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.
The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart.
- MeSH
- fibroblasty patologie MeSH
- lidé MeSH
- myokard patologie MeSH
- remodelace komor MeSH
- srdeční komory patologie MeSH
- srdeční selhání * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
AIMS: The goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs). METHODS: We examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234). RESULTS: Myocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02). CONCLUSION: We found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs.
- Publikační typ
- časopisecké články MeSH
Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.
- MeSH
- biologické markery krev MeSH
- biopsie MeSH
- dospělí MeSH
- ELISA MeSH
- interleukin-1 receptor-like 1 protein krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myokard patologie MeSH
- myokarditida krev komplikace diagnóza MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- následné studie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- sexuální faktory MeSH
- srdeční selhání krev diagnóza etiologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
