Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

Abstract

Novel risk stratification and non-invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant. Clonal hematopoiesis (CH) refers to the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes.The purpose of this study was to investigate the association between CH and OHT.Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 [42%] vs. 15 [15%], p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4-6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than

Increased clonal hematopoiesis involving DNA damage response genes in patients undergoing lung transplantation

“…Within a prospective subgroup, pretransplant specimens could detect 83% of DDR variants that occurred after transplant, including all variants with VAF greater than 1%. This finding is unique to lung transplant recipients; recently, the reported incidence of CH in DDR genes ( TP53 and PPM1D ) was only 4% in heart transplant recipients ( 30 ). DDR genes TP53 , ATM , and PPM1D are known to have regulatory roles in cell division, survival, and tumor suppression ( 2 ).…”

Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy

“…However, specific CH mutations may have distinct inflammatory profiles. 9,22 We observed that DNMT3A-driven CH was associated with IL-9 and CXCL12. TET2-driven CH was associated with the higher circulating levels of a different array of cytokines/chemokines including troponin I.…”

“…Interestingly, somatic mutations in haematopoietic stem cells occurring in the first decades of life are polyclonal and have unknown long-term effects. 27,28 Many studies have focused on the most common gene variants, such as DNMT3A, TET2 and ASXL1 9,12,22,26,29 , present in 17% of HCM patients with CH mutations. Unsurprisingly, we found that HCM patients with these specific genes showed worse clinical phenotype and outcome, similarly to other patient cohorts.…”

“…In addition, the levels of B-type natriuretic peptide and cardiac troponin I were evaluated. For CH genetic analysis, a single molecule molecular inversion probe method targeting 35 myeloid genes related to CH was implemented as previously described 9,22 . To call mutations we used SmMIP-tools 26 .…”

Clonal Hematopoiesis and the Heart: a Toxic Relationship

“…As will be reviewed here, the evidence implicating CH in poor cardiovascular outcomes is extensive, which is likely a primary driver for the association of CH with decreased OS in the general population [16]. The relationship between CH and coronary artery disease (CAD) was the first non-oncologic outcome to be recognized [15], with further cardiologic studies also linking CH to progression of heart failure [17][18][19][20], aortic aneurysm [21], pulmonary hypertension [22], deterioration from cardiogenic shock [23], aortic stenosis [24], poor outcomes after TAVR [25] or orthotopic heart transplantation [26], and increased sensitivity to cardiotoxic chemotherapy [27]. Here we will review the evidence connecting CH to cardiovascular outcomes, mechanistic explanations, potential practice changes, and future research directions.…”