Therapeutic Consequences and Prognostic Impact of Multimorbidity in Heart Failure: Time to Act

Background/Objectives: In heart failure (HF) with reduced ejection fraction (HFrEF), the early diagnosis and proper treatment of comorbidities (CMs) are of fundamental relevance. Our aim was to assess the prevalence of CMs among real-world patients requiring hospitalisation for HFrEF and to investigate the effect of CMs on the implementation of guideline-directed medical therapy (GDMT) and on all-cause mortality (ACM). Methods: The data of a consecutive HFrEF patient cohort hospitalised for HF between 2021 and 2024 were analysed retrospectively. Sixteen CMs (6 CV and 10 non-CV) were considered. Patients were divided into three categories: 0–3 vs. 4–6 vs. ≥7 CMs. GDMT at discharge and ACM were compared among CM categories. The predictors of 1-year ACM were also evaluated. Results: From the 388 patients (male: 76%, age: 61 [50–70] years; NT-proBNP: 5286 [2570–9923] pg/mL; ≥2 cardiovascular–kidney–metabolic disease overlap: 46%), a large proportion received GDMT (RASi: 91%; βB: 85%; MRA: 95%; SGLT2i: 59%; triple therapy [TT: RASi+βB+MRA]: 82%; quadruple therapy [QT: TT + SGLT2i]: 54%) at discharge. Multimorbidity was accompanied with a (p 0.05). Patients with multimorbidity were less likely to be treated with TT (93% vs. 82% vs. 73%, p = 0.001), while no difference was detected in the implementation of QT (56% vs. 54% vs. 50%, p = 0.685). The 1-year ACM of patients with an increased burden of CMs was higher (9% vs. 13% vs. 25%, p = 0.003). The risk of 1-year ACM was favourably affected by the use of TT/QT and less severe left ventricular systolic dysfunction, while having ≥5 CMs had an unfavourable impact on prognosis. Conclusions: According to our real-world analysis, HFrEF patients with an increased burden of CMs can expect a less favourable outcome. However, modern GDMT can even be applied in this patient population, resulting in a significantly improved prognosis. Thus, clinicians should insist on the early, conscious implementation of a prognosis-modifying drug regime in multimorbid HF patients as well

Eligibility for rapid up-titration of guideline-directed medical therapy of real-world patients hospitalised for heart failure

Introduction and aims: The 2023 Focused Update of the 2021 ESC Heart Failure (HF) Guidelines recommends the rapid up-titration (RT) of guideline-directed medical therapy (GDMT) for all patients hospitalised for HF to improve prognosis in light of STRONG-HF trial. However, the real-world feasibility of RT and the optimal selection of suitable patients may cause difficulties, as the STRONG-HF trial applied strict randomisation criteria. We aimed to assess the proportion of hospitalised HF patients suitable for RT after discharge.Methods: The proportion of patients eligible for RT based on the basic in- and exclusion criteria of the STRONG-HF trial (systolic blood pressure [SBP]≥100mmHg, heart rate [HR]≥60min-1, serum potassium≤5mmol/L, eGFR≥30mL/min/1.73m2, discharge NT-proBNP>1500pg/mL) was assessed in a consecutive patient cohort at a tertiary referral center between 01/04/2021 and 31/12/2023. Results: Data from 408 consecutive patients were analysed (male: 71%; age: 62[51-72]years; left ventricular ejection fraction: 27[20-35]%; HFrEF: 82%; hypertension: 67%; diabetes: 36%; atrial fibrillation: 47%). 78% of the patients were suitable for RT based on the SBP criterion, 93% on HR, 89% on serum potassium, and 91% on eGFR values. Thus, 60% were eligible for RT using the combined assessment of these parameters. When including the NT-proBNP value as well (60%), 34% of the cohort were eligible for RT.Conclusions: Based on our study, the proportion of patients suitable for RT of GDMT ranged from 34% to 60% based on the basic eligibility indicators of the STRONG-HF trial. Our results highlight the strategic importance of careful selection of patients eligible for RT

EKG-eltérések gyakorisága hypertrophiás cardiomyopathiában: aki keres, az talál [Prevalence of ECG abnormalities in hypertrophic cardiomyopathy: who seeks will find]

Bevezetés: Az Európai Kardiológus Társaság 2023-ban publikált, Cardiomyopathia Irányelve a cardiomyopathiák diagnosztikájában a multiparametrikus megközelítés fontosságát hangsúlyozza. A hypertrophiás cardiomyopathia kivizsgálásában az echokardiográfia, a szív mágnesesrezonancia-vizsgálata mellett az EKG is fontos szerepet játszik. Szakirodalmi adatok alapján a hypertrophiás cardiomyopathiában szenvedő betegek mindössze 4–18%-a rendelkezik eltérés nélküli EKG-val, ám a megfigyelt EKG-eltérések gyakorta aspecifikusak. Célkitűzés: Tercier kardiológiai centrumunk, a Gottsegen György Országos Kardiovaszkuláris Intézet Szívelégtelenség Ambulanciáján gondozott, hypertrophiás cardiomyopathiában szenvedő betegpopuláció EKG-jellemzőinek értékelése. Módszer: Intézetünk Szívelégtelenség Ambulanciáján 2023. 11. 01. és 2024. 09. 30. között gondozásba vett, a szív mágnesesrezonancia-vizsgálatával és/vagy genetikai vizsgálattal igazolt hypertrophiás cardiomyopathiában szenvedő betegek adatait, első ambuláns EKG-paramétereit elemeztük retrospektív módon. Eredmények: A vizsgált betegek (n = 72 fő) 58%-a volt férfi, mediánéletkoruk 49 (34–62) év, bal kamrai ejekciós frakciójuk 63 (47–72)%, NYHA funkcionális osztályuk 2 (1–2) volt, ICD-t/CRT-D-t 47%-uk viselt. A balkamrakiáramlási-pályaobstrukciójának ≥30 Hgmm értéke alapján a betegek 31%-a tartozott a hypertrophiás obstruktív cardiomyopathia csoportba. Az elemzett EKG-kon a betegek 6%-a pitvarfibrillált, az interatrialis vezetési zavarok a 29%-ukat érintették. Atrioventricularis és intraventricularis vezetési zavarok a betegek 50%-ában jelentkeztek (AV blokk: 20% [PQ-szakasz-megnyúlás: 18%, II. fokú AV blokk: 2%, III. fokú AV blokk: 0%], jobb-Tawara-szárblokk: 14%, bal-Tawara-szár-blokk: 16%, bal anterior hemiblokk: 13%, bal posterior hemiblokk: 3%, aspecifikus intraventricularis vezetési zavar: 8%). A Cornell, a Sokolow–Lyon-, illetve a Peguero–Lo Presti „high voltage” kritériumok szenzitivitása alacsonynak bizonyult (23–14–25%). Patológiás Q-hullám 42%-ban, QRS-fragmentáció 43%-ban, korrigált QT-idő-megnyúlás 44%-ban fordult elő. Repolarizációs eltérések, mint a T-hullám-inverzió, a csoport 94%-ában, szignifikáns ST-eleváció a 21%-ában és ST-depresszió a 48%-ában volt megfigyelhető, mindössze a páciensek 3%-a rendelkezett negatív EKG-val. A hypertrophiás obstruktív cardiomyopathia és a nonobstruktív hypertrophiás cardiomyopathia alcsoportok között egyedül a Cornell-kritérium gyakoriságában adódott különbség (45% vs. 15%, p = 0,044). Következtetés: A hypertrophiás cardiomyopathia diagnosztikájában elengedhetetlen a multimodális szemlélet. Eredményeink alapján hypertrophiás cardiomyopathiában gyakorta azonosíthatók heterogén EKG-eltérések, ám a gyanújelek időbeli felismerése a további diagnosztikus lépéseket segítheti, hozzájárulva a célzott kezelés megkezdéséhez, a prognózis javításához. | ntroduction: The 2023 European Society of Cardiology Cardiomyopathy Guidelines emphasize the crucial role of a multiparametric approach in diagnosing. During the diagnostic workup of hypertrophic cardiomyopathy, besides echocardiography and cardiac magnetic resonance, ECG plays an important role. Based on literature data, only 4–18% of patients with hypertrophic cardiomyopathy have normal ECG, however, ECG deviations are often non- specific. Objective: To evaluate the ECG characteristics in a hypertrophic cardiomyopathy patient cohort followed-up at the Heart Failure Outpatient Clinic of Gottsegen National Cardiovascular Center. Method: We retrospectively analyzed the data and the first ECGs registered of patients with hypertrophic cardiomyo- pathy, diagnosed by cardiac magnetic resonance and/or genetic testing, followed-up between 01. 11. 2023 and 30. 09. 2024 at our Heart Failure Outpatient Clinic. Results: Data from 72 patients were evaluated, male: 58%, age: 49 (34–62) years, left ventricular ejection fraction: 63 (47–72)%, NYHA functional class: 2 (1–2), ICD/CRT-D: 47%. Based on the left ventricular outflow tract obstruc- tion of ≥30 mmHg, 31% of the patients belonged to hypertrophic obstructive cardiomyopathy subgroup. Based on the ECGs analyzed, atrial fibrillation occurred in 6%. Interatrial conduction disturbances affected 29% of the patients. Atrioventricular and intraventricular conduction disturbances occurred in 50% (AV block: 20% [grade I: 18%, grade II: 2%, grade III: 0%], right bundle branch block: 14%, left bundle branch block: 16%, left anterior hemiblock: 13%, left posterior hemiblock: 3%, non-specific intraventricular conduction disturbance: 8%). The sensitivity of the Cor- nell, Sokolow–Lyon, and Peguero–Lo Presti “high voltage” criteria were low (23–14–25%). Pathological Q wave occurred in 42% of the patients, QRS fragmentation in 43% and corrected QT interval prolongation in 44%. T wave inversion was present in 94%, significant ST elevation in 21%, ST depression in 48%, while only 3% of patients had negative ECG. The only difference between hypertrophic obstructive cardiomyopathy and non-obstructive hyper- trophic cardiomyopathy patients was the fulfillment of the Cornell criterion (45% vs. 15%, p = 0.044). Conclusions: A multimodal approach is essential in the diagnosis of hypertrophic cardiomyopathy. Based on our re- sults, hypertrophic cardiomyopathy is often associated with heterogeneous ECG abnormalities. However, the early recognition of the ECG variations may help in the further diagnostic steps, contributing to the initiation of disease- modifying treatment

Expression of NADPH Oxidase (NOX) 5 in Rabbit Corneal Stromal Cells

To determine whether NOX 5 is expressed in rabbit corneal stromal cells (RCSC). NADPH oxidases (NOXes) are enzymes that preferentially use NADPH as a substrate and generate superoxide. Several isoforms of NOXes function as multi-protein complexes while NOX5 and DUOXs do not require the accessory proteins for their activity and possess calcium binding EF hands.Human NOX5 primers were used to amplify the rabbit NOX5 by RT-PCR. Amplified product was sequenced to confirm its identity. The protein encoded by the NOX5 was identified by western blot analysis. NOX5 siRNA was used to reduce transcript, protein, and calcium stimulated activity. In silico analyses were performed to establish the putative structure, functions, and evolution of rabbit NOX5.NOX activity was measured in RCSC with NADPH rather than NADH as a substrate. RT-PCR with NOX5 primers amplified 288 bp product using RCSC cDNA, which, when sequenced, confirmed its identity to human NOX5 mRNA. This sequence was used to predict the rabbit (Oryctolagus cuniculus) NOX5 gene. NOX5 siRNA reduced amounts of NOX5 mRNA in RCSC and reduced ionomycin stimulated superoxide production. A protein of about 65 to 70 kDa encoded by the NOX5 was detected by western blot analysis. In silico analysis predicted a putative rabbit NOX5 protein containing 801 amino acids. Motif searches predicted the presence of at least 3 putative EF-hands in N-terminus and a NOX domain in C terminal region.The data document that the NOX5 gene was expressed in cells of lagomorphs unlike rodents, making the rabbit an interesting model to study NOX5 functions. The activity of the rabbit NOX5 was calcium stimulated, a trait of NOX5 in general. NOX5 may also prove to be a useful genetic marker for studying the taxonomic position of lagomorphs and the Glires classification

Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation

Cisplatin is widely used for treating various solid tumors. However, this drug produces dose-limiting ototoxicity and nephrotoxicity, which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by diuresis, there is currently no approved treatment for hearing loss. Previous studies show that the ROS and inflammation are major contributors to cisplatin-induced hearing loss. In this study, we show that ROS trigger the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1). Activation of STAT1 activation was dependent on ROS generation through NOX3 NADPH oxidase, knockdown of which by siRNA reduced STAT1 activation. Moreover, STAT1 siRNA protected against activation of p53, reduced apoptosis, reduced damage to OHCs and preserved hearing in rats. STAT1 siRNA attenuated the increase in inflammatory mediators, such as TNF-α, inhibition of which protected cells from cisplatin-mediated apoptosis. Finally, we showed that trans-tympanic administration of etanercept, a TNF-α antagonist, protected against OHC damage and cisplatin-induced hearing loss. These studies suggest that controlling inflammation by inhibition of STAT1-dependent pathways in the cochlea could serve as an effective approach to treat cisplatin ototoxicity and improve the overall quality of life for cancer patients

A Claudin-9–Based Ion Permeability Barrier Is Essential for Hearing

Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)–mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU–induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9–defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9–defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function