Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Cromosomas Humanos Y , Humanos , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/mortalidad , Masculino , Cardiomiopatías/genética , Cromosomas Humanos Y/genética , Anciano , Femenino , Mosaicismo , Prealbúmina/genética , Persona de Mediana EdadRESUMEN
BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Ratones , Animales , Anciano , Anciano de 80 o más Años , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Función Ventricular Izquierda , Hematopoyesis Clonal/genética , Disfunción Ventricular Izquierda/genéticaRESUMEN
We present a brief introduction of loss of Y chromosome (LOY) in blood and describe the known risk factors for this condition. We then overview the associations between LOY and age-related disease traits. Finally, we discuss murine models and the potential mechanisms by which LOY contributes to disease.
Asunto(s)
Cromosomas Humanos Y , Salud del Hombre , Humanos , Animales , Masculino , Ratones , Mosaicismo , Leucocitos , FenotipoRESUMEN
PURPOSE OF REVIEW: Somatic mutations, described as noninherited changes in DNA that arise and are passed on to descendant cells, are well known to cause cancers; however, it is increasingly appreciated that the propagation of somatic mutations within a tissue may have a role in causing nonneoplastic disorders and abnormalities in elderly individuals. The nonmalignant clonal expansion of somatic mutations in the hematopoietic system is termed clonal hematopoiesis. This review will briefly discuss how this condition has been linked to various age-related diseases outside the hematopoietic system. RECENT FINDINGS: Clonal hematopoiesis, resulting from leukemic driver gene mutations or mosaic loss of the Y chromosome in leukocytes, is associated with the development of various forms of cardiovascular disease, including atherosclerosis and heart failure, in a mutation-dependent manner. SUMMARY: Accumulating evidence shows that clonal hematopoiesis represents a new mechanism for cardiovascular disease and a new risk factor that is as prevalent and consequential as the traditional risk factors that have been studied for decades.
Asunto(s)
Enfermedades Cardiovasculares , Humanos , Masculino , Anciano , Enfermedades Cardiovasculares/etiología , Hematopoyesis Clonal/genética , Cromosomas Humanos Y , Hematopoyesis/genética , Mosaicismo , MutaciónRESUMEN
Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor ß1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.