BUSCADOR RECOLECTA

Exercise intolerance remains a major unmet medical need in patients with heart failure (HF). Skeletal myopathy
is currently considered as the major limiting factor for exercise capacity in HF patients. On the other hand,
emerging evidence suggest that physical exercise can decrease morbidity and mortality in HF patients. Therefore,
mechanistic insights into skeletal myopathy may uncover critical aspects for therapeutic interventions to
improve exercise performance in HF. Emerging data reviewed in this article suggest that the assessment of
circulating myokines (molecules synthesized and secreted by skeletal muscle in response to contraction that
display autocrine, paracrine and endocrine actions) may provide new insights into the pathophysiology, phenotyping
and prognostic stratification of HF-related skeletal myopathy. Further studies are required to determine
whether myokines may also serve as biomarkers to personalize the modality and dose of physical training
prescribed for patients with HF and exercise intolerance. In addition, the production and secretion of myokines in
patients with HF may interact with systemic alterations (e.g., inflammation and metabolic disturbances),
frequently present in patients with HF. Furthermore, myokines may exert beneficial or detrimental effects on
cardiac structure and function, which may influence adverse cardiac remodelling and clinical outcomes in HF
patients. Collectively, these data suggest that a deeper knowledge on myokines regulation and actions may lead
to the identification of novel physical exercise-based therapeutic approaches for HF patients., Instituto de Salud Carlos III (Spain) (CB16/11/00483 to JD, PI18/01469 co-financed by “Fondos Europeos de Desarrollo Regional to AG, CP18/0150 Miguel Servet Fellow to AG-H); Ministerio de Ciencia e Innovación (Spain) (PID2020-113098RB-I00 to MI); European Commission CRUCIAL project (grant agreement 848109 to AG). Open access funding provided by Universidad Pública de Navarra.

In hypertensive patients with heart failure (HF) a serum biomarker combination of high
carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide
of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular
phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction
(DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated
the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection
fraction (HFpEF). Hypertensives (n = 365), 232 non-HF and 133 HFpEF, were studied, and 35%
non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2
or urine albumin-to-creatinine ratio ≥ 30 mg/g). Specific immunoassays were performed to determine
biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination.
A comparison with non-HF showed that the biomarker combination presence was increased in
HFpEF patients, being associated with CKD in all patients. CKD influenced the association of
the biomarker combination and HFpEF (p for interaction ≤ 0.019). The E:e’ ratio was associated
with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with
the biomarker combination exhibited higher (p = 0.016) E:e’ ratio than those without the pattern.
These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in
hypertensive HFpEF patients.

Heart failure with preserved ejection fraction (HFpEF) is a complex heterogeneous disease for which our pathophysiological
understanding is still limited and specifc prevention and treatment strategies are lacking. HFpEF is characterised by diastolic dysfunction and cardiac remodelling (fbrosis, infammation, and hypertrophy). Recently, microvascular dysfunction
and chronic low-grade infammation have been proposed to participate in HFpEF development. Furthermore, several recent
studies demonstrated the occurrence of generalized lymphatic dysfunction in experimental models of risk factors for HFpEF,
including obesity, hypercholesterolaemia, type 2 diabetes mellitus (T2DM), hypertension, and aging. Here, we review the
evidence for a combined role of coronary (micro)vascular dysfunction and lymphatic vessel alterations in mediating key pathological steps in HFpEF, including reduced cardiac perfusion, chronic low-grade infammation, and myocardial oedema, and
their impact on cardiac metabolic alterations (oxygen and nutrient supply/demand imbalance), fbrosis, and cardiomyocyte
stifness. We focus primarily on HFpEF caused by metabolic risk factors, such as obesity, T2DM, hypertension, and aging.

BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling
and functionally involved in heart failure development, a leading cause
of deaths worldwide. Clinically, no therapeutic strategy is available that
specifically attenuates maladaptive responses of cardiac fibroblasts, the
effector cells of fibrosis in the heart. Therefore, our aim was to develop
novel antifibrotic therapeutics based on naturally derived substance library
screens for the treatment of cardiac fibrosis.
METHODS: Antifibrotic drug candidates were identified by functional
screening of 480 chemically diverse natural compounds in primary human
cardiac fibroblasts, subsequent validation, and mechanistic in vitro and
in vivo studies. Hits were analyzed for dose-dependent inhibition of
proliferation of human cardiac fibroblasts, modulation of apoptosis, and
extracellular matrix expression. In vitro findings were confirmed in vivo
with an angiotensin II–mediated murine model of cardiac fibrosis in both
preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat
model. To investigate the mechanism underlying the antifibrotic potential
of the lead compounds, treatment-dependent changes in the noncoding
RNAome in primary human cardiac fibroblasts were analyzed by RNA
deep sequencing.
RESULTS: High-throughput natural compound library screening
identified 15 substances with antiproliferative effects in human cardiac
fibroblasts. Using multiple in vitro fibrosis assays and stringent selection
algorithms, we identified the steroid bufalin (from Chinese toad venom)
and the alkaloid lycorine (from Amaryllidaceae species) to be effective
antifibrotic molecules both in vitro and in vivo, leading to improvement
in diastolic function in 2 hypertension-dependent rodent models of
cardiac fibrosis. Administration at effective doses did not change plasma
damage markers or the morphology of kidney and liver, providing the first
toxicological safety data. Using next-generation sequencing, we identified
the conserved microRNA 671-5p and downstream the antifibrotic
selenoprotein P1 as common effectors of the antifibrotic compounds.
CONCLUSIONS: We identified the molecules bufalin and lycorine as drug
candidates for therapeutic applications in cardiac fibrosis and diastolic
dysfunction.