for AKI regardless of its underlying cause and are not specific for CIN, exposure to more risk factors should be considered as resulting in a higher incidence of CIN. Therefore, preventive measures for modifiable risk factors and caution for CIN should be adopted.The following procedure-related risk factors are considered to be associated with CIN: type, volume, and route of CM administration, and repetitive CM administration within a short period of time (24–72 h) .2O) [2O) and iso-osmolar CM  [+/CD41a− endothelial microparticles (EMPs) and platelet microparticles (PMPs) were higher in patients with diabetes who received intra-arterial (IA) iohexol than in those who received iodixanol or patients without diabetes who received iohexol, whereas CD62E+ EMPs decreased significantly in patients receiving iodixanol. In an in vitro experiment using human umbilical vein endothelial cells, iohexol induced the release of more CD31+/CD41a− EMPs than iodixanol, which resulted in greater apoptosis, whereas CD62E+ EMP levels were lower after exposure to iodixanol than to iohexol. Elevated EMPs and PMPs can lead to an increase in blood viscosity and be associated with inflammation and thrombosis that can contribute to endothelial damage. Given their results, those authors suggested that iodixanol was a better choice than iohexol in patients with diabetes undergoing CAG. IA CM administration is known to be associated with a higher risk of CIN than intravenous (IV) CM administration [2 for IA injection with first pass kidney exposure vs. eGFR < 30 mL/min/1.73 m2 for IV or IA injection with second pass kidney exposure. In addition to more abrupt and concentrated CM exposure to the kidneys with a supra-renal arterial CM injection, atheroembolism related to catheter manipulation also poses an increased risk of CIN during CAG.First generation CM had significant side effects due to its high osmolality (1000–2000 mOsmol/kg H2O) . The dev/kg H2O) ,36. High/kg H2O) ,37. Guid/kg H2O) ,39,40,41/kg H2O) . Those a/kg H2O) ,43. Howe/kg H2O) . The levstration ,46,47,482) <3.0, assuming a CM concentration of 350 mg iodine/mL, for IA administration with first pass kidney exposure [It has been shown that a higher volume of CM increases the risk of CIN, especially during CAG ,50. Althexposure . There iMehran first developed a risk scoring system, which involves eight clinical and procedural variables, such as age over 75 years, existence of decrease in renal function, hypotension, congestive heart failure, diabetes, anemia, use of intra-aortic balloon pump (IABP), and large contrast volume, to predict CIN after PCI. More than half of the patients with a higher score than 16 were reported to experience CIN. Exposure to more risk factors is valuable to define patients at risk for CIN .The exact pathophysiology of CIN is not fully understood. Direct cytotoxicity, altered intrarenal hemodynamics, and ROS generation have been proposed as the main pathophysiologic mechanisms of CIN . Those tCM has a direct cytotoxic effect on kidney tubular epithelial cells and vascular endothelial cells . All typCM administration induces transient vasodilation followed by vasoconstriction that can be sustained for several hours in the kidney vasculature as a result of alterations in kidney vasomodulators such as endothelin, adenosine, and NO ,55. VasoThe high osmolality and viscosity of CM causes osmotic diuresis, an increase in tubular pressure, and decrease in tubular and blood flow rates, all of which lead to an increase in tubular oxygen demand and a decrease in kidney blood supply . FurtherThe increase in ROS generation after exposure to CM has been observed in various in vitro and in vivo studies and can be explained partly by the diminished availability or activity of cellular antioxidant systems ,62. As eWith regard to the pathophysiologic role of ROS in CIN, Kusirisin et al. reviewed in vitro and in vivo reports from PubMed up to September 2019 . They suCM increased ROS generation by upregulating nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), Nox4, and p22phox, which led to apoptosis through the MAPK pathway ,65,66. RBoth the SIRT1-mediated and Nrf2-mediated pathways are involved in renoprotection against CM-induced oxidative stress and kidney cell apoptosis. SIRT1 decreased after exposure to CM, but Nrf2 expression increased during CM-induced oxidative stress as a cytoprotective response ,72,73,74+)-dependent deacetylases that is involved in multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity [Sirtuins belong to a conserved family of nicotinamide adenine dinucleotide , but the association was not observed in the seven RCTs . In a recent meta-analysis by Wang et al. that included 12 studies with 14 trials, containing 4864 patients (2484 treated with RAAS blockers and 2380 in the control group), the pooled relative risk of CIN incidence in the RAAS blocker group was 1.22 (95% CI 0.81–1.84) [When clinically feasible, it is recommended to withhold nonessential nephrotoxic medications before CM administration, these are listed in 81–1.84) . HoweverAmong studies included in the above described meta-analyses, only a few RCTs directly investigated the effects of withholding ACEI/ARB on the incidence of CIN. Discontinuing captopril 36 h before PCI did not change the incidence of CIN in patients with sCr ≤ 1.5 mg/dL or GFR ≥ 60 mL/min . WithholTherefore, it remains inconclusive whether ACEI/ARBs increase or decrease the incidence of CIN and, currently, withholding RAAS blockers before CM administration is not recommended in guidelines ,101. Add2 receiving IV CM or IA CM with second pass renal exposure, (2) patients receiving IA CM with first pass renal exposure, and (3) patients with AKI. They also recommend to measure eGFR within 48 h and restart metformin if renal function has not changed significantly [In diabetic patients, metformin is widely prescribed as the first-line therapy. Metformin is mainly excreted by the kidneys and confers an increased risk of lactic acidosis when CIN occurs, although it does not increase the risk of CIN. However, as the reported incidence of metformin-associated lactic acidosis has been very low  , guidelificantly ,103,104.Minimizing the total volume of CM and using the least nephrotoxic CM should be applied in all cases. There have been efforts to reduce the contrast volume (iodine dose) as low as reasonably achievable during both CAG and CECT ,105. CliIn addition to modifying patient-related risk factors and properly choosing the type and volume of CM, intravenous fluid hydration is the mainstay of CIN preventive strategies. Hydration is theoretically reasonable because it can correct or improve the patient’s volume status, dilute CM concentration, and increase kidney blood flow and tubular urine flow, which can subsequently reduce CM retention and toxic effects in the tubular lumen. Guidelines recommend intravascular volume expansion as CIN prophylaxis, but there is no consensus on the optimal hydration regime ,51,92. Tp < 0.001), and significantly fewer cases of CIN occurred in that group . Noticeably, the odds of CIN decreased by 9% for every additional 100 mL of normal saline administered . The reported rate of shortness of breath was 1.5% and similar in the two groups. The 6-month composite outcome that considered all-cause mortality, myocardial infarction, and renal replacement therapy (RRT) was better in the LVEDP-guided group than in the control group.The POSEIDON  trial compared LVEDP-guided hydration with standard hydration in 396 patients undergoing cardiac catheterization . All patIncreasing the UFR above 150 mL/h was reported to reduce CIN . Theoretp = 0.013), and three (0.8%) patients experienced complications related to foley catheter insertion in the RenalGuard system.Briguori et al. compared these two tailored hydration regimens in an RCT with 708 patients scheduled for coronary or peripheral angiography or angioplasty . The totBoth preventive regimens mentioned above require relatively invasive procedures, and they were investigated mostly during coronary intervention or transcatheter aortic valve implantation. Recently, non-invasive methods to guide hydration have been reported.p = 0.0001), and they showed a significantly lower incidence of CIN  than the standard volume saline group. In addition, the occurrence of CIN was lower  in patients with an optimal BIVA level on admission who were included in a registry group and received standard volume saline.The HYDRA study by Maioli et al. evaluated the effect of bioimpedance vector analysis (BIVA) to determine IV infusion volumes . Three hp = 0.004). Additionally, major adverse cardiovascular or cerebrovascular events during the 18-month follow-up occurred less often in patients who received IVCU-guided hydration.Yan et al. used inferior vena cava ultrasonography (IVCU) to guide hydration in chronic heart failure patients with New York Heart Association functional classification ≥2 and left ventricular ejection fraction <50% . Two hun2, p = 0.002) due to non-stratified randomization. These results indicate that a patient’s hydration status is a crucial factor associated with the development of CIN, and a sufficient volume expansion within a safe range under various guidance methods could be an important preventive strategy. As a non-invasive and cost-effective hydration method, oral hydration has been compared with IV hydration. Oral hydration can suppress the release of vasopressin and lead to rapid diuresis . It has 2, which possibly reflected patients’ baseline hydration status. A more recent meta-analysis by Michel et al. analyzed 37 RCTs with 12,166 patients to assess IV volume expansion strategies [Although hydration is the only evidence-based recommendation for the prevention of CIN, few studies have compared the incidence of CIN with and without hydration. The AMACING trial investigated the prophylactic value of hydration in 660 high-risk patients undergoing an elective procedure requiring CM administration . The incrategies . Again, Cai et al. reviewed hydration strategies in 60 RCTs and performed a network meta-analysis to find an optimal strategy . They reWith regard to the type of hydration, normal saline (0.9% sodium chloride) is recommended in the guidelines as the primary choice. Another type of fluid, apart from sodium bicarbonate, was investigated recently. Park et al. conducted a multicenter RCT to determine the efficacy of a balanced salt solution versus normal saline in high-risk patients undergoing scheduled CECT . HoweverDue to concerns about CIN furthering renal damage, particularly in patients with advanced CKD (stage 4 or 5) who are not on maintenance dialysis, prophylactic hemodialysis or hemofiltration has been applied to remove CM. A meta-analysis by Cruz et al. in 2012 that included nine RCTs and two non-RCTs with 1010 patients  demonstrated no benefit of periprocedural RRT compared to standard medical therapy , and hemodialysis appeared to actually increase the incidence of CIN  . With noNonetheless, studies on prophylactic hemofiltration against CIN have been conducted. Two studies by Marenzi et al. in 2003 and 2006 ,128, incAs another preventive measure, scavenging of the ROS produced during CM administration was suggested, and IV sodium bicarbonate and oral N-acetylcysteine (NAC) have been widely tried for that purpose.p = 0.0009).In the 2007 RENO study, 111 acute coronary syndrome patients undergoing emergency PCI were randomized . The act2 or 45–59.9 mL/min/1.73 m2 with diabetes. They received either IV 1.26% sodium bicarbonate or IV normal saline and either 5 days of 1200 mg NAC orally or an oral placebo. The trial demonstrated no benefit of IV sodium bicarbonate or oral NAC on the incidence of CIN and the 90-day composite outcome of death, need for dialysis, or persistent decline in kidney function.However, the PRESERVE trial showed different results. It was a large RCT using a 2-by-2 factorial design  and invoThe PRIMARY trial by Boccalandro et al. is a single center RCT of 382 CKD stage III–IV patients undergoing elective CAG to evaluate the 5-year outcomes of patients with CIN and to assess the long-term effects of hydration with sodium bicarbonate . PatientAnother large RCT of 2308 patients that added 1200 mg of oral NAC to hydration  also showed that NAC offered no benefit in reducing the risk of CIN . TherefoVarious pharmacologic strategies for preventing CIN have been evaluated, but the results have often conflicted with one another. Su et al. reviewed 150 RCTs that evaluated pharmaceutical agents in combination with hydration and classified the agents into 12 categories based on drug species or dose as follows: (1) natriuretic peptides: atrial natriuretic peptide, B-type natriuretic peptide, and carperitide; (2) vitamins and analogues: ascorbic acid, tocopherol, and α-lipoic acid; (3) high-dose statins: simvastatin (40–80 mg), rosuvastatin (20–40 mg), and atorvastatin (40–80 mg); (4) low-dose statins: simvastatin (10–20 mg), rosuvastatin (10 mg), and atorvastatin (10–20 mg); (5) prostaglandins: iloprost, alprostadil, misoprostol, and prostaglandin E1; (6) theophylline (aminophylline); (7) NAC; (8) fenoldopam; (9) sodium bicarbonate; (10) sodium bicarbonate plus NAC; (11) high-dose statins plus NAC; (12) hydration . They asA meta-analysis by Ma et al. of 107 studies with 21,450 patients also demonstrated that the use of statins plus NAC plus saline hydration was the most effective strategy for preventing CIN in patients undergoing CAG .Statins have pleiotropic effects, including causing improvements in vascular tone by increasing endothelial NO production and antiinflammatory and antioxidant effects that can contribute to renoprotection in CIN ,137,138.However, most of the patients included in the studies using statins received CAG or cardiac catheterization, and, in those patients, statins might reduce the incidence of CIN via their beneficial effects on underlying vascular disease, including coronary artery disease. For statins to be generally recommended as a preventive measure for CIN, further studies of patients with different underlying diseases and procedures are needed.In summary, both the ESUR and KDIGO guidelines currently recommend IV volume expansion with either saline or sodium bicarbonate solutions in patients at risk of CIN, although no benefit of IV sodium bicarbonate has been demonstrated over normal saline, and IV saline hydration is preferred. Neither guideline recommends oral hydration as the sole preventive method ,92. In a2 are generally considered to be safe from CIN. Although the threshold of eGFR for prophylactic hydration is different according to guidelines and the ideal hydration regime is uncertain, the basic principle is to provide sufficient volume expansion without increasing the risk of pulmonary edema. The typical hydration volume is 1–3 mL/kg/h or a fixed volume  and the duration is 1–4 h before and 3–12 h after CM administration. The hydration regimen should be individualized, particularly in patients at risk of volume overload, and an assessment of patient’s volume status before CM administration is needed. Statins with or without NAC, combined with hydration, may mitigate the risk of CIN in patients undergoing coronary intervention, but further studies are required to recommend it. In the future, novel pharmaceutical agents targeting the pathogenic signaling pathways of CIN should be developed and validated in large-scale clinical trials to reverse the course of CIN, which is the ultimate goal for CIN management. Moreover, the accumulation of data from studies that take into account individual characteristics and risk factors will be able to provide detailed preventive strategies against CIN. Patients at risk of CIN should be carefully identified before procedures requiring CM. Patients exposed to multiple risk factors for CIN including accompanied comorbidities such as impaired renal function, heart failure, and diabetes, the amount of contrast volume, and hypotension are at increased risk. Some risk scoring systems such as Mehran’s score are available for patients undergoing CAG or PCI. Modifiable risk factors, both patient- and procedure-related, should be corrected. It is advisable to withhold nonessential nephrotoxic medications in at-risk patients. Guidelines recommend using IOCM or LOCM with efforts to lower the CM volume. However, minimizing contrast volume should not decrease diagnostic accuracy, even in patients with advanced CKD. Currently, hydration is the only evidence-based method for CIN prevention and normal saline is preferred. As renal impairment is the most important risk factor of CIN, prophylaxis with saline hydration is guided based on a patient’s eGFR. Patients with a stable baseline eGFR ≥ 45 mL/min/1.73 m


The retinal venous pressure (RVP) is a determining factor for the blood supply of the retina as well as the optic nerve head and until recently has been measured by contact lens dynamometry (CLD). A new method has been developed, potentially offering better acceptance. The applicability and the results of both methods were compared.The type of this study is cross sectional. The subjects were 36 healthy volunteers, age 26 ± 5 years (mean ± s). Tonometry: rebound tonometer (RT) (iCare). The measurements were performed during an increase in airway pressure of 20 mmHg . Principle of RVP measurement: the central retinal vein (CRV) is observed during an increase of intraocular pressure (IOP) and at the start of pulsation, which corresponds with the RVP. Two different instruments for the IOP enhancement where used: contact lens dynamometry and the new instrument, IOPstim. Principle: a deflated balloon of 8 mm diameter—placed on the sclera laterally of the cornea—is filled with air. As soon as a venous pulsation occurs, filling is stopped and the IOP is measured, equalling the RVP. Examination procedure: randomization of the sequence: CLD or IOPstim, IOP, mydriasis, IOP three single measurements (SM) of the IOP with RT or of the pressure increase with CLD at an airway pressure of 20 mmHg, 5 min break, IOP, and three SM using the second method at equal pressure (20 mmHg).t test: p < 0.001). Range of SM: 3.2 ± 1.8/2.9 ± 1.3 (t test: p = 0.36). Intraclass correlation coefficient (ICC) of SM: 0.88/0.83. ANOVA in SM: p = 0.48/0.08. MRVP CLD minus MRVP IOPstim: 13.0 ± 5.6. Ratio MRVP CLD/MRVP IOPstim: 1.56 ± 3.1. Cooperation and agreeability were slightly better with the IOPstim.Spontaneous pulsation of the CRV was present in all 36 subjects. Pressures are given in mmHg. IOP in mydriasis 15.6 ± 3.3 (m ± s). Median RVP (MRVP)) of the three SM: CLD/IOPstim, 37.7 ± 5.2/24.7 ± 4.8 (This first study with the IOPstim in humans was deliberately performed in healthy volunteers using Valsalva conditions. As demonstrated by ICC and ANOVA, reproducible SM can be obtained by both methods and the range of the SM does not differ greatly. The higher MRVP in CLD could be explained by the different directions of the force vectors. Bailliart first described the use of dynamometry to measure the blood pressure of the eye . The terThe new instrument Fig.  enhancesThe instrument is called IOPstim because it may stimulate the retinal vessels to pulsate. It is manufactured by Imedos Health GmbH in Jena, Germany.The results obtained with this new method were compared with those obtained by a contact lens dynamometer (CLD). The CLD has, until now, been the method of choice to measure the RVP . The insThis cross-sectional study was performed in accordance with the Declaration of Helsinki and was approved by the institutional ethics committee of the Technical University of Dresden (EK 322062019). The measurements were performed in 36 healthy Caucasian volunteers (Table The cooperation of the subjects was rated using 4 classes: (1) the lids were fully slack, indicating excellent cooperation; (2) there was low lid tension, indicating good cooperation; (3) it was very difficult to attach the instrument to the globe, indicating fair cooperation; (4) the examination was terminated early, indicating insufficient cooperation. Agreeability was assessed by a 5-stage classification system: (1) contact was sensed, and there was no irritation, indicating an excellent outcome; (2) contact was sensed, and it was well tolerated, indicating a good outcome; (3) contact was poor, and it was tolerated for some minutes only, indicating a fair outcome; (4) contact was painful, and it was nearly intolerable; (5) the examination disrupted because of pain. Parametric and non-parametric descriptive tests were performed, depending on the distribution of the variables. In the examination session, the patient was asked about the subjective comfort of the two methods, and the examiner reported which of the two methods was easier to handle.p value lower than 0.05 was considered statistically significant. The repeatability of three consecutive measurements was assessed by the intraclass correlation coefficient.The statistical analysis was performed using spreadsheet software  to collect the data as well as SPSS  and Statistica  to perform the statistical tests. The normality of the data was assessed by p-p diagrams. Different test methods were used according to whether the data were normally distributed. A measurement values obtained by CLD did not differ significantly (Friedman ANOVA: p = 0.64). However, as measured by the IOPstim, the median of the third value was 0.9 mmHg smaller (Friedman ANOVA: p = 0.03) . There was a slight difference between the second and third measurements with the IOPstim method (IOPstimM) (p = 0.04). The median range of the three single measurements was 2.7 mmHg with the CLDM and 2.9 mmHg with the IOPstimM (Table The demographic characteristics of the study population are presented in Table p < 0.001). The variability was higher with the IOPstimM.When the CLD or the IOPstim were attached to the globe, a force was needed. The median IOP increase induced by that force Table  was 10.0p < 0.001). For the CLDM, the RVP is defined as the sum of the IOP prior to the insertion of the CLD and the pressure increase induced by the instrument displayed on the LCD screen: RVP = IOP + ΔIOP.The median IOP decreased by 3.8 mmHg from baseline to the end of the experimental session. This difference was statistically significant (p = 0.23). The measurement did not need to be interrupted because of pain for any of the subjects  with the CLDM than with the IOPstimM. It may be discussed whether this difference may be caused by a calibration error in the CLDM. Morgan et al. [An unexpected finding was that the median RVP values Fig.  were 13 n et al. , howevern et al. . Thus, an et al. . This coIOPstimM is not probable because the artificially increased IOP during the measurement of the RVP was performed by the standardized iCare tonometer. The purpose of the IOPstim is only the increase of IOP and its maintenance during a short time span in which the increased IOP is measured.A calibration error in the A tonographic effect may be discussed in the IOPstimM because there is a maximal time span of 1 min between the observation of the pulsation and the measurement of the IOP. According to Ulrich and Ulrich, the pressure drop during this interval may approximately be 1.4 mmHg . In thisAnother reason may be that we conducted measurements under Valsalva conditions, in which an increase in central  venous pressure takes place . These aIn contrast, with the IOPstimM, the main vector of the applied force is directed toward the medial wall of the orbit. Additionally, it may be assumed that the tissue pressure in the orbit is lower than in the skull during the VM because the frontal orbital wall is distensible. Thus, the resulting tissue pressure on the CRV outside the eye may be less with the IOPstimM than with the CLDM. Consequently, the CRV is associated with a smaller resistance and, therefore, a smaller pressure within the eye.In the IOPstimM, the globe is deformed by the balloon. This condition may influence the physical properties of the cornea what in turn may alter the measurement values of the iCare tonometer. We cannot exclude this possibility but there are to the best of our knowledge no results in the literature which may back this hypothesis.Whether the difference in the measurement values between the two methods is due to technical differences or due to the VM may be determined by the measurements without the VM. This investigation may be possible in glaucoma patients, as the SVP is not present in approximately 50% of these individuals , 20.healthy volunteers, measurements had to be taken during the VM. As we pointed out, this condition may be the major reason for the significant change in the median by 13 mmHg.To test the new IOPstim in The subjects included Caucasians only. The question of whether the IOPstim may also be applicable in subjects or patients with narrower palpebral fissures remains.The judgments regarding cooperation and agreeability are subjective. Because the results are positive, we feel it justifiable to use the IOPstim in patients.The new IOPstim was well accepted by the subjects and by the examiner. The results show good reliability. The use of this instrument in clinical diagnostics seems justified. A further study in glaucoma patients is necessary in order to investigate whether the difference in the results of the two methods of measuring the RVP used here may also be present in glaucoma patients in which no VM is necessary because the pulsation of the central retinal vein is absent in about half of them.


Aims: The EMPA-REG OUTCOME trial demonstrated that the sodium-glucose cotransporter-2 inhibitor (SGLT2) empagliflozin reduces the risk of cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. We previously developed the parameter response efficacy (PRE) score, which translates drug effects on multiple short-term risk markers into a predicted long-term treatment effect on clinical outcomes. The main objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of empagliflozin in reducing the risk of CV and kidney outcomes.Methods: Short-term (baseline to 6-months) changes in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, uric acid, and potassium were determined among 7020 patients with type 2 diabetes and established CV disease in the EMPA-REG OUTCOME trial. The beta-coefficients, derived from a Cox proportional hazards model in a pooled database consisting of 6355 patients with type 2 diabetes, were applied to the short-term risk markers in the EMPA-REG OUTCOME trial to predict the empagliflozin-induced impact on CV  and kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) outcomes.Results: Empagliflozin compared to placebo reduced HbA1c (0.6%), SBP (4.2 mmHg), UACR (13.0%), body weight (2.1 kg), uric acid (20.4 μmol/L), and increased hemoglobin (6.6 g/L), LDL-cholesterol (0.1 mmol/L) and HDL-cholesterol (0.04 mmol/L) . Integrating these effects in the PRE score resulted in a predicted relative risk reduction (RRR) for the CV outcome of 6.4% (95% CI 1.4–11.7), which was less than the observed 14.7% (95% CI 1.3–26.4%) RRR. For the kidney outcome, the PRE score predicted a RRR of 33.4% (95% CI 26.2–39.8); the observed RRR was 46.9% (95% CI 26.8–61.5). In a subgroup of 2,811 patients with UACR ≥30 mg/g at baseline, the PRE score predicted RRR was 40.8% (95% CI 31.2–49.1) vs. the observed RRR of 40.8% (95% CI 12.4–60.0) for the kidney outcome.Conclusions: Integrating multiple short-term risk marker changes in the PRE score underestimated the effect of empagliflozin on CV and kidney outcomes, suggesting that the currently used risk markers do not fully capture the effect of empagliflozin. In patients with increased albuminuria, the PRE score adequately predicted the effect of empagliflozin on kidney outcomes. Major cardiovascular (CV) outcomes trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors, developed as anti-hyperglycemic drugs for the treatment of type 2 diabetes, have consistently demonstrated that these drugs reduce the relative risks of CV outcomes and slow the progression of kidney function decline in patients with type 2 diabetes at high CV risk . The EMPThe efficacy of SGLT2 inhibitors in preventing CV outcomes and delaying diabetic kidney disease progression is unlikely explained by improvement in glycemic control alone. Head-to-head comparison of the SGLT2 inhibitor canagliflozin with the sulfonylurea derivative glimepiride showed that at equal glycemic control, canagliflozin reduced the rate of kidney function decline . In patiNumerous studies have shown that SGLT2 inhibitors exert additional effects beyond their effects on HbA1c. These effects can contribute to long-term CV and kidney protection . For exaSince SGLT2 inhibitors exert multiple effects on CV and kidney risk markers, we hypothesized that integrating the effects of empagliflozin on multiple CV or kidney risk factors may be able to better predict the effect of empagliflozin on these clinical outcomes than focusing on changes in a single risk marker. We have previously developed a multivariable drug efficacy prediction algorithm  score) to predict long-term drug effects on CV and kidney outcomes. Specifically, the PRE score was used to predict the efficacy of angiotensin receptor blockers, the endothelin receptor antagonist atrasentan, and the glucagon-like peptide-1 receptor agonists exenatide and liraglutide in patients with type 2 diabetes at high risk of CV disease or with established chronic kidney disease  The objeThe PRE score was used to estimate the effect of empagliflozin on CV and kidney outcomes. The PRE score is a flexible algorithm that is intended to be used to any population or drug by fitting the beta coefficients in the underlying Cox proportional hazards model to the appropriate set of risk markers in an independent population. For this specific study, the relationships between risk markers and CV, or kidney outcomes were established at baseline in a background population derived from the ALTITUDE, RENAAL and IDNT trials, clinical trials conducted in patients with type 2 diabetes at high risk of kidney events or with established CV disease . This coThe estimated risk relationships were subsequently applied to all patients from the EMPA-REG OUTCOME trial to assess the accuracy of the PRE score. Since patients with elevated albuminuria are at higher risk of CV and kidney outcomes compared to patients in whom albuminuria is in the normal range, we performed a subgroup analysis in patients with urinary-albumin-creatinine-ratio (UACR) >30 mg/g. The PRE score predictions were compared to the observed CV and kidney outcomes in the EMPA-REG OUTCOME trial. We also predicted the effect of empagliflozin in the EMPA-KIDNEY trial (NCT03594110), an ongoing clinical trial designed to assess the effect of empagliflozin on kidney outcomes for which the outcome of the trial is not yet known. To this end, we selected patients from the EMPA-REG OUTCOME trial who met the inclusion criteria of the EMPA-KIDNEY (NCT03594110) trial. We applied the PRE score to the subgroup of patients to predict the effect of empagliflozin on the primary endpoint in the EMPA-KIDNEY trial .Variables measured in the intention-to-treat population of the EMPA-REG OUTCOME trial at baseline and after 6 months which were previously identified as risk markers for CV and kidney outcomes were used, i.e., glycated hemoglobin (HbA1c), systolic blood pressure (SBP), UACR, hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, uric acid, and potassium (K). The 6 month timepoint was chosen since all biomarkers were measured at this timepoint.In this study, the CV outcome was defined as a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The kidney outcome was defined as the composite of a confirmed doubling of serum creatinine (DSCR) or end-stage kidney disease (ESKD). In exploratory analyses, we also predicted the effect of empagliflozin on the composite heart failure hospitalization or CV death outcome and the composite kidney outcome of a sustained declined in estimated glomerular filtration rate (eGFR) by 40%, or ESKD. For the ongoing EMPA-KIDNEY trial, the primary outcome is defined as a composite of a sustained 40% decline in eGFR from baseline, ESKD, or kidney or CV death .o(t) o(t)] and the sum of the linear form of the estimated β coefficients and the respective risk maker measurement(s) (X). The mean difference in the predicted risk in the empagliflozin arm, adjusted for the mean difference in their predicted risk in the placebo arm, represented the PRE score and reflected an estimation of the expected CV or kidney relative risk reduction (RRR) induced by empagliflozin treatment. To generate 95% confidence intervals (CI) on the predicted RRR, 100 sets of coefficients were generated from independent normal distributions based on the estimated regression coefficients and their standard error from the Cox proportional hazards model.A Cox proportional hazards model was fitted to estimate the coefficients associated with CV or kidney outcomes in the background dataset. These regression coefficients were then applied to the baseline and 6-months risk marker measurements for patients in the EMPA-REG OUTCOME trial, to estimate the risk for cardiorenal outcomes at both time points in both the placebo and empagliflozin arms, h(t) = hSince the observed changes in the EMPA-REG OUTCOME trial may differ from the actual risk marker changes in the EMPA-KIDNEY trial, we conducted simulations using a simulated range of empagliflozin induced responses on albuminuria, HbA1c, SBP, and body weight. These risk markers were simulated because they are important risk markers for the kidney and CV outcomes and were reduced by empagliflozin treatment. Simulations were performed by shifting the distribution of responses in these risk markers. We selected different proportions of patients with changes in these risk markers during empagliflozin treatment where response was defined as a reduction more or equal than the median risk marker changes from baseline.p-values <0.05 were considered statistically significant. All statistical analyses were conducted with R version 4.1.1 .To account for missing data, Multiple Imputations by Chained-Equation  was performed on all variables that had missing values. Imputations were performed by a predictive mean matching, a semi-parametric approach which replaces missing values according to a multivariable regression. . Covaria2 and 1819 (25.9%) participants had an eGFR <60 ml/min/1.73m2. Median UACR was 17.7 mg/g, and 2811 (40.0%) patients had a UACR ≥30 mg/g. Demographic and clinical characteristics of the patients were well balanced between the treatment and placebo group  or placebo (N = 2333) and were included in the intention-to-treat population. The EMPA-REG OUTCOME trial participants were characterized by a high CV risk and generally low risk of complications due to kidney disease. At baseline, the mean HbA1c was 8.1%, SBP was 135.4 mmHg, and all participants had a CV disease history. Mean eGFR was 74.0 ml/min/1.73mbo group .The changes in short-term risk markers for the total population and individuals with UACR >30 mg/g in the EMPA-REG OUTCOME trial are presented. Empagliflozin compared to placebo significantly reduced HbA1c (0.6%), SBP (4.2 mmHg), UACR (13.0%), body weight (2.1 kg), uric acid (20.4 umol/L) after 6 months of treatment, and increased hemoglobin (6.6 g/L), HDL-cholesterol (0.04 mmol/L), and LDL-cholesterol (0.1 mmol/L) . The dirDuring 3.1 years of follow-up, 772 (11.0%) composite CV outcomes, 150 (2.1%) composite kidney outcomes and 489 (7.0%) heart failure hospitalizations or CV deaths were recorded in the EMPA-REG OUTCOME trial. The observed RRR of empagliflozin on the composite CV outcome was 14.7% (95% CI 1.3–26.4) and the RRR for the composite kidney outcome was 46.9% (95% CI 26.8–61.5). The prediction of the treatment effect of empagliflozin based on single risk markers underestimated the overall treatment effect for the CV and kidney outcomes. For example, based on the observed placebo-corrected change in HbA1c alone, it was estimated that empagliflozin would reduce the risk of the composite CV outcome by 2.2% (95% CI 0.2–4.4) and the kidney outcome by 1.9% (95% CI 0.9–4.3). Based on the change in albuminuria alone, the predicted effect of empagliflozin on the CV outcome was 2.3% (95% CI 0.8–4.4) and 17.8% (95% CI 12.0–24.1) for the kidney outcome. Integrating changes in multiple short-term risk markers using the PRE score resulted in a predicted RRR for the CV outcome of 6.4% (95% CI 1.4–11.7) and for the kidney outcome of 33.4% (95% CI 26.2–39.7) . The pre2 and there were 964 (34.3%) patients who had an eGFR <60 ml/min/1.73m2. The median UACR at baseline was 106.1 mg/g  patients from the EMPA-REG OUTCOME trial who met the inclusion criteria of the EMPA-KIDNEY trial. In this subgroup, the mean age was 65.8 years, mean eGFR was 52.9 ml/min/1.73m360 mg/g . The bas360 mg/g .Using the PRE score, we estimated that empagliflozin, as compared to placebo, will lead to a RRR of 25.3% (95% CI 14.5–35.4) for the composite kidney or CV death outcome in the EMPA-KIDNEY trial . The simIn this study, we integrated multiple effects of the SGLT2 inhibitor empagliflozin on cardiorenal risk markers in a response efficacy score to predict the effect of empagliflozin on CV and kidney outcomes in the EMPA-REG OUTCOME trial. In the overall population, the PRE score underestimated the effect of empagliflozin on CV and kidney outcomes. However, in the subgroup analyses among individuals with UACR ≥30 mg/g, the PRE score accurately predicted the kidney outcome which was similar to the observed RRR achieved with empagliflozin.The underestimation of the PRE score prediction suggests that the underlying mechanisms for CV and kidney protection are not fully captured by the clinical markers included in the current PRE score. The mechanism of action of SGLT2 inhibitors is complex and multifactorial and it is plausible that the set of readily available clinical markers cannot capture the multiple mechanistic pathways targeted by SGLT2 inhibitors . Indeed,SGLT2 inhibitors were initially developed as oral glucose lowering drugs and approved by the regulatory agencies based on their HbA1c lowering effects . HoweverAlbuminuria was a strong predictor of the effect of empagliflozin on kidney protective effects. Previous studies with the PRE score have also shown that the reduction in albuminuria was a strong contributor to the kidney protective effect of angiotensin receptor blockers, endothelin receptor antagonists and the SGLT2 inhibitor dapagliflozin . InteresThe EMPA-KIDNEY trial is the first dedicated kidney outcome trial with empagliflozin. The trial enrolled patients with chronic kidney disease with and without diabetes across a wide spectrum of eGFR and albuminuria values . We estiThere are several limitations in this study. First, the selection of parameters in the PRE score depends on the availability of the risk markers in the trial dataset. Second, the majority of the patients included in the EMPA-REG OUTCOME trial had mild to moderate chronic kidney disease and only few patients met the entry criteria for the EMPA-KIDNEY trial. As a result, the prediction of the EMPA-KIDNEY endpoint is based on a limited sample size and low precision. Furthermore, we note that the EMPA-KIDNEY trial enrolled patients with and without diabetes and our predictions only apply to diabetes patients since patients without diabetes were not included in the background population nor the EMPA-REG OUTCOME trial. Nevertheless, given the consistent effects of SGLT2 inhibitors in patients with and without diabetes this should not affect our findings .To conclude, the PRE score underestimated the treatment effect of empagliflozin on CV and kidney outcomes in patients with type 2 diabetes and established CV disease. Whether the addition of novel biomarkers, which capture mechanistic pathways targeted by empagliflozin, to the PRE score improves treatment effect predictions requires further study.


Genetic models of the ANP gene or the GCA receptor together with genomic medicine have solidified the concept that both cardiac hormones are fundamental for blood pressure homeostasis and when deficient or disrupted they may contribute to human hypertension. Advances in peptide engineering have led to novel peptide therapeutics including the ANP-analog MANP for human hypertension. Most importantly a first in human study of MANP in essential hypertension has demonstrated its unique properties of aldosterone suppression and blood pressure reduction. Physiology and pharmacology ultimately lead us to innovative peptide-based therapeutics to reduce the burden of cardiovascular disease.The heart serves as an endocrine organ producing the hormones atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP) which  Hypertension still represents the leading cause of death worldwide. Importantly, ranking number two in cause of death is metabolic disease including diabetes and obesity both of which are predisposing and coexisting factors for hypertensive disease . Much prThe work of via a hormonal mechanism regulates blood pressure under physiologic conditions. Various studies involving additional genetic mice models reinforced the notion of cardiac hormones as blood pressure regulators. Further investigations also revealed that beyond blood pressure, GC-A protects the cardiomyocyte from hypertrophy  study, Cannone and colleagues extended studies on rs198389 focusing on a population with cardiovascular risk factors. Specifically, these investigators utilized the landmark St. Vincent Screening to Prevent Heart Failure Study (Stop-Heart Failure Study), which investigated the efficacy of using BNP based screening in combination with collaborative care between primary care physicians and cardiovascular specialists in the prevention of new onset heart failure and left ventricular dysfunction (LVD) . ImportaTherefore, Thus, this later study went beyond a simple biomarker investigation with relevance to precision medicine . The stuInvestigations of ANP and BNP since the discovery ANP by DeBold (1981) have resulted in thousands of publications elucidating mechanisms of action supporting therapeutic potential especially in hypertension . Centralin vivo study of MANP compared to ANP in normal canines, MANP demonstrated widespread superiority to ANP in reducing blood pressure, augmenting sodium excretion and inhibiting angiotensin II and aldosterone  design in multiple cohorts of hypertensive subjects. Three doses were employed. Natriuretic, aldosterone suppressing and BP lowering actions were assessed. Twelve patients were recruited. Inclusion criteria included (1) hypertensive subjects with SBP above 140 mm Hg; (2) on at least one anti-hypertensive medication; and (3) DBP equal to or in excess of 90 mm Hg. Exclusion criteria included (1) known hypersensitivity or allergy to MANP or its components, carperitide, other natriuretic peptides, or related compounds; (2) women who are pregnant or breast-feeding; (3) any disease or condition  which, in the opinion of the investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism, or excretion of study drug, or would place the subject at increased risk; (4) the presence of abnormal laboratory values considered clinically significant by the Investigator; (5) positive screen for Hepatitis B , Hepatitis C , or HIV (anti-HIV 1/2); (6) received an investigational drug within a 30-day period of Visit 1; (7) consumption of alcohol within 48 h prior to dose administration or during any in-patient period; (8) a positive urine drug screen including ethanol, cocaine, THC, barbiturates, amphetamines, benzodiazepines, and opiates unless, in the opinion of the Investigator, a positive finding is as a result of a legitimate medical prescription for a valid medical condition; (9) a history (within the last 2 years) of alcohol abuse, illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction; (10) a history of difficulty with donating blood or donated blood or blood products within 45 days prior to enrollment; (11) clinically significant new illness in the 1 month before screening in the opinion of the Investigator; (12) history of severe allergies ; (13) history of coronary artery disease; (14) history of cerebrovascular disease; (15) history of epilepsy or other seizure disorder; (16) history of syncope; (17) history of organ transplantation; and (18) malignancy within 5 years of the screening visit .The first in human study of MANP was recently reported and performed in subjects with essential hypertension bypassing normal volunteers based upon MANP’s efficacy and safety in multiple studies in normal, hypertensive and heart failure canines and rodent models . The goavia GC-A/cGMP. In this first in human study, investigators reported a dose response to MANP in natriuresis during the 4 h after SQ MANP. While the duration of aldosterone reduction was variable among the treatment cohorts, a signal for a reduction and off-response by 24 h was clearly observed, thus, extending to the human the aldosterone suppressing actions of GC-A activation previously reported by in vitro and in animal studies , angiotensin A1 (AT1) receptor blockers and calcium channel blockers. Thus, data will be available on the blood pressure reducing actions of MANP on top of conventional anti-hypertensive agents. A new expanded clinical trial has been initiated in 40 patients with resistant hypertension (20 Caucasians and 20 African Americans) which is placebo controlled and with multiple ascending doses. MANP is administered once daily for 5 days.The current delivery method for MANP is by subcutaneous injection once daily. As advances in peptide therapeutics in cardiovascular and metabolic disease accelerate, SQ delivery is emerging as with GLP-1 agonists for diabetes and PKC9 inhibitors for hypercholesterolemia. Nonetheless, research and development of MANP also includes the development of oral delivery of MANP. Here, advances in oral delivery of peptides such as BNP and GLP-1 agonists have also been reported supporting the feasibility of this exciting delivery strategy for peptides such as MANP .It should be stated that several questions remain to be addressed as MANP studies continue. These include establishing the ability of MANP to chronically reduce blood pressure and activate the cGMP pathway thus not having drug tolerance. In addition, the role of gender in responsiveness to MANP also needs to be established as sex-based differences in circulating ANP and BNP exist with plasma ANP and BNP being higher in females. Further, the potential modulating action of ANP and BNP genetic variants, which are associated with variations in circulating levels of the two hormones, should also be investigated in regard to blood pressure response to MANP. While ANP as an intravenous drug for heart failure has proved successful in Japan, the use of BNP (nesiritide) and urodilatin (ularitide) in heart failure has been disappointing. This may be related to excessively high doses which are hypotensive as well as their use only as acute drugs as opposed to chronic therapy at a lower dosage. Indeed, hypertension may be the most physiologic target for natriuretic peptide therapy based upon the evidence of a relative deficiency of ANP and BNP in human hypertension and blood pressure reduction being the signature pharmacologic action of MANP.Another drug breakthrough that involves the natriuretic peptides system by augmenting their circulating levels is sacubitril/valsartan. Sacubitril inhibits the enzyme neprilysin (NEP) which is widely expressed in the human body and degrades ANP and BNP. Valsartan serves as an AT1 blocker. Sacubitril/valsartan was approved for heart failure based upon an improvement in mortality in the pivotal PARADIGM HF trial . RuilopeSince the discovery of ANP by Adolfo DeBold that established the heart as an endocrine organ, the field of natriuretic peptides is again accelerating. It is not unusual that it has taken four decades to also establish the therapeutic potential natriuretic peptides and testing in humans. That may be the usual cycle of drug development. This includes designer peptides such as MANP and novel small molecules as sacubitril/valsartan which may inhibit the breakdown of endogenous ANP and BNP and boost their circulating levels . PerhapsThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Both authors conceived the outline of the manuscript, wrote the first and final draft, contributed to the article, and approved the submitted version. JB designed the figures. VC finalized the references.Mayo Clinic has licensed MANP to E-STAR BIO and JB is the inventor of MANP. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Pulmonary arterial (PA) wave reflection provides additional information for assessing right ventricular afterload, but its applications is hampered by the need for invasive pressure and flow measurements. We tested the hypothesis that PA pressure and flow waveforms estimated by Doppler echocardiography could be used to quantify PA wave reflection.Methods: Doppler echocardiographic images of tricuspid regurgitation and right ventricular outflow tract flow used to estimate PA pressure and flow waveforms were acquired simultaneously with direct measurements with a dual sensor-tipped catheter under various hemodynamic conditions in a canine model of pulmonary hypertension (n = 8). Wave separation analysis was performed on echo-Doppler derived as well as catheter derived waveforms to separate PA pressure into forward (Pf) and backward (Pb) pressures and derive wave reflection coefficient (RC) defined as the ratio of peak Pb to peak Pf.Results: Wave reflection indices by echo-Doppler agreed well with corresponding indices by catheter . RC correlated negatively with PA compliance.Conclusion: This echo-Doppler method yields reasonable measurement of reflected wave in the pulmonary circulation, paving the way to a more integrative assessment of pulmonary hemodynamics in the clinical setting. Pulmonary hypertension (PH) is a serious disease characterized by increased pulmonary artery pressure (PAP) associated with pulmonary vascular remodeling. It causes right-sided heart failure due to increased afterload on the right ventricle and has been shown to carry poor prognosis . Mean PAPulmonary blood flows are pulsatile in nature. A complete description of right ventricular afterload, therefore, should also include the load to pulsatile component. In the pulmonary circulation, it accounts for approximately 25% of the total workload of right ventricle ; the proOne promising method of estimating the magnitude of wave reflection is to separate pressure into its forward and backward components by wave separation analysis . This anPulmonary arterial wave reflection can be assessed based on the concept of wave separation analysis. This analysis determines the origin, type and timing of traveling waves in a circulation from combined P and U measurements and allows wave separation into forward-traveling and backward-traveling components. Theoretical background and practical applications have been described elsewhere . BrieflydP and dU are the changes in P and U, ρ is the density of blood (1050 kg/m3) and c is WS. Pulse pressure can be separated into those attributed to forward-traveling (Pf) and backward-traveling (Pb) waves using equations 2 and 3.where The new noninvasive method we propose herein uses echo-Doppler derived P and U waveforms, instead of the direct measurements. A pulsed-wave Doppler tracing of RVOT flow is used as a surrogate for U waveform. On the other hand, P waveform is estimated by applying the simplified Bernoulli equation to an instantaneous Doppler velocities of TR jet and adding a term of right atrial pressure as below. This clinical equation has been derived from the more complex Bernoulli equation by assuming that viscous losses and acceleration effects are negligible and by using an approximation for the constant that relates to the mass density of blood, a conversion factor for measurement units .where it is time, TRV is TR velocity and RAP is right atrial pressure which we assume is constant throughout the cardiac cycle.P-value at the beginning of ejection (shown as t0) identified from the U waveform.End diastolic P is determined as Subtracting end-diastolic P from P waveform yields pulse pressure waveform; this subtraction eliminates the term of right atrial pressure.Wave separation analysis is performed on the pulse pressure and flow velocity waveforms by synchronizing waveforms of TR flow and RVOT flow using electrocardiogram. The pulse pressure waveform will then be separated into Pf and Pb. This analysis yields 1 arterial stiffness and 3 wave reflection indices: WS, peak Pb, peak Pf, and reflection coefficient (RC) calculated as the ratio of peak Pb to peak Pf.in vivo Experiments) guidelines and the regulations on animal experiments and the guide for the care and use of laboratory animals of Tokyo University of Agriculture and Technology . All process of the study was carried out in compliance with the ARRIVE  was inserted into the right femoral artery to monitor systemic arterial pressure. A 4.2-Fr multipurpose angiographic catheter  was advanced retrograde into the left atrium through the left carotid artery to monitor left atrial pressure. Another 4.2-Fr multipurpose angiographic catheter was placed in the right atrium through the left jugular vein to monitor right atrial pressure. These fluid-filled catheters were connected to pressure transducers  and pressure waveforms were displayed using a multi-channel monitor . These two catheters were also used to sample blood from the left and right atriums to calculate cardiac output.To obtain P and U waveforms as a reference for validating the new echo-Doppler method, a dual sensor-tipped pressure and flow wire  was advanced to approximately 1 cm beyond the pulmonary valve through another 4.2-Fr multipurpose angiographic catheter inserted from the left jugular vein. Careful catheter and wire manipulation ensured that signals were steadily obtained.The study design is outlined in Cardiac output was calculated by Fick method from oxygen content of blood sampled from the left and right atriums and oxygen consumption estimated using Sykes’ formula . Stroke P and U data were acquired simultaneously for 30 to 60 s during end-expiration apnea, using the dual sensor-tipped catheter. The sampling rate at the acquisition was 200 Hz . The data were then exported digitally for subsequent wave separation analysis.Comprehensive echocardiographic examination was performed, using a ProSound F75 premier CV with a 5-MHz transducer . Left ventricular ejection fraction were measured by the disk summation method. To assess right ventricular systolic function, TAPSE was measured in an apical 4-chamber view. A pulsed-wave Doppler tracing of RVOT flow and a continuous-wave Doppler tracing of TR jet were recorded at a sweep speed of 300 mm/s to assess pulmonary hemodynamics. Careful attention was paid to obtain clear spectral Doppler envelopes. TR jet was able to be detected in all cases, because angiographic catheters passed across the tricuspid valve may create TR. To assess the severity of PH, peak TR velocity was measured. The time from the onset of ejection to peak TR velocity was also measured to evaluate peak pattern of TR velocity profile. From the RVOT flow profile, acceleration time was measured as the time from the onset of ejection to the peak velocity. Mid-systolic notching was considered present, if there was a distinct notch in the mid portion of the RVOT flow profile, dividing the flow profile into two different peaks. These Doppler echocardiographic images were stored in a digital format for subsequent echo-Doppler based wave separation analysis.The above echocardiographic images were processed using in-house program code written in MATLAB . The envelope of RVOT flow Doppler signal was traced semi-automatically to obtain U waveform. This waveform was smoothed using a Savitzky–Golay filter and then ensemble averaged over 3 cardiac cycles with reference to the R wave on electrocardiogram. The timing of beginning and end of ejection were identified from the U waveform. P waveform was estimated by applying the simplified Bernoulli equation to a semi-automatic tracing of the envelope of TR Doppler signal. This waveform was smoothed using a Savitzky–Golay filter and then ensemble averaged over 3 cardiac cycles with reference to the R wave on electrocardiogram. Pulse pressure waveform was obtained by subtracting end-diastolic P from the P waveform [equation (8)]. The temporal resolution for both waveforms was approximately 2.0 msec for all acquisitions that resulted from the setting of sweep speed at the acquisition (300 mm/s) and a pixel size of the echocardiographic images. The velocity resolution was dependent on the Nyquist limit and a pixel size of the echocardiographic images; this yielded a velocity resolution of 0.5 ± 0.7 cm/s for RVOT flow and 1.4 ± 0.4 cm/s for TR jet. The pressure resolution varied depending on the level of pressure, since pressure was estimated proportional to the square of velocity. The waveforms were then interpolated using cubic spline and resampled to 1 msec temporal resolution .The reference P and U waveforms measured directly with the catheter were processed similarly as were the echo-Doppler waveforms. The waveforms were smoothed using a Savitzky–Golay filter and then ensemble averaged over 3 cardiac cycles with reference to the R wave on electrocardiogram. These waveforms were then interpolated using cubic spline and resampled to 1 msec temporal resolution . The timings of the beginning and end of ejection were identified from the U waveform. End-diastolic P was subtracted from the P waveform to obtain pulse pressure waveform before wave separation analysis.Wave separation analysis was performed separately on the echo-Doppler derived waveforms and reference waveforms, using in-house program code written in MATLAB. To determine WS, pulse pressure was plotted against velocity over the ejection period. At the beginning of ejection, a linear portion was always observed on the P-U loop, suggesting that a wavefront during this period was only that generated by the contraction of right ventricle. The slope of the linear portion was calculated from the loop and divided by the density of blood to obtain WS. Pulse pressure waveform was then separated into Pf and Pb waveforms, as described earlier in this section. In this study, Pf and Pb were presented as the peak value and these peak values were used for calculating RC.post hoc test was used to compare variables between each result. Linear regression analysis was used to compare echo-Doppler derived wave reflection and arterial stiffness indices against catheter derived indices. Bland-Altman plot was used to visualize random and systematic errors. Linear regression analyses were also performed to identify the hemodynamic determinants of wave reflection and arterial stiffness indices. Explanatory variables included PVR, pulmonary arterial compliance, cardiac output and heart rate. Analysis of covariance was used to determine the effect of fluid loading and inotropic stimulation on the relationship between wave reflection and arterial stiffness indices and right ventricular systolic function. P-value < 0.05 was considered as statistically significant. All statistical analyses were performed using IBM SPSS statistics version 19  and GraphPad Prism version 8.0 .Categorical variables were expressed as number and percentage and were compared using Fisher’s exact test. Continuous variables were expressed as mean ± standard deviation. After an assessment of the differences in the before challenge, fluid challenge, and dobutamine challenge results using two-way repeated-measures ANOVA, Tukey’s honestly significant difference p = 0.008) and PVR from 2.9 ± 1.0 to 13.7 ± 4.9 Woods unit (p = 0.011). Cardiac output decreased (p = 0.04). Right ventricular systolic function was also reduced, as demonstrated by a significant decrease in tricuspid annular plane systolic excursion (TAPSE) (p = 0.015). There were alterations in RVOT flow profile such as the presence of mid-systolic notching; TR jet profile exhibited high and late peaking pattern as shown by higher TR velocity (p = 0.006) and longer time to peak velocity (p = 0.01). Fluid loading did not change PVR ; it did not increase cardiac output at both baseline (p = 0.46) or not at all at PH state (p = 0.61). Inotropic stimulation did not change PVR , although it significantly increased cardiac output at baseline (p < 0.001), but did not increase cardiac output at PH state (p = 0.36).The changes in pulmonary hemodynamics and right ventricular function induced by pulmonary arterial microembolization and hemodynamic manipulations are summarized in When the data for all load-state conditions were pooled, Pb, Pf, and RC by Doppler correlated linearly with the corresponding indices by catheter with acceptable variabilities . Lower pp = 0.4; Pb in Fluid challenge Pulmonary hypertension before vs. after, p = 0.57; Pf in Fluid challenge Baseline before vs. after, p = 0.4; Pf in Fluid challenge Pulmonary hypertension before vs. after, p = 0.89; RC in Fluid challenge Baseline before vs. after, p = 0.44; RC in Fluid challenge Pulmonary hypertension before vs. after, p = 0.16; WS in Fluid challenge Baseline before vs. after, p = 0.23; WS in Fluid challenge Pulmonary hypertension before vs. after, p = 0.84. Inotropic stimulation produced a larger increase in cardiac output than fluid loading . In p = 0.03; Pb in Dobutamine challenge Pulmonary hypertension before vs. after, p = 0.01; Pf in Dobutamine challenge Baseline before vs. after, p = 0.03; Pf in Dobutamine challenge Pulmonary hypertension before vs. after, p = 0.04; RC in Dobutamine challenge Baseline before vs. after, p = 0.62; RC in Dobutamine challenge Pulmonary hypertension before vs. after, p = 0.78; WS in Dobutamine challenge Baseline before vs. after, p = 0.07; WS in Dobutamine challenge Pulmonary hypertension before vs. after, p = 0.07. indices . In Suppr = −0.85; WS by Doppler, r = −0.71). Stepwise multiple linear regression analysis revealed that PAC and cardiac output were independent determinants of RC, and PAC was an independent determinant of WS. PAC was also identified as the strongest hemodynamic determinant for catheter-derived RC and WS  and WS . When analyzed separately for loading conditions, the relationships of TAPSE with RC and WS did not change by fluid loading . However, the relationships were shifted upward by inotropic stimulation . When catheter-derived RC and WS were used instead for the above analysis, similar upward shifts by inotropic stimulation were observed (observed .The present study investigated that pulmonary arterial wave reflection can be assessed noninvasively using Doppler echocardiography. Pulmonary arterial wave reflection was gained by performing wave separation analysis to separate pulmonary arterial pressure waveform estimated from TR velocity profile into its forward and backward components. As the result, we reported that the echo-Doppler method yields reasonable measurement of pulmonary arterial wave reflection and may detect the alterations associated with the development of PH.To infer a diagnosis of PH, the effects of PH on the right heart are imaged with echocardiography in clinical practice. Some of such echocardiographic signs are related to the presence of pulmonary arterial wave reflection. For example, a late-peaking pattern on TR velocity profile is caused by PAP augmentation by early arrival of reflected wave . A mid-sTo provide a more accurate assessment of wave reflection, wave separation analysis is performed on pulmonary arterial pressure and flow waveforms into their forward and backward components. This analysis is classically undertaken in the frequency domain, but it is fairly complicated and needs sophisticated software . An alteMost previous studies of pulmonary arterial wave separation analysis measured pressure and flow waveforms directly with catheters, which hinders its use in the clinical setting . A recenThe magnitude of wave reflection was usually quantified by RC that was defined as a ratio of backward to forward component of either energy of waves or pressure. This study has reported that RC was not zero, but small at 0.16 ± 0.10 at baseline in dogs. This may be because dogs have inherently a mild degree of PH with a PVR of 2.9 ± 1.0 Woods unit. This finding suggested that wave separation analysis may be sensitive for detecting a mild degree of PH. This study also found that RC correlated negatively with right ventricular systolic function. This negative correlation suggested that RC was able to reasonably capture right ventricular – arterial coupling in the acute setting. The experimental model in this study was different from typical clinical scenarios, i.e., a long-term adaptation or maladaptation of pulmonary vasculature and right ventricular myocardium in response to chronic pressure loading. Thus, it needs to be tested whether RC was able to describe the coupling in the clinical setting.This echo-Doppler method involves several assumptions. Firstly, right atrial pressure is assumed to be constant during systole. The fluctuation in right atrial pressure during this period is usually small enough to be negligible, when compared with PAP. This assumption seemed valid from the results of this validation study demonstrating that the echo-Doppler method accurately quantified wave reflection. It may be because all dogs used in this study presented with only mild degree of TR. Once severe, it causes a significant rise in right atrial pressure in late systole; thus, we assume that the echo-Doppler method may not be applicable to those with severe TR. Secondly, a pulsed-wave Doppler tracing of RVOT flow was used as a surrogate for PA flow velocity waveform. The velocity should be higher when measured at RVOT than when measured at pulmonary arterial trunk, which should result in higher characteristic impedance, i.e., wave speed when assessed by the echo-Doppler method. This overestimation was confirmed by the present study showing that wave speed measured by the echo-Doppler method was higher, by a mean of 0.42 m/s, than that by direct measurement. Thirdly, RR interval on electrocardiogram is assumed to be constant throughout image acquisitions. In this method, pressure and flow waveforms are obtained from echo-Doppler images acquired at different cardiac cycle and the both waveforms are aligned in time with reference to the R wave on electrocardiogram. Therefore, this method cannot be applied to patients with large heart rate variability such as atrial fibrillation. Fourthly, Hollander et al. reported the existence of negative reflections which occurs in early systole in dogs, indicating which casts doubt on the validity of early systole being reflection-free which is a necessary assumption for use of the Water Hammer equation. However, we think that the impact of this negative reflections in systole are small.Despite the above assumptions, the present study demonstrated that the echo-Doppler method can quantify pulmonary arterial wave reflection with reasonable accuracy and it is sensitive for detecting the changes in pulmonary arterial wave reflection associated with the development of PH.Pulmonary arterial hypertension remains a fatal disease with a 1-year mortality of approximately 20%, despite advances in disease-specific therapies . This maPH-specific treatments do not always produce desirable clinical outcomes. For example, some patients with chronic thromboembolic pulmonary hypertension exhibit exercise intolerance even after pulmonary endarterectomy, often despite normalization of pulmonary arterial hemodynamics. This may partly be attributable to persistent pulmonary arterial wave reflection after the surgery. A previous study demonstrated using wave separation analysis that there remained a large reflected pressure wave 3 months after the surgery, even in patients without residual PH . PulmonaWave reflection is one component of pulsatile load, so it is inherently included in arterial compliance. This is why RC correlated with pulmonary arterial compliance. Pulse pressure, a major component of arterial compliance, is a sum of forward pressure representing stiffness of proximal artery and backward pressure representing pathology of more peripheral arteries. When pulse pressure is elevated, we are not sure which of the two pressures is elevated. Therefore, assessing wave reflection may offer benefits over pulmonary arterial compliance for discriminating diseases with different sites of arteries affected, for example, primary pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. While the clinical implication of wave reflection in the systemic circulation is becoming more apparent, only a few studies have applied wave reflection in the pulmonary circulation and these have mainly been in animal models . TherefoThe scale of verification in this study was small and that limits being able to affirm that the technique has been validated completely. In addition, to validate the echo-Doppler method, the present study created an animal model of PH which mimicked pulmonary arterial hypertension by embolizing peripheral pulmonary arterial with microsphere. The magnitude and timing of wave reflection vary depending on the site of narrowing in pulmonary vasculature; this was evidenced by previous studies of wave separation analysis observing a larger reflected wave that arrived earlier during systole in chronic thromboembolic pulmonary hypertension than that in pulmonary arterial hypertension . It needBrand-Altman analysis showed that the error tended to increase as the wave reflection increased. The estimates of the limits of agreement from Bland Altman analysis are likely to be underestimated due to the non-independence of data from the same animals.Although TR was effectively induced by the catheter passing the tricuspid valve in this study, TR is not always evident in the clinical setting. Therefore, in clinical cases, measuring the PA wave reflection in cases that do not exhibit TR can be difficult. In addition, some studies questioned the accuracy of echocardiographic estimates of pulmonary arterial systolic pressure in the clinical setting, because TR velocity is sometimes difficult to measure or to obtain clear spectral Doppler envelopes . ConsequThe new echo-Doppler method yields reasonable measurement of pulmonary arterial wave reflection and can detect the alterations associated with the development of PH. This work shows that the methodological approach used could be useful for the non-invasive assessment of pulmonary wave reflections; although more animal research and subsequent research in humans are necessaryThe original contributions presented in the study are included in the article/The animal study was reviewed and approved by Animal Experimental Committee of Tokyo University of Agriculture and Technology.TYo and TYa designed the study and wrote the initial draft of the manuscript. SK and KM acquired and analyzed the data and performed the experiment. AU, HH, and ZY interpreted the results and critically revised the results. TU and RT edited the manuscript and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The respiratory system reacts instantaneously to intrinsic and extrinsic inputs. This adaptability results in significant fluctuations in breathing parameters, such as respiratory rate, tidal volume, and inspiratory flow profiles. Breathing variability is influenced by several conditions, including sleep, various pulmonary diseases, hypoxia, and anxiety disorders. Recent studies have suggested that weaning failure during mechanical ventilation may be predicted by low respiratory variability. This review describes methods for quantifying breathing variability, summarises the conditions and comorbidities that affect breathing variability, and discusses the potential implications of breathing variability for anaesthesia and intensive care. The control of breathing involves a complex system that balances the opposing goals of efficiency, redundancy, responsiveness, and stability . It is cIf this regulation is too rigid, respiratory variability is low or absent, and the respiratory system cannot adequately react to stimuli. In contrast, if the respiratory system is overreacting to internal and external stimuli, the system shows large fluctuations and loses control.The exact determinants of breathing variability are not precisely known; however, it has been shown that the increase and decrease in breathing variability are strongly associated with pathological states. Normal breathing variability is influenced by several factors, such as aging, cognitive load, sleep pattern, and hypoxia, as well as medical conditions such as anxiety, obstructive or restrictive lung disease, and arterial hypertension. During anaesthesia and intensive care, additional factors, such as drugs and the effects of mechanical ventilation, may also influence breathing variability.This review describes the methods for quantifying breathing variability, summarises the conditions and comorbidities that affect breathing variability, and discusses the potential implications of breathing variability for anaesthesia and intensive care.The regulation of breathing facilitates adequate gas exchange for metabolic needs. The impulses for inspiration and expiration are generated within the respiratory centre in the medulla oblongata after receiving and processing input from various subsystems Fig. . Consequ2 partial pressure) and estimated parameters  and integrated the result into a compartmental model using differential Eqs. [8]. For these calculations, several assumptions were necessary, including constant hemodynamic parameters, absence of intracardiac or pulmonary shunting, and instant intra-alveolar equilibration of CO2 and oxygen tensions. Another more recent approach used spectral analysis of all variables to predict oscillatory rhythmicity  showed greater quantitative variability than younger participants [21–50 years], especially during non-REM sleep , 26. AslSpecific changes in respiratory patterns are observed under hypoxic conditions , 28. DurIn addition, arterial hypertension may influence breathing variability. The quantitative variability of tidal volume, respiratory rate, and minute ventilation was significantly higher in a cohort of women at rest with elevated systolic blood pressure . The incaCO2, suggesting a role of chemical feedback loops. Interestingly, ibuprofen suppressed the increase in the correlated behaviour of respiratory frequency.The systemic inflammatory response to endotoxins induces alterations in respiratory frequency and minute ventilation, as well as the respiratory pattern . Even thMarked differences in breathing variability have been reported in children and adolescents with anxiety disorders, such as panic disorder , 33. DurAsthma and chronic obstructive pulmonary disease (COPD) affect breathing variability in different ways. Patients with COPD have higher quantitative variabilities of minute ventilation and tidal volume than age-and sex-matched controls . They haIn contrast, the variability of respiration is increased in patients with asthma, and this effect is related to disease severity. The quantitative variability of tidal breathing parameters in children with asthma aged 7–16 years was 25% greater than that in age-matched children, independent of the use of a bronchodilator . In younThese distinctively different effects of COPD and asthma on breathing variability were confirmed by a study that used the forced oscillation technique  to deterVariability in breathing was also reduced in patients with restrictive lung disease. For instance, during resting wakefulness, the quantitative variability of tidal volume was reduced by 56%, inspiratory time was reduced by 33%, expiratory time was reduced by 46%, and minute ventilation was reduced by 43% compared to those of healthy participants . Concurr2 is significantly lower in patients with chronic lung disease of infancy than in patients without supplementary oxygen or CPAP [Variability in breathing is also influenced by lung maturity. In preterm infants , quantitative variability of tidal volume and end-tidal expiratory CO or CPAP . At the  or CPAP . In pret or CPAP .Various drugs administered during the perioperative period influence breathing control. Propofol decreases the respiratory response to hypoxia and hypercarbia , 47 resuDuring weaning from mechanical ventilation, variability in breathing may be valuable for clinical decision-making . Weaning2O of pressure support although the aim was to assess the intrinsic variability of a patient [Interesting findings were reported in a study of patients requiring prolonged ventilation (> 7 days) . During  patient .The quantitative variability of the respiratory rate increases significantly during the reduction or interruption of sedation with propofol, midazolam, or their combination . This reVarious studies on the prognostic value of respiratory variability are presented in Table There is increasing attention for temporal variations of physiologic variables, such as heart rate variability , and theThe variability of respiration over time may be a promising tool for identifying patients at risk of pulmonary complications. The variability of respiration is complex and not fully understood yet. Measuring the variability of a single parameter, such as the respiratory rate, does not necessarily reflect the variability of the respiratory system as a whole. The overall variability of breathing is decreased by COPD, restrictive lung disease, chronic lung disease of infancy, non-REM sleep, and highly demanding cognitive tasks. In contrast, it is increased in older adults during the performance of complex arithmetic tasks during hypoxia and in patients with asthma, hypertension, or anxiety disorder. Further research is required to elucidate the full potential of respiratory variability in critical care and anaesthesiology.