Search Results (247)

Background and Clinical Significance: Obstructive sleep apnea (OSA) is a common comorbidity in patients with cardiac and metabolic disorders. The coexistence of central sleep apnea with Cheyne–Stokes breathing (CSA-CSB) in heart failure patients, especially those with preserved ejection fraction (HFpEF), represents a diagnostic and therapeutic challenge. Data on continuous positive airway pressure (CPAP) failure and successful adaptation to servo-ventilation (ASV) in the context of complex comorbidities remain limited. Case Presentation: We present the case of a 74-year-old male with a history of type 2 diabetes mellitus, paroxysmal atrial fibrillation, HFpEF, essential hypertension, and bladder carcinoma. He was referred for pre-operative OSA screening, reporting excessive daytime sleepiness, insomnia, and witnessed apneas. Initial respiratory polygraphy revealed severe sleep-disordered breathing with dominant CSA-CSB and moderate OSA. Laboratory investigations also revealed severe iron-deficiency anemia, which was managed with parenteral iron supplementation. The patient underwent CPAP titration, which led to modest improvement and residual high apnea–hypopnea index (AHI). After persistent symptoms and an inadequate CPAP response, an ASV device was initiated with significant clinical and respiratory improvement, demonstrating normalization of hypoxic burden and optimal adherence. Conclusions: CSA-CSB in HFpEF patients with anemia poses unique therapeutic difficulties. This case highlights the importance of individualized diagnostic and therapeutic strategies, including transitioning to ASV in CPAP-refractory cases, which can lead to improved adherence, reduced hypoxia, and better overall outcomes in high-risk patients. Full article

Background: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used to support patients with refractory cardiogenic shock or cardiac arrest. While femoral artery cannulation remains the most common arterial access, axillary artery cannulation has emerged as a valuable alternative in selected cases. Objective: This narrative review aims to synthesize current evidence and expert opinion on axillary artery cannulation in V-A ECMO, focusing on its technical feasibility, physiologic implications, and clinical outcomes. Methods: A comprehensive literature search was performed in PubMed and Scopus using relevant keywords related to ECMO, axillary artery, cannulation techniques, and outcomes. Emphasis was placed on prospective and retrospective clinical studies, expert consensus statements, and technical reports published over the past two decades. Results: Axillary cannulation provides antegrade aortic flow, potentially reducing the risk of differential hypoxia and improving upper body perfusion. However, the technique presents unique technical challenges and may carry risks such as hyperperfusion syndrome or arterial complications. Emerging data suggest favorable outcomes in selected patient populations when performed in experienced centers. Conclusions: Axillary cannulation represents a promising arterial access route in V-A ECMO, particularly in cases with contraindications to femoral cannulation or when upper-body perfusion is a concern. Further prospective studies are needed to better define patient selection criteria and long-term outcomes. Full article

Acute myocardial hypoxia/ischemia is associated with abnormal accumulation of myocardial lipids, including dihydroceramides. Here, we characterized how dihydroceramides are remodeled in response to hypoxia and assessed how dihydroceramide remodeling correlates to human cardiac pathophysiology. Hypoxia resulted in a marked accumulation of very-long-chain (VLC)-dihydroceramides in cultured HL-1 cardiomyocytes. In humans, we identified a correlation between the abundance of VLC-dihydroceramides in myocardial biopsies and arrhythmias and heart failure and showed that cardiac expression of CERS2, coding for an enzyme that promotes synthesis of VLC-dihydroceramides, was associated with signaling pathways linked to cardiac arrhythmia and cardiomyopathy. In cultured HL-1 cardiomyocytes, we showed that CerS2 knockdown reduced accumulation of VLC dihydroceramides and altered the expression of mediators regulating Ca²⁺ cycling and electrical conduction. In conclusion, our findings indicate that increased abundance of VLC-dihydroceramides, promoted by increased activity of CerS2 in response to hypoxia, could play a role in cardiac arrhythmias and heart failure. Full article

The yak (Bos grunniens) has exceptional hypoxia resilience, making it an ideal model for studying high-altitude adaptation. Here, we investigated the effects of oxygen concentration on yak cardiac fibroblast proliferation and the underlying molecular regulatory pathways using RNA sequencing (RNA-seq) and metabolic analyses. Decreased oxygen levels significantly inhibited cardiac fibroblast proliferation and activity. Intriguingly, while the mitochondrial DNA (mtDNA) content remained stable, we observed coordinated upregulation of mtDNA-encoded oxidative phosphorylation components. Live-cell metabolic assessment further demonstrated that hypoxia led to mitochondrial respiratory inhibition and enhanced glycolysis. RNA-seq analysis identified key hypoxia adaptation genes, including glycolysis regulators (e.g., HK2, TPI1), and hypoxia-inducible factor 1-alpha (HIF-1α), with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighting their involvement in metabolic regulation. The protein–protein interaction network identified three consensus hub genes across five topological algorithms (CCNA2, PLK1, and TP53) that may be involved in hypoxia adaptation. These findings highlight the importance of metabolic reprogramming underlying yak adaptation to hypoxia, providing valuable molecular insights into the mechanisms underlying high-altitude survival. Full article

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia. Full article

Background: Among patients with congenital heart disease, particularly those with a history of undergoing the Fontan operation, pregnancy presents a significant maternal–fetal risk, especially when complicated by severe valvular dysfunction. Lung reperfusion syndrome (LRS) is a rare but life-threatening complication occurring following valve intervention. Multidisciplinary management, including by Cardio-Obstetrics teams, is essential for optimizing outcomes in such high-risk cases. Methods: We present the case of a 37-year-old pregnant patient with previously repaired tetralogy of Fallot (via the Fontan procedure) who presented at 24 weeks gestation with worsening severe pulmonary stenosis and right-ventricular dysfunction. The patient had been lost to cardiac follow-up for over a decade. She experienced recurrent arrhythmias, including supraventricular and non-sustained ventricular tachycardia, prompting hospital admission. A multidisciplinary team recommended transcatheter pulmonic valve replacement (TPVR), performed at 28 weeks’ gestation. Results: Post-TPVR, the patient developed acute hypoxia and hypotension, consistent with Lung Reperfusion Syndrome, necessitating intensive cardiopulmonary support. Despite initial stabilization, progressive maternal respiratory failure and fetal compromise led to an emergent cesarean delivery. The neonate’s neonatal intensive care unit (NICU) course was complicated by spontaneous intestinal perforation, while the mother required intensive care unit (ICU)-level care and a bronchoscopy due to new pulmonary findings. She was extubated and discharged in stable condition on postoperative day five. Conclusions: This case underscores the complexity of managing severe congenital heart disease and valve pathology during pregnancy. Lung reperfusion syndrome should be recognized as a potential complication following TPVR, particularly in pregnant patients with Fontan physiology. Early involvement of a multidisciplinary Cardio-Obstetrics team and structured peripartum planning are critical to improving both maternal and neonatal outcomes. Full article

Background/Objectives: This study aims to investigate the potential etiopathogenesis of HFpEF development and identify possible different phenotypes of HFpEF in patients with chronic obstructive pulmonary disease (COPD) and systemic sclerosis-associated interstitial lung diseases (SS-ILDs). It could help clinicians improve early HFpEF personalized detection and management. Methods: This study included 150 patients with chronic lung diseases (CLDs), such as COPD and SS-ILD, who were outside of exacerbation, had no history of chronic heart failure (CHF), and had a left ventricular ejection fraction (LV EF) of ≥50%. The functional status of the lungs, heart, endothelial dysfunction, and acid–base balance was assessed. The results obtained were compared in groups of patients with CLD depending on the presence or absence of HF with preserved ejection fraction (HFpEF). The diagnosis of HFpEF was established based on the HFA-PEFF Score classification. Nonparametric statistical methods were used. Results: In patients with CLD, indicators such as age, longitudinal size of the right atrium, mid-regional pro-atrial natriuretic peptide (MR-proANP), and highly sensitive cardiac troponin T (hsTnT) were higher than in the group of patients without HFpEF. In patients with COPD and HFpEF, statistically significant changes were found in the volume of the left atrium. In patients with SS-ILD and HFpEF, statistically significant differenceswere found in SBP before and after the 6 min walk test (6MWT), the Borg scale before 6MWT, MR-proANP, and the longitudinal dimension of the right atrium. Conclusions: The results of our study allow us to identify two different mechanisms of HFpEF development: In patients with COPD, the predominant factor in the development of HFpEF was hypoxia, while in patients with SS-ILD, myocardial dysfunction with remodeling developed against the background of secondary pulmonary hypertension, highlighting the importance of phenotype-specific evaluation. These findings suggest potential approaches for personalized risk stratification and the development of targeted management strategies for patients with HFpEF. Full article

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling. Full article

Myocardial oxidative stress increases under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, leading to cellular damage. Inhibition of oxidative stress is involved in the cardioprotective effects of hydrogen sulfide (H₂S) during I/R and diabetes, and H₂S has the potential to protect the heart. However, the mechanism by which H₂S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H₂S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia–reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Treatment with NaHS (100 μM) as an H₂S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH₄) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2′-deoxyguanosine, and dihydrobiopterin (BH₂) concentrations. Additionally, the H₂S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC-1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD, and CAT, and decreased the expression of Keap1, p47phox and NOX4. Therefore, the treatment with the H₂S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and “cardiomyocyte ultrastructure”. Full article

Brain injury and cerebral inflammation are frequent complications following cardiopulmonary bypass (CPB) resulting in neurocognitive dysfunction, encephalopathy, or stroke. We compared cerebral inflammation induced by del Nido and histidine-tryptophan-α-ketoglutarate (HTK) cardioplegia in a porcine model. Pigs underwent 90 min cardiac arrest using HTK (n = 9) or Jonosteril^®-based del Nido cardioplegia (n = 9), followed by a 120 min reperfusion. Brain biopsies were collected and analyzed for the mRNA and protein expression of hypoxia-inducible factor-1α (HIF-1α) and cytokines. HTK induced a decrease in blood sodium, chloride, and calcium concentration (cross-clamp aorta: p_sodium < 0.01, p_chloride < 0.01, p_calcium < 0.01; 90 min ischemia: p_sodium < 0.01, p_chloride < 0.01, p_calcium = 0.03) compared to the more stable physiological electrolyte concentrations during del Nido cardioplegia. Hyponatremia and hypochloremia persisted after a 120 min reperfusion in the HTK group (p_sodium < 0.01, p_chloride = 0.04). Compared to del Nido, a higher mRNA expression of the proinflammatory cytokine IL-1β was detected in the frontal cortex (HTK: ∆Ct 6.5 ± 1.7; del Nido: ∆Ct 8.8 ± 1.5, p = 0.01) and the brain stem (HTK: ∆Ct 5.7 ± 1.5; del Nido: ∆Ct 7.5 ± 1.6, p = 0.02) of the HTK group. In conclusion, we showed comparability of HTK and del Nido for cerebral inflammation except for IL-1β expression. Based on our study results, we conclude that del Nido cardioplegia is a suitable and safe alternative to the conventional HTK solution. Full article

Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. Study Design: Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8–12-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1^−/−) mice. WT sham (S) and PHD1^−/−S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1^−/−MI group mices’ heart tissue was used for RNA isolation, then hybridization to a GeneChip™ Mouse Gene 1.0 ST Array as per the manufacturer’s instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. Results: The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1^−/−MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1^−/−MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1α DNA binding activity was higher in PHD1^−/−MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1^−/−MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, p < 0.05) showed 174 differentially regulated genes. Conclusions: In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction. Full article

While the beneficial effects of colchicine on inflammation and infarcted myocardium have been documented, its impact on cardiac fibroblast activation in the context of myocardial infarction (MI) remains unknown. This study aimed to investigate the effect of colchicine on the regulation of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and Interleukin-1β (IL-1β) expression in fibroblasts. 3T3 fibroblasts were exposed to 600 μM CoCl₂ for 24 h to simulate hypoxia, with normoxic cells as controls. Colchicine (1 μM) was administered for 24 h. ASC-NLRP3 colocalization and IL-1β expression were evaluated using immunofluorescence and flow cytometry, respectively. Data were analyzed using t-tests and one-way ANOVA with post hoc tests. Hypoxia treatment significantly induced apoptosis-associated speck-like protein containing a CARD (ASC)-NLRP3 colocalization (p < 0.05). Colchicine treatment of hypoxic 3T3 cells reduced ASC-NLRP3 colocalization, although this reduction was not statistically significant. Additionally, IL-1β expression was significantly inhibited in colchicine-treated hypoxic 3T3 cells compared to those treated with placebo (p < 0.05). The findings of this study indicate that colchicine treatment inhibits the activation of the NLRP3 inflammasome by disrupting the colocalization of ASC and NLRP3, thereby reducing IL-1β expression in CoCl₂-treated 3T3 cells. Full article

In rats, normobaric hypoxia significantly reduced left ventricular (LV) inotropic function while right ventricular (RV) function was not impaired. In parallel, the animals developed pulmonary edema and inflammation. In the present study, we investigated whether cardiac function and pulmonary injury would aggravate after three and six days of hypoxia exposure or whether cardiopulmonary reactions to prolonged hypoxia would become weaker due to hypoxic acclimatization. Sixty-four female rats were exposed for 72 or 144 h to normoxia. They received a low-rate infusion (0.1 mL/h) with 0.9% NaCl solution. We evaluated indicators of the general condition, blood gas parameters, and hemodynamic function of the rats. In addition, we performed histological and immunohistochemical analyses of the lung. Despite a significant increase in hemoglobin concentration, the LV function deteriorated with prolonged hypoxia. In contrast, the RV systolic pressure and contractility steadily increased by six days of hypoxia. The pulmonary edema and inflammation persisted and rather increased with prolonged hypoxia. Furthermore, elevated protein concentration in the pleural fluid indicated capillary wall stress, which may have aggravated the pulmonary edema. In conclusion, six days of hypoxia and NaCl infusion place significant stress on the cardiopulmonary system of rats, as is also reflected by the 33% of premature deaths in this rat group. Full article

Cell proliferation and migration mediated by hypoxia-inducible factor-1α (HIF-1α) are important processes of hypoxic cardiac vascular remodeling. HIF-1α also regulates the physiological hypoxic adaptation of the coronary artery in the yak heart, but the potential mechanism remains to be completely elucidated. In this study, coronary artery proliferation increased with age and hypoxia adaptation time. In vitro analysis showed that hypoxia can promote the proliferation of coronary vascular smooth muscle cells (CASMCs). Meanwhile, HIF-1α plays an important role in the regulation of proliferation and migration under hypoxia. Autophagy regulates cell proliferation and migration to participate in hypoxia adaptation in plateau animals. Here, the level of autophagy increased significantly in yak coronary arteries with age and was regulated by HIF-1α-mediated hypoxia. In addition, autophagy could also mediate the hypoxic effect on the proliferation and migration of CASMCs. In summary, the results revealed that the increase in yak heart coronary artery thickening with age increases vascular smooth muscle cell proliferation and migration, mainly achieved through hypoxia-mediated HIF-1α-regulated autophagy. These results contribute to understanding how the heart adapts to life in a hypoxic environment. Full article

Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs’ hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies. Full article