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2.
Eur J Heart Fail ; 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38896048

RESUMEN

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) has been firmly established; however, the entity of diabetic myocardial disorder (previously called diabetic cardiomyopathy) remains a matter of debate. Diabetic myocardial disorder was originally described as the occurrence of myocardial structural/functional abnormalities associated with T2DM in the absence of coronary heart disease, hypertension and/or obesity. However, supporting evidence has been derived from experimental and small clinical studies. Only a minority of T2DM patients are recognized as having this condition in the absence of contributing factors, thereby limiting its clinical utility. Therefore, this concept is increasingly being viewed along the evolving HF trajectory, where patients with T2DM and asymptomatic structural/functional cardiac abnormalities could be considered as having pre-HF. The importance of recognizing this stage has gained interest due to the potential for current treatments to halt or delay the progression to overt HF in some patients. This document is an expert consensus statement of the Heart Failure Association of the ESC and the ESC Working Group on Myocardial & Pericardial Diseases. It summarizes contemporary understanding of the association between T2DM and HF and discuses current knowledge and uncertainties about diabetic myocardial disorder that deserve future research. It also proposes a new definition, whereby diabetic myocardial disorder is defined as systolic and/or diastolic myocardial dysfunction in the presence of diabetes. Diabetes is rarely exclusively responsible for myocardial dysfunction, but usually acts in association with obesity, arterial hypertension, chronic kidney disease and/or coronary artery disease, causing additive myocardial impairment.

3.
ESC Heart Fail ; 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38806171

RESUMEN

In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

4.
Eur J Heart Fail ; 26(4): 707-729, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38639017

RESUMEN

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.


Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Circulación Pulmonar , Función Ventricular Derecha , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/terapia , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Función Ventricular Derecha/fisiología , Circulación Pulmonar/fisiología
5.
Geroscience ; 46(5): 4543-4561, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38656649

RESUMEN

INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.


Asunto(s)
Insuficiencia Cardíaca , Hipertensión , Miocitos Cardíacos , Ratas Transgénicas , Remodelación Ventricular , Animales , Masculino , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Hipertensión/metabolismo , Hipertensión/fisiopatología , Ratas , Remodelación Ventricular/fisiología , Factores Sexuales , Miocitos Cardíacos/metabolismo , Conectina/metabolismo , Modelos Animales de Enfermedad , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ecocardiografía , Fosforilación , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología
6.
Int J Mol Sci ; 25(3)2024 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-38339143

RESUMEN

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free ß-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free ß-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-ß-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.


Asunto(s)
Aborto Habitual , Proteínas Gestacionales , Embarazo , Femenino , Humanos , Proteína Plasmática A Asociada al Embarazo/metabolismo , Factor de Crecimiento Placentario , Primer Trimestre del Embarazo , Placenta/metabolismo , Gonadotropina Coriónica Humana de Subunidad beta , Biomarcadores , Aborto Habitual/diagnóstico , Proteínas Sanguíneas
7.
Clin Chem Lab Med ; 62(7): 1393-1401, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38205624

RESUMEN

OBJECTIVES: Serum angiotensin-converting enzyme (ACE) is the only biomarker routinely used in the laboratory diagnostics of sarcoidosis, and ACE inhibitor (ACEi) drugs are among the most prescribed drugs worldwide. Taking ACEi can mislead medical teams by lowering ACE activity, delaying diagnosis and giving a false impression of disease activity of sarcoidosis. We aimed to develop a simple method to detect the presence of ACEi drugs in samples, to investigate the ACEi medication-caused interference and consequences in a retrospective study. METHODS: ACE activity and the level of ACE inhibition were determined for 1823 patients with suspected sarcoidosis. These values were compared with the therapeutic information at the first and follow-up visits. RESULTS: A total of 302 patients had biochemical evidence of an ACEi drug effect during diagnostic ACE activity testing. In their case, ACE activity was significantly lower (median(IQR): 4.41 U/L(2.93-6.72)) than in patients not taking ACEi (11.32 U/L(8.79-13.92), p<0.01). In 62 sarcoidosis patients, the ACEi reduced ACE activity to the reference range or below. Only in 40 % of the cases was the medication list recorded in the outpatient chart and only in 3 cases was low ACE activity associated with ACEi use. 67 % of the repeated ACE activity measurements were also performed during ACEi therapy. CONCLUSIONS: Our study revealed that the use of ACEi is common in patients with suspected sarcoidosis. The ACE activity lowering effect of ACEi drugs may escape the attention of medical teams which can lead to diagnostic errors and unnecessary tests. Nevertheless, these pitfalls can be avoided by using a method suggested by our team.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Peptidil-Dipeptidasa A , Sarcoidosis , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/diagnóstico , Sarcoidosis/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Peptidil-Dipeptidasa A/sangre , Adulto , Biomarcadores/sangre
8.
J Reprod Immunol ; 161: 104172, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38141514

RESUMEN

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.


Asunto(s)
Preeclampsia , Embarazo , Femenino , Humanos , Preeclampsia/diagnóstico , Preeclampsia/prevención & control , Placenta/metabolismo , Proteómica , Objetivos , Primer Trimestre del Embarazo , Biomarcadores/metabolismo
9.
Biomedicines ; 11(12)2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-38137544

RESUMEN

Angiotensin-converting enzyme (ACE) inhibitors are the primarily chosen drugs to treat various cardiovascular diseases, such as hypertension. Although the most recent guidelines do not differentiate among the various ACE inhibitory drugs, there are substantial pharmacological differences. GOAL: Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. METHODS: We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. RESULTS: Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. CONCLUSION: The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

10.
Animals (Basel) ; 14(1)2023 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-38200866

RESUMEN

Sound analysis is an important field of research for improving precision livestock farming systems. If the information carried by livestock sounds is interpreted correctly, it could be used to improve management and welfare assessment in this field. Therefore, we hypothesized that the nasal vocalization of a mother cow could have a calming effect on conspecifics. The nasal vocalization in our study was recorded from a mother cow (not part of the test herd) while it was licking its day-old calf. The raw sound was analyzed, cleaned from noises, and the most representative vocalization was lengthened to two minutes. Thirty cows having calves were randomly selected from eighty Hungarian grey cattle cows. Two test days were selected, one week apart; the weather circumstances in both days were similar. The herd was collected in a paddock, and the test site (a restraining crate with a headlock) was 21 m away from them. The cows from the herd were gently moved to the restraining crate, and, after the installation of the headlock, Polar® heart rate monitors were fixed on the animals. The recording of the RR intervals was carried out for two minutes. On day one of the test, the processed nasal sound was played to every second cow during the heart rate monitoring. When the sound ended, the heart rate monitor was removed. On test day two, the sound and no sound treatments were switched among the participating cows. At the end of the measurement, the headlock was opened, letting the animals out voluntarily, and a flight test was performed along a 5 m distance. The time needed to pass the 5 m length was measured with a stopwatch and divided by the distance. The RR intervals were analyzed with the Kubios HRV Standard (ver. 3.5.0) software. The following data were recorded for the entire measurement: average and maximum heart rate; SD1 and SD2; pNN50; VLF, LF, and HF. The quasi-periodic signal detected in the sound analyses can hardly be heard, even when it is enhanced to the maximum. This can be considered a vibration probably caused by the basis of articulation, such as a vibration of the tongue, for example. The SD2/SD1 ratio (0.97 vs. 1.07 for the animals having no sound and sound played, respectively, p = 0.0110) and the flight speed (0.92 vs. 1.08 s/m for the animals having no sound and sound played, respectively, p = 0.0409) indicate that the sound treatment had a calming effect on the restrained cows. The day of the test did not influence any of the measured parameters; therefore, no effect of the routine was observed. The yes-no sequence of the sound treatment significantly reduced the pNN50 and flight speed values, suggesting a somewhat more positive association with the headlock and the effectiveness of the processed nasal sound. In conclusion, we have demonstrated that, by means of sound analyses, not only information about individuals and the herd can be gathered but that, with proper processing, the sound obtained can be used to improve animal welfare.

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