Evolución de la lesión orgánica mediada por hipertensión en pacientes con hipertensión arterial resistente tras añadir espironolactona / Hypertensive mediated organ damage evolution in resistant hypertension patients after adding spironolactone

Introducción: La hipertensión arterial resistente (HTAR) supone un importante impacto a nivel multiorgánico e incrementa la morbimortalidad. Este trabajo evalúa la evolución de la lesión orgánica mediada por hipertensión en pacientes con HTAR tras añadir espironolactona. Material y métodos: Estudio retrospectivo de 58 pacientes con HTAR a quienes se añadió espironolactona (12,5-25mg/día). Se obtuvieron parámetros de presión arterial clínica y MAPA-24h, cociente albúmina/creatinina y datos ecocardiográficos previos a iniciar espironolactona y tras 12 meses de tratamiento. Resultados: El 36,2% de los pacientes eran mujeres y la edad media de 67,3±10,1 años. Se objetivó un descenso en albuminuria (mediana [RIC25-75]) de 27,0 (7,5-255,4) a 11,3 (3,1-37,8) mg/g (p = 0,009), siendo más marcado en pacientes con albuminuria grado A2 y A3: de 371,2 (139,5-797,4) a 68,4 (26,5-186,5) mg/g, p =0,02.. A nivel ecocardiográfico se evidenció: pared posterior: −1,0±0,4mm (p<0,001), tabique interventricular: −0,6±0,5mm (p=0,01), índice de masa del ventrículo izquierdo (VI): −14,7±10,2g/m2 (p=0,006), índice de remodelado del VI: −0,04±0,036 (p=0,03), sin cambios estadísticamente significativos en fracción de eyección VI, diámetro diastólico VI, diámetro sistólico VI, diámetro de aurícula izquierda, relación entre onda de llenado ventricular temprano y contracción auricular ni en índice de presión llenado VI. La presión arterial clínica sistólica/diastólica presentó un descenso de −12,5±4,9/−4,9±3,0mmHg, p<0,001. En los MAPA-24h se observó un descenso significativo de presión arterial sistólica y diastólica en los períodos diurno y nocturno, y un cambio favorable en el patrón circadiano en el 38,1% de los pacientes, p<0,001. Conclusiones: Añadir espironolactona en HTAR contribuye a la reducción de la lesión orgánica mediada por hipertensión a nivel de albuminuria y de parámetros ecocardiográficos de cardiopatía hipertensiva. (AU)

Introduction: Resistant hypertension (RH) represents an important multi-organic impact and increases the morbi-mortality. We aimed to evaluate the evolution of hypertensive mediated organ damage in patients with RH after adding spironolactone. Material and methods: Retrospective study of 58 patients with RH who started spironolactone (12.5–25mg daily). Office blood pressure, 24-h ambulatory blood pressure monitoring (24h-ABPM), urine albumin-to-creatinine ratio and echocardiographic parameters were analyzed prior to initiation of spironolactone and after 12 months of treatment. Results: Thirty-six percent of patients were women and mean age was 67.3±10.1 years. We observed a decrease in urine albumin-to-creatinine ratio (median [RIQ25–75]) of 27.0 (7.5-255.4) to 11.3 (3.1–37.8) mg/g, P = .009. This was more relevant in patients with albuminuria grade A2 and A3: 371.2 (139.5–797.4) to 68.4 (26.5–186.5) mg/g, P = .02. The echocardiographic changes were: posterior wall thickness: −1.0±0.4mm (P<.001), interventricular septal thickness: −0.6±0.5mm (P=.01), left ventricular (LV) mass index: −14.7±10.2g/m2 (P=.006), LV remodeling index: −0.04±0.036 (P=.03), without statistically significant changes in LV ejection fraction, LV end-diastolic diameter, LV end-systolic diameter, left atrial diameter, relationship between early ventricular filling wave and atrial contraction and LV filling pressure index. Systolic/diastolic office blood pressure decreased −12.5±4.9/−4.9±3.0mmHg, P<.001. In 24h-ABPM, systolic and diastolic BP had a significant decrease in diurnal and nocturnal periods and 38.1% of patients presented a favorable change in the circadian pattern, P<.001. Conclusions: Adding spironolactone to patients with RH contributes to improve hypertensive mediated organ damage by reducing albuminuria levels and echocardiographic parameters of hypertensive heart disease. (AU)

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi.

BACKGROUND: In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity. METHODS: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). RESULTS: One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex. CONCLUSION: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered. TRIAL REGISTRATION: The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial.

OBJECTIVE: To assess the effectiveness of oral spironolactone for acne vulgaris in adult women. DESIGN: Pragmatic, multicentre, phase 3, double blind, randomised controlled trial. SETTING: Primary and secondary healthcare, and advertising in the community and on social media in England and Wales. PARTICIPANTS: Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics. INTERVENTIONS: Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment. MAIN OUTCOME MEASURES: Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator's global assessment (IGA) for treatment success; and adverse reactions. RESULTS: From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% v 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% v 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% v 12%; p=0.02). No serious adverse reactions were reported. CONCLUSIONS: Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne. TRIAL REGISTRATION: ISRCTN12892056.

Predicting hospitalization by TAPSE/SPAP and the role of spironolactone in asymptomatic heart failure patients.

Aim: To appraise the prediction of tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (SPAP) with regard to hospitalization and the effect of spironolactone use. Materials & methods: A total of 245 patients were evaluated for the study. Patients were followed for 1 year and cardiovascular outcomes were determined. Results: It was determined that TAPSE/SPAP was an independent predictor of hospitalization. A 0.1-mmHg decrease in TAPSE/SPAP was associated with a 9% increase in relative risk. No event was observed above the 0.47 level. Negative correlation with TAPSE (uncoupling) began in the spironolactone group when SPAP was ≥43 and in nonusers when SPAP was 38 (Pearson's correlation coefficient: -,731 vs -,383; p < 0.001 vs p = 0.037). Conclusion: TAPSE/SPAP measurement may be useful in predicting 1-year hospitalization in asymptomatic heart failure patients. This ratio was also found to be higher in patients who used spironolactone.

Role of eplerenone in the threatment of cardiovascular diseases.

Eplerenone is a selective mineralocorticoid receptor antagonist. Its approved for the therapy of patients with chronic heart failure with left ventricular systolic dysfunction and for the patients after myocardial infarction complicated by heart failure and left ventricular dysfunction. It´s also recommended for the therapy of primary hyperaldosteronism and the treatment of drug resistant hypertension.

Unique Case of Cardiomyopathy Secondary to Adrenal Adenoma (Primary-Aldosteronism).

INTRODUCTION: To our knowledge this is the first & only case report in India wherein primary aldosteronism (adrenal adenoma) presented with cardiomyopathy (regressed post-surgery). MATERIALS: First reported case in India. RESULT: Herein August 2018 IPGMER-SSKM-Kolkata 29-year female presented with 1-month exertional dyspnoea, occasional chest pain, sweating, fainting. On examination (Pulsus-bisferiens, forceful-well sustained-double-kicking-apex, grade-3-ejection-systolic-murmur (left 3rd intercostal space) (murmur intensity increased by Valsalva & standing). Left-ventricular-hypertrophy by ECG (R(I)+S(III) 35 mm) & Echocardiography (LVO Tobstruction, RWMA, wall-hypokinesia, systolic-anterior-motion, asymmetric-septal-hypertrophy excluded). Cardiac-MRI confirmed cardiomyopathy (patchy late gadolinium enhancements). She refused endomyocardial biopsy (normal troponin & NT-pro-BNP). Uncontrolled hypertension (BP 190/150) despite maximum Prazosin20 & Clonidine 100 dosage, besides persistent hypokalemia (despite repeated Intravenous KCL). With raised 24 hour Urine K + 52 meq/day raised TTKG 17.5, high serum AR Ratio (87.65) high Aldosterone (44.7) (normal Plasma Renin Activity (PRA 0.5) normal Cortisol (12.1). 24 x 22 x 15 mm hypodense mixed enhancing mass Left Adrenal in Contrast CT abdomen. Spironolactone 50, Ramipril 5, Ramipril5 subsequently added. Following unilateral adrenalectomy (histopathology 4 x 4 x 1 cm benign adrenal cortical adenoma) (without pleomorphism nor necrosis). (BP finally controlled before discharge following week. Patients cardiac function improved over next 6-months (complete regression of LVH in ECG-Echo & LGE in cardiac-MRI). Patient been regularly followed (till October 2022) at AIIMS-kalyani. Well controlled Hypertension (only Amlodipine 2.5 mg) (normal K + level, still in remission, normal potassium & normal cardiac function). CONCLUSION: Prior in-vitro studies suggested possible aldosterone (excess) induced direct activation of mineralocorticoid receptors in (low-density/serum-free) ventricular myocytes (culture); also aldosterone increases mRNA for cardiac-ANF & alpha/beta-myosin heavy-chains (aldosterone also effects collagen deposition & fibroblast proliferation). All of these were clearly prevented by adding spironolactone. References Higuchi S, Ota H, Tezuka Y, et al. Aldosterone-induced cardiac damage in primary aldosteronism depends on its subtypes, Endocr Connect 2021;10(1):29-36. Petramala L, Concistrè A, Olmati F, et al. Cardiomyopathies and adrenal diseases. Int J Mol Sci 2020;21(14):5047.

The Idiosyncratic Efficacy of Spironolactone-Loaded PLGA Nanoparticles Against Murine Intestinal Schistosomiasis.

Background: Schistosomiasis is a chronic debilitating parasitic disease accompanied with severe mortality rates. Although praziquantel (PZQ) acts as the sole drug for the management of this disease, it has many limitations that restrict the use of this treatment approach. Repurposing of spironolactone (SPL) and nanomedicine represents a promising approach to improve anti-schistosomal therapy. We have developed SPL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to enhance the solubility, efficacy, and drug delivery and hence decrease the frequency of administration, which is of great clinical value. Methods: The physico-chemical assessment was performed starting with particle size analysis and confirmed using TEM, FT-IR, DSC, and XRD. The antischistosomal effect of the SPL-loaded PLGA NPs against Schistosoma mansoni (S. mansoni)-induced infection in mice was also estimated. Results: Our results manifested that the optimized prepared NPs had particle size of 238.00 ± 7.21 nm, and the zeta potential was -19.66 ± 0.98 nm, effective encapsulation 90.43±8.81%. Other physico-chemical features emphasized that nanoparticles were completely encapsulated inside the polymer matrix. The in vitro dissolution studies revealed that SPL-loaded PLGA NPs showed sustained biphasic release pattern and followed Korsmeyer-Peppas kinetics corresponding to Fickian diffusion (n<0.45). The used regimen was efficient against S. mansoni infection and induced significant reduction in spleen, liver indices, and total worm count (ρ<0.05). Besides, when targeting the adult stages, it induced decline in the hepatic egg load and the small intestinal egg load by 57.75% and 54.17%, respectively, when compared to the control group. SPL-loaded PLGA NPs caused extensive damage to adult worms on tegument and suckers, leading to the death of the parasites in less time, plus marked improvement in liver pathology. Conclusion: Collectively, these findings provided proof-of-evidence that the developed SPL-loaded PLGA NPs could be potentially used as a promising candidate for new antischistosomal drug development.

Fabrication and characterization of anti-rosacea 3D nanofibrous customized sheet masks as a novel scaffold for repurposed use of spironolactone with pre-clinical studies.

The repurposed oral use of spironolactone (SP) as an anti-rosacea drug faces many challenges that hinder its efficacy and compliance. In this study, a topically applied nanofibers (NFs) scaffold was evaluated as a promising nanocarrier that enhances SP activity and avoids the friction routine that exaggerates rosacea patients' inflamed, sensitive skin. SP-loaded poly-vinylpyrrolidone (40% PVP) nanofibers (SP-PVP NFs) were electrospun. Scanning electron microscopy showed that SP-PVP NFs have a smooth homogenous surface with a diameter of about 426.60 nm. Wettability, solid state, and mechanical properties of NFs were evaluated. Encapsulation efficiency and drug loading were 96.34% ± 1.20 and 11.89% ± 0.15, respectively. The in vitro release study showed a higher amount of SP released over pure SP with a controlled release pattern. Ex vivo results showed that the permeated amount of SP from SP-PVP NFs sheets was 4.1 times greater than that of pure SP gel. A higher percentage of SP was retained in different skin layers. Moreover, the in vivo anti-rosacea efficacy of SP-PVP NFs using croton oil challenge showed a significant reduction in erythema score compared to the pure SP. The stability and safety of NFs mats were proved, indicating that SP-PVP NFs are promising carriers of SP.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Betahistine prevents development of endolymphatic hydrops in a mouse model of insulin resistance and diabetes.

BACKGROUND: Diabetes is associated with inner ear dysfunction. Furthermore, C57BL/6J mice fed high fat diet (HFD), a model for insulin resistance and diabetes, develop endolymphatic hydrops (EH). AIM: Evaluate if betahistine, spironolactone (aldosterone antagonist) and empagliflozin (sodium -glucose cotransporter2 inhibitor) can prevent EH induced by HFD and explore potential mechanisms. METHODS: C57BL/6J mice fed HFD were treated with respective drug. The size of the endolymphatic fluid compartment was measured using contrast enhanced MRI. Secondarily, mice treated with cilostamide, a phosphodiesterase3 inhibitor, to induce EH and HEI-OC1 auditory cells were used to study potential cellular mechanisms of betahistine. RESULTS: HFD-induced EH was prevented by betahistine but not by spironolactone and empagliflozin. Betahistine induced phosphorylation of protein kinaseA substrates but did not prevent cilostamide-induced EH. CONCLUSIONS: Betahistine prevents the development of EH in mice fed HFD, most likely not involving pathways downstream of phosphodiesterase3, an enzyme with implications for dysfunction in diabetes. The finding that spironolactone did not prevent HFD-induced EH suggests different mechanisms for EH induction/treatment since spironolactone prevents EH induced by vasopressin, as previously observed. SIGNIFICANCE: This further demonstrates that independent mechanisms can cause hydropic inner ear diseases which suggests different therapeutic approaches and emphazises the need for personalized medicine.

Spironolactone effect on circulating procollagen type I carboxy-terminal propeptide: Pooled analysis of three randomized trials.

BACKGROUND: Spironolactone might improve the prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFpEF), but the mechanisms by which it acts are uncertain. Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate well with histologically proven cardiac fibrosis. AIMS: To investigate the effect of spironolactone on serum PICP concentration in patients with stage B and C HFpEF across three trials (HOMAGE, ALDO-DHF, and TOPCAT) for which measurements of serum PICP were available. METHODS: Random-effects meta-analysis. RESULTS: A total of 1038 patients with PICP measurements available both at baseline and 9-12 months were included in this analysis: 488 (47.0%) from HOMAGE, 386 (37.2%) from ALDO-DHF, and 164 (15.8%) from TOPCAT. The median (percentile25-75) serum PICP was 98 (76-128) ng/mL. Compared to placebo or usual care, administration of spironolactone for 9 to 12 months reduced serum PICP by -7.4 ng/mL, 95%CI -13.9 to -0.9, P-value =0.02. The effect was moderately heterogeneous (I2 = 64%) with the most pronounced effect seen in TOPCAT where PICP was reduced by -27.0 ng/mL, followed by HOMAGE where PICP was reduced by -8.1 ng/mL, and was least marked in ALDO-DHF where PICP changed by -2.9 ng/mL. The association between spironolactone and serum PICP was not mediated substantially by blood pressure. CONCLUSIONS: Spironolactone reduced serum concentrations of PICP in patients with HFpEF with different severity and stages of disease. These findings are consistent with spironolactone having an anti-fibrotic effect.

Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial).

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confidence interval -4.6 to -1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.

Research Progress on the Efficacy and Safety of Spironolactone in Reversing Left Ventricular Hypertrophy in Hemodialysis Patients.

The mineralocorticoid receptor antagonist spironolactone has been shown to improve cardiac function and reverse left ventricular hypertrophy in heart failure patients, but there are no consistent findings on the efficacy and safety in hemodialysis patients. Abnormal aldosterone secretion plays a critical role in the formation of left ventricular hypertrophy. Because of the existence of "aldosterone escape", the routine use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers does not completely inhibit aldosterone secretion. Low-dose spironolactone (25 mg/d) has been found in small-sample clinical studies to have a significant positive impact with respect to decreasing left ventricular mass index, increasing left ventricular ejection fraction, reversing left ventricular hypertrophy, and improving cardiovascular function while still being safe. More prospective multicenter clinical trials with large sample sizes are needed, however, to provide convincing evidence.

Mean corpuscular haemoglobin concentration and outcomes in heart failure with preserved ejection fraction.

AIMS: This study aims to evaluate the prognostic value of mean corpuscular haemoglobin concentration (MCHC) on clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analysed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1747). Patients were grouped into hypochromia or non-hypochromia group according to a MCHC cut-off level of 330 g/L. Cox proportional hazard model was used to explore the prognostic value of hypochromia on the long-term clinical outcomes (the primary endpoint [composite of cardiovascular mortality, HF hospitalization and aborted cardiac arrest], any-cause and HF hospitalization, all-cause and cardiovascular mortality). Patients were further stratified according to baseline estimated glomerular filtration rate (eGFR) to explore the impact of renal dysfunction on the prognostic value of hypochromia. Baseline hypochromia was prevalent (n = 662, 37.9%) and strongly associated with worse clinical outcomes. In patients with worse renal function (eGFR < 60 mL/min per 1.73 m2 ), hypochromia was independently associated with primary endpoint (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.23-1.98; P < 0.001), any-cause hospitalization (HR, 1.43; 95% CI, 1.20-1.71, P < 0.001) and HF hospitalization (HR, 1.40; 95% CI, 1.07-1.84; P = 0.015), whereas no significant association between hypochromia and these outcomes was found in patients with better renal function. CONCLUSIONS: Among HFpEF patients, hypochromia (i.e. MCHC ≤ 330 g/L) is independently associated with adverse clinical outcomes, especially when in the presence of co-morbidity renal dysfunction.