Clonal hematopoiesis of indeterminate potential (CHIP) is both clinically relevant in cardiovascular disease and an independent cardiovascular risk factor of the outcomes of patients with cardiogenic shock (CS), according to a new analysis. Matthias Böhme, MD, of Leipzig University Hospital, Germany, Steffen Desch, MD, of the Heart Center Leipzig, and colleagues reported these findings from an analysis of the CULPRIT-SHOCK trial Monday online and in the Oct. 18 issue of the Journal of the American College of Cardiology. The international, randomized CULPRIT-SHOCK trial showed a lower rate of the composite of mortality or renal replacement therapy at 30 days in patients with multivessel coronary artery disease who presented with acute myocardial infarction (AMI) complicated by CS who underwent percutaneous coronary intervention (PCI) of only the culprit lesion as compared to those who underwent immediate multivessel PCI. CHIP is common in older people and is associated with a higher risk of hematologic malignancies and cardiovascular disease. Therefore, this analysis of the CULPRIT-SHOCK trial sought to determine the prognostic impact of CHIP in AMI complicated by CS. CS occurs in up to 10% of patients immediately following AMI and is associated with mortality rates of nearly 40% at 30 days and 50% at 1 year. Survival depends on the severity of the shock, the phenotypes, and the cause, but also on risk modifiers such as age, comorbidities, previous cardiac arrest, and systemic inflammatory response. In an accompanying editorial, Jean-Philippe Collet MD, PhD, from the Hôpital Pitié-Salpêtrière, Paris, and colleagues noted that hematopoietic stem cells acquire random mutations constantly over years, and a few of these mutations may affect a “driver” gene and lead to the progressive expansion of the mutant cell. This so-called CHIP, defined by the presence of multiple somatic genomic non-leukemogenic variants from whole-exome sequencing, is present in >20% of cancer-free individuals >60 years old and is associated with an increased risk of coronary artery disease and ischemic stroke, independent of conventional cardiovascular risk factors. This association is mainly driven by acquired mutations in DNMT3A, TET2, ASXL1, and JAK2. Böhme, Desch and colleagues explained that CHIP was at first considered a subclinical condition that can progress to overt hematologic malignancy, with an annual rate of 1%, but that it is now also known to be associated with a higher risk of atherosclerotic vascular diseases and poorer outcomes in chronic ischemic heart failure. The current analysis examined blood samples that were obtained at randomization in the CULPRIT-SHOCK trial from 446 patients. The investigators assessed CHIP using what they termed a next-generation sequencing approach that targeted the most commonly mutated genes. The primary outcome was the same as the main trial, all-cause mortality and renal replacement therapy at 30 days. CHIP variants with a variant allele frequency of 2% or greater were detected in 29% (n=129) of the analysis population, most commonly in the DNMT3A gene, which housed 47% of all mutations, or TET2 genes, which accounted for 36% of all mutations. Compared to non-CHIP patients, CHIP carriers were older and had lower renal function and higher levels of N-terminal pro-B-type natriuretic peptide and inflammatory biomarkers. CHIP was associated with the primary endpoint independent of age and biomarkers reflecting kidney function, heart failure severity and inflammation (odds ratio [OR]: 1.83; 95% confidence interval [CI]: 1.05-3.21; P = 0.03). However, there was no significant difference between CHIP and non-CHIP patients in terms of all-cause mortality alone (OR: 1.67; 95% CI: 0.96-2.90; P = 0.069). Böhme, Desch and colleagues concluded that CHIP is frequent among AMI-CS patients and that it is associated with worse clinical outcomes. They concluded that “interventions that target the inflammatory response mediated by clonally altered immune cells in this patient population, as well as rapidly accessible biomarkers that may predict the effectiveness of such interventions, should be investigated.” In their editorial, Collet and colleagues congratulated the researchers on their results and further mentioned that the question arises whether CHIP may be used beyond conventional prognostication. According to the editorial comment, this has potentially important practical implications. Because CHIP detection is currently determined using exome or genome sequencing of blood DNA, a rapid assay would be required for translation to patients with acute conditions, such as CS, they wrote. The editorialists added that CHIP detection should be considered a guiding tool for specific therapies. This approach, however, would require more supportive scientific evidence, and CHIP is not currently detectable through conventional clinical assessments. “There is no doubt that CHIP detection is a marker of risk that can be used beyond conventional tools for prognostication,” Collet and colleagues concluded. “The next step is to demonstrate whether it can be considered a risk factor.” Sources: Böhme M, Desch S, Rosolowski M, et al. Impact of Clonal Hematopoiesis in Patients With Cardiogenic Shock Complicating Acute Myocardial Infarction. J Am Coll Cardiol 2022;80:1545–1556. Collet J-P, Rahoual G, Hulot J-S. Clonal Hematopoiesis in Cardiogenic Shock Beyond Conventional Prognostication? J Am Coll Cardiol 2022;80:1557–1559. Image Credit: lucadp – stock.adobe.com