Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Venous thromboembolism (VTE) developing after ankle sprain. Comparison with VTE after knee arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) is a critical complication after non-major trauma or surgery. While the risk and severity of VTE following major orthopedic surgery is well-documented, there is significant knowledge gap regarding, non-major trauma such as ankle sprains. METHODS: We analyzed data from the RIETE registry to assess the clinical characteristics, VTE prophylaxis usage, and outcomes in patients with VTE following ankle sprain versus those post elective knee arthroplasty. We aimed to assess the risk and severity of VTE in a population traditionally considered at lower risk. Risk stratification was performed using the TRiP(cast) score. RESULTS: Among 1,250 patients with VTE, those with ankle sprain (n = 459) were much younger than those post knee arthroplasty (n = 791), less often female, had fewer comorbidities, and received VTE prophylaxis less often (27% vs. 93 %). During anticoagulation, 26 patients developed recurrent VTE, 31 had major bleeding, and 12 died (fatal PE 3, fatal bleeding 2). There were no differences between the two groups in the rates of VTE recurrences (rate ratio (RR): 1.65; 95%CI: 0.69-3.88) or death (RR: 1.12; 95%CI: 0.33-3.46), but patients with VTE after ankle sprain had a lower rate of major bleeding (RR: 0.39; 95%CI: 0.13-0.99). CONCLUSIONS: Ankle sprain patients are often undertreated for VTE prophylaxis and have similar severity of VTE than those undergoing elective knee surgery, indicating the need for a more customized approach to VTE management.

Lead-associated mortality in the US 1999-2020: a time-stratified analysis of a national cohort.

OBJECTIVES: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999-2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). METHODS: Vital status of participants, 20-79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. RESULTS: In time-stratified analyses, BL decreased from 1.76 µg/dl in 1999-2004 to 0.93 µg/dl in 2017-2020, while the proportion of individuals with BL < 1 µg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93-1.17]). The HR for cardiovascular death was 1.44 (1.01-2.07) in the 1999-2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007-2010. From 1999-2004 to 2017-2020, cardiovascular PAF decreased (P < 0.001) from 7.80% (0.17-14.4%) to 2.50% (0.05-4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167-99 253) to 7539 (160-14 108). CONCLUSION: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.

Mortality and Cardiovascular End Points In Relation to the Aortic Pulse Wave Components: An Individual-Participant Meta-Analysis.

BACKGROUND: Wave separation analysis enables individualized evaluation of the aortic pulse wave components. Previous studies focused on the pressure height with overall positive but differing results. In the present analysis, we assessed the associations of the pressure of forward and backward (Pfor and Pref) pulse waves with prospective cardiovascular end points, with extended analysis for time to pressure peak (Tfor and Tref). METHODS: Participants in 3 IDCARS (International Database of Central Arterial Properties for Risk Stratification) cohorts (Argentina, Belgium, and Finland) aged ≥20 years with valid pulse wave analysis and follow-up data were included. Pulse wave analysis was done using the SphygmoCor device, and pulse wave separation was done using the triangular method. The primary end points consisted of cardiovascular mortality and nonfatal cardiovascular and cerebrovascular events. Multivariable-adjusted Cox regression was used to calculate hazard ratios. RESULTS: A total of 2206 participants (mean age, 57.0 years; 55.0% women) were analyzed. Mean±SDs for Pfor, Pref, Tfor, and Tfor/Tref were 31.0±9.1 mm Hg, 20.8±8.4 mm Hg, 130.8±35.5, and 0.51±0.11, respectively. Over a median follow-up of 4.4 years, 146 (6.6%) participants experienced a primary end point. Every 1 SD increment in Pfor, Tfor, and Tfor/Tref was associated with 27% (95% CI, 1.07-1.49), 25% (95% CI, 1.07-1.45), and 32% (95% CI, 1.12-1.56) higher risk, respectively. Adding Tfor and Tfor/Tref to existing risk models improved model prediction (∆Uno's C, 0.020; P<0.01). CONCLUSIONS: Pulse wave components were predictive of composite cardiovascular end points, with Tfor/Tref showing significant improvement in risk prediction. Pending further confirmation, the ratio of time to forward and backward pressure peak may be useful to evaluate increased afterload and signify increased cardiovascular risk.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

Clotting of the Extracorporeal Circuit in Hemodialysis: Beyond Contact-Activated Coagulation.

Thrombotic complications in patients with end-stage kidney disease are frequent. While being a lifesaving treatment for these patients, hemodialysis introduces a thromboinflammatory environment. Additionally, the extracorporeal hemodialysis circuit itself is prone to clotting because of an interaction between different activation mechanisms of the coagulation system, platelets, and the immune system. Anticoagulation of the patient and the machine is frequently complicated by bleeding. We discuss the factors important in this balancing act and touch on potential strategies that are on the horizon to target thromboinflammation.

Factor XI Inhibitors: Potential Role in End-Stage Kidney Disease.

Patients with end-stage kidney disease (ESKD) experience a high thrombotic risk but are also at increased risk of bleeding. There is an unmet need for safer antithrombotic therapy in patients with ESKD on hemodialysis. Factor XI (FXI) represents an attractive therapeutic target for anticoagulation because of the potential to mitigate the bleeding risks associated with currently approved anticoagulants, especially in patients at high risk of bleeding. FXI inhibition is also an attractive option in settings where coagulation is activated by exposure of the blood to artificial surfaces, including the extracorporeal circuit during hemodialysis. Therapies targeting FXI that are in the most advanced stages of clinical development include antisense oligonucleotides, monoclonal antibodies, and synthetic small molecules, which serve either to lower FXI levels or block its physiological effects. This review article presents the most recent pharmacological data with FXI inhibitors, briefly describes phase 2 and 3 clinical trials with these agents, and critically examines the potential future use of FXI inhibitors for extracorporeal circuit anticoagulation in patients with ESKD. In addition, laboratory monitoring and reversal of FXI inhibitors are briefly discussed.

Enoxaparin for Long-Term Therapy of Venous Thromboembolism in Patients with Cancer and Renal Insufficiency.

BACKGROUND: The optimal therapy of venous thromboembolism (VTE) in cancer patients with renal insufficiency (RI) is unknown. Current guidelines recommend to use low-molecular-weight heparin over direct oral anticoagulants to treat VTE in cancer patients at high risk of bleeding. METHODS: We used the Registro Informatizado Enfermedad Tromboemb00F3lica (RIETE) registry to compare the 6-month incidence rates of (1) VTE recurrences versus major bleeding and (2) fatal pulmonary embolism (PE) versus fatal bleeding in three subgroups (those with mild, moderate, or severe RI) of cancer patients receiving enoxaparin monotherapy. RESULTS: From January 2009 through June 2022, 2,844 patients with RI received enoxaparin for ≥6 months: 1,432 (50%) had mild RI, 1,168 (41%) moderate RI, and 244 (8.6%) had severe RI. Overall, 68, 62, and 12%, respectively, received the recommended doses. Among patients with mild RI, the rates of VTE recurrences versus major bleeding (4.6 vs. 5.4%) and fatal PE versus fatal bleeding (1.3 vs. 1.2%) were similar. Among patients with moderate RI, VTE recurrences were half as common as major bleeding (3.1 vs. 6.3%), but fatal PE and fatal bleeding were close (1.8 vs. 1.2%). Among patients with severe RI, VTE recurrences were threefold less common than major bleeding (4.1 vs. 13%), but fatal PE was threefold more frequent than fatal bleeding (2.5 vs. 0.8%). During the first 10 days, fatal PE was fivefold more common than fatal bleeding (2.1 vs. 0.4%). CONCLUSION: Among cancer patients with severe RI, fatal PE was fivefold more common than fatal bleeding. The recommended doses of enoxaparin in these patients should be revisited.

Incidence and predictors of post-thrombotic syndrome in patients with proximal DVT in a real-world setting: findings from the GARFIELD-VTE registry.

Although substantial progress has been made in the pathophysiology and management of the post-thrombotic syndrome (PTS), several aspects still need clarification. Among them, the incidence and severity of PTS in the real world, the risk factors for its development, the value of patient's self-evaluation, and the ability to identify patients at risk for severe PTS. Eligible participants (n = 1107) with proximal deep-vein thrombosis (DVT) from the global GARFIELD-VTE registry underwent conventional physician's evaluation for PTS 36 months after diagnosis of their DVT using the Villalta score. In addition, 856 patients completed a Villalta questionnaire at 24 months. Variable selection was performed using stepwise algorithm, and predictors of severe PTS were incorporated into a multivariable risk model. The optimistic adjusted c-index was calculated using bootstrapping techniques. Over 36-months, 27.8% of patients developed incident PTS (mild in 18.7%, moderate in 5.7%, severe in 3.4%). Patients with incident PTS were older, had a lower prevalence of transient risk factors of DVT and a higher prevalence of persistent risk factors of DVT. Self-assessment of overall PTS at 24 months showed an agreement of 63.4% with respect to physician's evaluations at 36 months. The severe PTS multivariable model provided an optimistic adjusted c-index of 0.68 (95% CI 0.59-0.77). Approximately a quarter of DVT patients experienced PTS over 36 months after VTE diagnosis. Patient's self-assessment after 24 months provided added value for estimating incident PTS over 36 months. Multivariable risk analysis allowed good discrimination for severe PTS.

Therapy and guideline adherence at a multidisciplinary hypertension clinic: A prospective, observational study.

BACKGROUND: Hypertension is highly prevalent and remains one of the most frequent and preventable causes of cardiovascular morbidity and mortality. Yet, suboptimal blood pressure control is common. Hypertension clinics might play an important role in improving target attainment, by targeting drug therapy adherence, improving guideline compliance and by involving pharmacists. OBJECTIVES: We aimed to characterize patient drug therapy adherence, prescriber guideline compliance and pharmacist interventions at the hypertension clinic. METHODS: A prospective observational study was performed at the hypertension clinic of a large, academic hospital. Adult Dutch-speaking patients were eligible for inclusion. Following data were collected: patient demographics, medication use, patient adherence to prescribed antihypertensive drug therapies according to the BAASIS tool and prescriber compliance to the 2018 European Society of Cardiology (ESC) hypertension guidelines. RESULTS: A cohort of 108 patients was included with 51.9% male and aged 65 (IQR: 52-75) years. In total, 104 patients took at least 1 antihypertensive drug and 46 patients (44.2%) were classified as non-adherent with regard to their antihypertensive treatment; 82 patients (78.8%) had suboptimal blood pressure control. Compliance with the ESC guidelines was 66.3% prior to the consultation at the clinic and significantly increased to 77.9% thereafter (p = 0.0015). The clinical pharmacist performed a medication review for 27 patients with a total of 44 recommendations and an acceptance rate of 59.1%. CONCLUSION: A visit to the multidisciplinary hypertension clinic improved prescriber guideline compliance and the use of single pill combinations. Involvement of a clinical pharmacist could be beneficial to further improve patient drug therapy adherence and guideline compliance.

Protective Effect of Ticagrelor Against Infective Endocarditis Induced by Virulent Staphylococcus aureus in Mice.

In addition to its potent antiplatelet activity, ticagrelor possesses antibacterial properties against gram-positive bacteria. We wondered whether the typical clinical dosage of ticagrelor could prevent the development of infective endocarditis caused by highly virulent Staphylococcus aureus. Ticagrelor prevented vegetation formation in a mouse model of inflammation-induced endocarditis. The dosage achieved in patients under ticagrelor therapy altered bacterial toxin production and adherence on activated endothelial cells, thereby mitigating bacterial virulence. Besides the previously described bactericidal activity at high doses, ticagrelor at typical clinical doses possesses antivirulence activity against S aureus. Ticagrelor antiplatelet activity further interferes with the interplay between platelets and bacteria.

Percutaneous embolization of pulmonary arteriovenous malformations in adult patient with Rendu-Osler-Weber: a case report.

Background: Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a rare genetic disorder characterized by the development of telangiectasias and arteriovenous malformations (AVMs) throughout the body. We present a case of percutaneous embolization of pulmonary AVMs in an adult patient. Case summary: A 26-year-old male patient with polycythaemia of unknown origin and a family history of secundum atrial septal defect underwent cardiac evaluation which revealed clubbing as a sign of peripheral cyanosis. Transthoracic echocardiography showed no intracardiac shunting, but further imaging revealed pulmonary AVMs in the lower lobe of the left lung. Magnetic resonance imaging of the brain detected vascular-ischaemic lesions, likely due to embolization through the pulmonary malformations. Right heart catheterization and pulmonary angiography confirmed the presence of large AVMs in the left lower pulmonary lobe. Percutaneous closure using Amplatzer devices was performed, followed by temporary anticoagulation therapy. Oxygen saturation improved and follow-up imaging confirmed successful closure of the AVMs. Genetic testing using whole exome sequencing identified a mutation in the ENG gene, confirming the diagnosis of HHT. Discussion: Our case highlights the importance of investigating both intra- and extracardiac shunting in patients with clinical features of right-to-left shunting. Arteriovenous malformations can serve as a pathway for paradoxical emboli, potentially leading to ischaemic brain events, and might cause pulmonary arterial hypertension. Screening for arteriovenous malformations in various organs and embolization of significant shunts are essential aspects of managing HHT. Genetic testing aids in confirming the diagnosis and guides family testing.

Blood pressure and renal function responses in workers exposed to lead for up to six years.

The Study for Promotion of Health in Recycling Lead (SPHERL) assessed the blood pressure (BP) and renal function (RF) responses for up to 6 years in the workers without previous occupational lead exposure. BP was the average of five consecutive readings and the estimated glomerular filtration rate was derived from serum creatinine (eGFRcrt) and cystatin C (eGFRcys). Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dL). The statistical methods included multivariable-adjusted mixed models and interval-censored Cox regression analysis. The 234 workers analyzed were on average 28.5 years old and included 91.9% men. The baseline BL concentration was 4.35 µg/dL and increased 3.17-fold over follow-up (median: 2.03 years; range: 0.92-6.45 years). The changes in BP and RF were not significantly correlated with the follow-up-to-baseline BL ratio (p ≥ .51 and p ≥ .18, respectively). The fully-adjusted changes in systolic/diastolic BP associated with a doubling of BL were -0.25/-0.12 mm Hg (CI: -0.94 to 0.44/-0.66 to 0.42 mm Hg). Accordingly, the incidence of stage-1 or -2 hypertension was not associated with the BL change (p ≥ .063). Similarly, the changes in eGFRcrt and eGFRcys associated with a 3-fold BL increment were not significant, amounting to -0.70 mL/min/1.73 m2 (CI: -1.70 to 0.30 mL/min/1.73 m2 ) and -1.06 mL/min/1.73 m2 (-2.16 to 0.03 mL/min/1.73 m2 ). In conclusion, the BP and RF responses to an over 3-fold BL increment were small and not significant confirming the safety of modern lead-handing facilities operating under current safety rules.

Peptidylarginine deiminase 4 and ADAMTS13 activity in Staphylococcus aureus bacteraemia.

Staphylococcus aureus infection is associated with increased levels of neutrophil extracellular traps (NETs) and von Willebrand factor (VWF), and with reduced activity of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Peptidylarginine deiminase 4 (PAD4) contributes to NET formation and inactivates ADAMTS13 in vitro. The role of PADs in the dynamics of NETs, VWF and ADAMTS13 has not yet been studied. We thus aimed to assess the longitudinal evolution of NETs, PADs, VWF and ADAMTS13 activity in S. aureus infection. Plasma samples from S. aureus bacteraemia patients were longitudinally collected and analysed for NETs, PAD4/PAD2, VWF and ADAMTS13 activity. Correlation analyses with clinical data were performed. Recombinant PAD4 and S. aureus were assessed in vitro for their potential to modulate ADAMTS13 activity. Sixty-seven patients were included. Plasma levels of NETs, VWF, PAD4 and PAD2 were increased and ADAMTS13 activity was decreased. Levels of PADs were negatively correlated with ADAMTS13 activity. NETs were positively correlated with PADs, and negatively with ADAMTS13 activity. In vitro, recombinant PAD4 but not S. aureus reduced ADAMTS13 activity in plasma. Levels of PAD4 and PAD2 correlate with reduced ADAMTS13 activity, with neutrophils as the likely source of PAD activity in S. aureus bacteraemia. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Effect of 24-h blood pressure dysregulations and reduced ocular perfusion pressure in open-angle glaucoma progression.

BACKGROUND: Low ocular perfusion pressure (OPP), which depends on the mean arterial pressure (MAP) and intraocular pressure (IOP), is associated with glaucoma. We studied 24-h MAP dysregulations and OPP in relation to the progression of glaucoma damage. METHODS: We retrospectively analyzed 155 normal-tension glaucoma (NTG) and 110 primary open-angle glaucoma (POAG) patients aged 18 years old followed at the University Hospital Leuven with repeated visual field tests ( n  = 7000 measures, including both eyes) who underwent 24-h ambulatory blood pressure monitoring. Twenty-four-hour MAP dysregulations were variability independent of the mean (VIM), and the five lowest dips in MAP readings over 24 h. OPP was the difference between 2/3 of the MAP and IOP. Glaucoma progression was the deterioration of the visual field, expressed as decibel (dB) changes in mean deviation analyzed by applying multivariable linear mixed regression models. RESULTS: The mean age was 68 years (53% were women). High 24-h VIMmap was associated with glaucoma progression in POAG ( P  < 0.001) independently of the 24-h MAP level. The estimated changes in mean deviation in relation to dip MAP measures ranged from -2.84 dB [95% confidence interval (CI) -4.12 to -1.57] to -2.16 dB (95% CI -3.46 to -0.85) in POAG. Reduced OPP along with high variability and dips in MAP resulted in worse mean deviation deterioration. CONCLUSION: The progression of glaucoma damage associates with repetitive and extreme dips in MAP caused by high variability in MAP throughout 24 h. This progression exacerbates if 24-h MAP dysregulations occur along with reduced OPP.