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Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.
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MicroARNs , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Función Ventricular Derecha , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratas , Humanos , Ratones , Masculino , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Modelos Animales de Enfermedad , Monocrotalina , Proliferación Celular/genética , Miocitos del Músculo Liso/metabolismo , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/metabolismo , Remodelación Vascular/genética , Ratas Sprague-DawleyRESUMEN
Obesity is among the most common chronic disorders, worldwide. It is a complex disease that reflects the interactions between environmental influences, multiple genetic allelic variants, and behavioral factors. Recent developments have also shown that biological conditions in utero play an important role in the programming of energy homeostasis systems and might have an impact on obesity and metabolic disease risk. The corticotropin-releasing hormone (CRH) family of neuropeptides, as a central element of energy homeostasis, has been evaluated for its role in the pathophysiology of obesity. This review aims to summarize the relevance and effects of the CRH family of peptides in the pathophysiology of obesity spanning from fetal life to adulthood.
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Hormona Liberadora de Corticotropina , Obesidad , Humanos , Hormona Liberadora de Corticotropina/metabolismo , Obesidad/metabolismo , Embarazo , Femenino , Metabolismo Energético/fisiología , Adulto , Efectos Tardíos de la Exposición Prenatal , Homeostasis/fisiologíaRESUMEN
Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a "super-fuel" because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels-such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors-have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.
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Heart failure (HF) is a complex clinical syndrome associated with high rates of morbidity and mortality. Over the years, it has been crucial to find accurate biomarkers capable of doing a precise monitor of HF and provide an early diagnosis. Of these, it has been established an important role of natriuretic peptides in HF assessment. Moreover, the development of biosensors has been garnering interest as new diagnostic medical tools. In this review we first provide a general overview of HF, its pathogenesis, and diagnostic features. We then discuss the role of natriuretic peptides in heart failure by characterizing them and point out their potential as biomarkers. Finally, we adress the evolution of biosensors development and the available natriuretic peptides biosensors for disease monitoring.
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Técnicas Biosensibles , Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Humanos , Enfermedades Cardiovasculares/diagnóstico , Péptidos Natriuréticos , Biomarcadores , Insuficiencia Cardíaca/diagnósticoRESUMEN
Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Ratones , Ratas , Animales , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Función Ventricular Derecha , Arteria Pulmonar , Hipertensión Pulmonar Primaria Familiar , Hipertensión Pulmonar/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
The hormone relaxin-2 has emerged as a promising player in regulating the physiology of the cardiovascular system. Through binding to the relaxin family peptide receptor 1 (RXFP1), this hormone elicits multiple physiological responses including vasodilation induction, reduction of inflammation and oxidative stress, and angiogenesis stimulation. The role of relaxin-2, or its recombinant human form known as serelaxin, has been investigated in preclinical and clinical studies as a potential therapy for cardiovascular diseases, especially heart failure, whose current therapy is still unoptimized. However, evidence from past clinical trials has been inconsistent and further research is needed to fully understand the potential applications of relaxin-2. This review provides an overview of serelaxin use in clinical trials and discusses future directions in the development of relaxin-2 mimetics, which may offer new therapeutic options for patients with heart failure.
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Potassium channel subfamily K member 3 (KCNK3), encoded by the KCNK3 gene, is part of the two-pore domain potassium channel family, constitutively active at resting membrane potentials in excitable cells, including smooth muscle and cardiac cells. Several physiological and pharmacological mediators, such as intracellular signalling pathways, extracellular pH, hypoxia and anaesthetics, regulate KCNK3 channel function. Recent studies show that modulation of KCNK3 channel expression and function strongly influences pulmonary vascular cell and cardiomyocyte function. The altered activity of KCNK3 in pathological situations such as atrial fibrillation, pulmonary arterial hypertension and right ventricular dysfunction demonstrates the crucial role of KCNK3 in cardiovascular homeostasis. Furthermore, loss of function variants of KCNK3 have been identified in patients suffering from pulmonary arterial hypertension and atrial fibrillation. This review focuses on current knowledge of the role of the KCNK3 channel in pulmonary circulation and the heart, in healthy and pathological conditions.
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Fibrilación Atrial , Canales de Potasio de Dominio Poro en Tándem , Hipertensión Arterial Pulmonar , Humanos , Circulación Pulmonar , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Potenciales de la Membrana , Pulmón/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismoRESUMEN
Prevalence of congenital heart diseases worldwide is around 9 per 1000 newborns, 20% of which affect the pulmonary valve or right ventricular outflow tract. As survival after surgical repair of these defects has improved over time, there is the need to address the long-term issues of older children and young adults with "repaired" congenital heart diseases. In recent decades, the most used types of valves are the mechanical and bioprosthetic valves. Despite improving patients' quality of life, these effects are suboptimal due to their limitations, such as the inability to grow and adapt to hemodynamic changes. These issues have led to the search for living valve solutions through tissue engineering to respond to these challenges. This article aims to review the performance of traditional pulmonary valves and understand how tissue engineering-based valves can improve the management of these patients.
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Bioprótesis , Cardiopatías Congénitas , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Válvula Pulmonar , Recién Nacido , Niño , Adulto Joven , Humanos , Adolescente , Válvula Pulmonar/cirugía , Ingeniería de Tejidos , Calidad de Vida , Resultado del Tratamiento , Cardiopatías Congénitas/cirugíaRESUMEN
While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.
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Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Volumen Sistólico , Calidad de Vida , ComorbilidadRESUMEN
Over the last years, the importance of microRNAs (miRNAs) has increasingly been recognised. Each miRNA is a short sequence of non-coding RNA that influences countless genes' expression and, thereby, contributes to several physiological pathways and diseases. It has been demonstrated that miRNAs participate in the development of many cardiovascular diseases (CVDs). This review synopsises the most recent studies emphasising miRNA's influence in several CVDs affecting dogs and cats. It provides a concise outline of miRNA's biology and function, the diagnostic potential of circulating miRNAs as biomarkers, and their role in different CVDs. It also discusses known and future roles for miRNAs as potential clinical biomarkers and therapeutic targets. So, this review gives a comprehensive outline of the most relevant miRNAs related to CVDs in Veterinary Medicine.
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BACKGROUND: Heart failure (HF) is a high prevalent syndrome with significant burden worldwide. B-type natriuretic peptide (BNP) and N-terminal proBNP are the gold standard biomarkers in HF management. Although useful in clinical practice, they have limitations as their expression can be influenced by ventricular function, aging, obesity, renal failure and atrial arrhythmias. MicroRNAs have recently emerged as potential diagnostic and prognostic biomarkers, given that they are related to cell growth, proliferation, differentiation, and metabolism. An increasing amount of research has highlighted some microRNAs for their potential as HF biomarkers. However, different study designs, methods and study groups have led to inconsistent results. METHODS AND RESULTS: We performed a systematic search of available literature on Pubmed and Scopus reporting the prognostic value of microRNAs in HF, followed by a review of risk of bias, according to Quadas Group Standards. Simultaneously, microRNAs' potential as differential diagnosis and severity biomarkers was also analyzed. Studies have described circulating microRNA as potential diagnostic, prognostic, and severity markers. Mir-622, -519 and -499 were significantly related to HF with reduced ejection fraction, whereas miR-22-3p revealed greater ability as a severity biomarker. Let-7i-5p, miR-223-5p, miR-423-5p, miR-21, miR-1306-5p and miR-122 serum expressions presented a consistent correlation with HF prognosis. Furthermore, identified miR targets were associated with signaling pathways already known to be involved in HF progression. CONCLUSION: Several miRs were related to HF pathophysiology and demonstrated potential as biomarkers for disease progression. MicroRNAs have a promising role in HF, and although unquestionable, we require a deeper and broader understanding of their role and function for future research.
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MicroARN Circulante , Insuficiencia Cardíaca , MicroARNs , Biomarcadores , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Péptido Natriurético Encefálico , PronósticoRESUMEN
Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.
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Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K+, Ca2+, Na+, and Cl- channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Enfermedades Vasculares , Humanos , Hipertensión Pulmonar/patología , Canales Iónicos/genética , Canales Iónicos/metabolismo , VasoconstricciónRESUMEN
Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.
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Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (Pâ¯=â¯0.022), hepatomegaly (Pâ¯=â¯0.007) and sodium retention score (ρâ¯=â¯0.37, Pâ¯=â¯0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρâ¯=â¯-0.37, Pâ¯=â¯0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (Pâ¯=â¯0.027), right ventricle dilation (Pâ¯=â¯0.008), and higher systolic pulmonary artery pressure (ρâ¯=â¯0.34, Pâ¯=â¯0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (râ¯=â¯0.22, Pâ¯=â¯0.055) and inversely with uric acid (râ¯=â¯0.24, Pâ¯=â¯0.029) and total (râ¯=â¯-0.30, Pâ¯=â¯0.007) and low-density lipoprotein cholesterol (râ¯=â¯-0.23, Pâ¯=â¯0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients.
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Insuficiencia Cardíaca , Hipertensión Pulmonar , Anciano , Biomarcadores , Ecocardiografía , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Humanos , Hipertensión Pulmonar/diagnóstico , Masculino , UrocortinasRESUMEN
The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.
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Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Urocortinas/sangre , Animales , HumanosRESUMEN
AIMS: Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. METHODS AND RESULTS: We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. CONCLUSIONS: Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.
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Presión Arterial , Proteínas del Tejido Nervioso/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Hipertensión Arterial Pulmonar/etiología , Arteria Pulmonar/metabolismo , Disfunción Ventricular Izquierda/complicaciones , Función Ventricular Izquierda , Animales , Modelos Animales de Enfermedad , Mutación , Proteínas del Tejido Nervioso/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Ratas Transgénicas , Transducción de Señal , Remodelación Vascular , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Presión VentricularRESUMEN
NTP42 is a novel antagonist of the thromboxane A2 receptor (TP) in development for the treatment of pulmonary arterial hypertension (PAH). Recent studies demonstrated that NTP42 and TP antagonism have a role in alleviating PAH pathophysiology. However, the efficacy of NTP42 when used in combination with existing PAH therapies has not yet been investigated. Herein, the Sugen 5416/hypoxia (SuHx)-induced PAH model was employed to evaluate the efficacy of NTP42 when used alone or in dual-therapy with Sildenafil, a PAH standard-of-care. PAH was induced in rats by injection of Sugen 5416 and exposure to hypoxia for 21 days. Thereafter, animals were treated orally twice-daily for 28 days with either vehicle, NTP42 (0.05 mg/kg), Sildenafil (50 mg/kg), or NTP42+Sildenafil (0.05 mg/kg + 50 mg/kg, respectively). While Sildenafil or NTP42 mono-therapy led to non-significant reductions in the SuHx-induced rises in mean pulmonary arterial pressure (mPAP) or right ventricular systolic pressure (RSVP), combined use of NTP42+Sildenafil significantly reduced these increases in mPAP and RVSP. Detailed histologic analyses of pulmonary vessel remodelling, right ventricular hypertrophy and fibrosis demonstrated that while NTP42 and Sildenafil in mono-therapy resulted in significant benefits, NTP42+Sildenafil in dual-therapy showed an even greater benefit over either drug used alone. In summary, combined use of NTP42+Sildenafil in dual-therapy confers an even greater benefit in treating or offsetting key aetiologies underlying PAH. These findings corroborate earlier preclinical findings suggesting that, through antagonism of TP signalling, NTP42 attenuates PAH pathophysiology, positioning it as a novel therapeutic for use alone or in combination therapy regimens.
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Hipoxia/tratamiento farmacológico , Indoles/toxicidad , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Pirroles/toxicidad , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Citrato de Sildenafil/administración & dosificación , Inhibidores de la Angiogénesis/toxicidad , Animales , Quimioterapia Combinada , Hipoxia/inducido químicamente , Hipoxia/metabolismo , Masculino , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/metabolismo , Ratas , Ratas Wistar , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Resultado del Tratamiento , Vasodilatadores/administración & dosificaciónRESUMEN
Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.