Chemoriflesso ed apnee centrali nello scompenso cardiaco: influenza sull'ipertensione polmonare.

Introduzione: Nei pazienti con scompenso cardiaco sistolico è frequente il riscontro di apnee centrali (respiro di Cheyne-Stokes, RCS) non solamente durante la notte (sleep apnea) ma anche durante il giorno, correlato con la severità della malattia e con la prognosi. Anche l’ipertensione arteriosa polmonare è riconosciuta come un fattore prognostico indipendente nei pazienti con scompenso cardiaco. Essa, oltre a una componente definita passiva relativa all’aumento della pressione nel ventricolo sinistro, ha una componente legata alla vasocostrizione arteriosa polmonare, i cui meccanismi non sono stati completamente chiariti. Abbiamo ipotizzato che le apnee centrali, con il tramite della stimolazione del chemoriflesso, possano contribuire all’entità dell’ipertensione arteriosa polmonare nello scompenso sistolico. Questa ipotesi è stata confrontata con l’analisi di dati relativi alle apnee, alla sensibilità chemocettiva e all’ipertensione polmonare in una popolazione di pazienti con scompenso sistolico. Metodi: In questo studio sono stati arruolati prospetticamente 54 pazienti (43 maschi, 80%, età 64±13 anni, frazione d’eiezione del ventricolo sinistro <50%), in trattamento farmacologico ottimale, in assenza di insufficienza mitralica e disfunzione diastolica di grado severo. Tutti i pazienti sono stati sottoposti a valutazione del profilo neuroormonale, studio ecocardiografico-Doppler, monitoraggio cardiorespiratorio nelle 24 ore per l’identificazione di apnee e a test di chemosensibilità per valutazione della risposta ventilatoria all’ipossia (Hypoxic Ventilatory Response, HVR) e all’ipercapnia (Hypercapnic Ventilatory Response, HCVR) per mezzo della tecnica di rebreathing. Risultati: Undici pazienti (20%) hanno presentato apnee significative, definite attraverso l’indice di apnea-ipopnea (apnea-hypopnea index, AHI) >15 eventi/ora, valore medio nel periodo delle 24 ore (mediana 24, range interquartile 16-40 eventi/ora). Nei pazienti con scompenso cardiaco e RCS significativo era presente una pressione arteriosa polmonare sistolica stimata -PAPs- all’ecocardiogramma più elevata (PAPs: 40.1±7.6 vs 33.1±5.0 mmHg, p<0.01). I due gruppi presentavano una funzione ventricolare sinistra sistolica e diastolica e una funzione ventricolare destra sistolica simile. Inoltre nei pazienti con apnee centrali era presente un aumento dell’HVR (mediana 0.79, range interquartile -IR 0.62-1.27 vs 0.43, IR 0.19-0.69 L/min/%, p<0.05) e dell’HCVR (1.18, IR 1.10-1.31 vs 0.73, IR 0.51-0.95 L/min/mmHg, p<0.01), come anche dei livelli di noradrenalina plasmatica (559, IR 446-770 vs 367, IR 229-508.5 ng/L, p<0.05). Infine la PAPs era inoltre correlata con l’AHI (Spearman’s Rho, R=0.6, p<0.001), HVR (R=0.497, p<0.001), HCVR (R=0.479, p<0.001) e con i livelli di noradrenalina (R=0.29, p<0.05). All’analisi multivariata solo l’AHI manteneva il suo valore di predittività per la PAPs (p=0.014). Conclusioni: Nei pazienti con scompenso cardiaco sistolico il RCS sembra responsabile di una cascata di eventi che attraverso l’alternarsi di cicli di ipossia e ipercapnia, l’attivazione del chemoriflesso, l’attivazione adrenergica e la vasocostrizione arteriosa polmonare contribuisce al determinismo e alla severità dell’ipertensione polmonare

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI

Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches

Mitochondria are cellular organelles responsible for energy production, calcium handling, controlled synthesis of reactive oxygen species (ROS), and regulation of apoptosis. All these functions are crucial for cardiac homeostasis, and may be impaired in chronic heart failure (CHF). Therefore, mitochondrial dysfunction might represent a crucial element in the onset and progression of CHF and, as such, a promising therapeutic target

Cheyne-Stokes respiration related oscillations in cardiopulmonary hemodynamics in patients with heart failure

Background: Although Cheyne-Stokes respiration (CSR) is an oscillatory phenomenon, the direct effects of cyclical hyperventilation and apnea on cardiopulmonary hemodynamics have been poorly investigated. The aim of the study was to examine the echocardiographic changes associated with CSR phases in a group of patients with systolic heart failure (HF) and daytime CSR. Methods: 14 HF patients (age 70 ± 9 years, LVEF 24 ± 5) underwent a thorough clinical evaluation, 24-h respiratory polygraphy, chemoreflex evaluation by rebreathing technique and neuro-hormonal assessment. Furthermore, they received a simultaneous echocardiographic and respiratory monitoring embedding the respiratory signal in the echocardiographic machine. Results: All patients had daytime CSR (diurnal apnea-hypopnea index, AHI: 18.5, interquartile range: 15.3–39.5 events/h). Systolic pulmonary artery pressure and pulmonary vascular resistances (PVR) increased from hyperventilation to apnea (H 45.3 ± 11.4 vs A 52.4 ± 13.8 mmHg, p = 0.004, and H 3.3 ± 2.5 vs A 5.1 ± 3.2 Wood units, p = 0.0003, respectively), while acceleration time of the pulmonary artery decreased (H 110.1 ± 19.8 vs A 92.0 ± 19.9 ms, p = 0.001). During apnea a reduction of right and left ventricular outflow tract VTI (H 12.8 ± 4.9 versus A 9.9 ± 3.1, p = 0.002 and H 26.9 ± 8.8 versus A 22.8 ± 7.9 mm, p = 0.006, respectively), and a reduction in tricuspid annular plane systolic excursion (H 15.9 ± 4.4 versus A 14.4 ± 4.1 mm, p = 0.005) were also observed. Notably, PVR variation strongly correlated with chemosensitivity to hypercapnia (R = 0.89, p = 0.0004) and plasma norepinephrine level (R = 0.78, p = 0.003). Conclusions: In HF patients with CSR, an increase in pulmonary pressure and pulmonary vascular resistances was observed during apnea. Pulmonary vasoconstriction strongly correlated with chemosensitivity to hypercapnia and indexes of adrenergic activation

Influence of central apneas and chemoreflex activation on pulmonary artery pressure in chronic heart failure

Pulmonary artery hypertension (PH), associated with increased left ventricular (LV) diastolic pressure and pulmonary vasoconstriction, is frequently observed in heart failure (HF), where it holds prognostic significance. We hypothesized that Cheyne-Stokes respiration (CSR) may contribute to increased pulmonary arterartery pressure (PAP) and right ventricular (RV) remodeling in HF, via hypoxia/hypercapnia cycles and adrenergic activation by the chemoreflex stimulation

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype&ndash;phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation

Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease

Aims: Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement. Methods and results: Twenty-five MD patients (aged 46±3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P &lt; 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P &lt; 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO2/kg) than controls (P &lt; 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO2/kg (both P &lt; 0.001), and several indicators of autonomic imbalance (P &lt; 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P &lt; 0.05). Conclusions: Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation