Table 2.

Key experimental studies in mice linking CHIP to CVD

Phenotype	CHIP subtype	Findings	Ref.
Atherosclerotic heart disease	Tet2 LOF	Ldlr−/− mice that received a BMT of Tet2−/− or Tet2+/− HSPCs and were subsequently fed an atherogenic diet in two independent studies had larger atherosclerotic plaques in the aortic root. Inhibiting IL-1β production with an NLRP3 inflammasome inhibitor abrogated the development of atherosclerosis in this mouse model.	38,39
	Dnmt3a LOF	Ldlr−/− mice that had received a BMT of Dnmt3a−/− HSPCs and were subsequently fed an atherogenic diet had larger atherosclerotic plaques in the aortic root.	105
	Jak2 V617F	Ldlr−/− mice that received a BMT of Jak2V617F HSPCs and were subsequently fed an atherogenic diet in two independent studies had larger atherosclerotic plaques in the aortic root. Genetic inactivation of the AIM2 inflammasome (Aim2−/−) or treatment with anti-IL-1β antibodies in these mice decreased intralesional macrophage proliferation and improved plaque stability.	102,103
Heart failure	Tet2 LOF	Mice that received a BMT of Tet2−/− or Tet2+/− HSPCs and subsequently underwent one of two surgical procedures to induce heart failure (LAD ligation or transverse aortic constriction) had larger myocardial infarct size, poorer post-ischaemic remodeling, and lower ejection fractions. Inhibiting IL-1β production with an NLRP3 inflammasome inhibitor abrogated the development of heart failure in this mouse model.	99
		Aged, non-irradiateda mice who had received a BMT of Tet2−/− HSPCs developed spontaneous cardiac fibrosis and hypertrophy.	82
		Mice that received a BMT of HSPCs with CRISPR/Cas9-guided inactivation of Tet2 and subsequently received an angiotensin II infusion had greater cardiac fibrosis and hypertrophy.	40
	Dnmt3a LOF	Mice that received a BMT of HSPCs with CRISPR/Cas9-guided inactivation of Dnmt3a and subsequently received an angiotensin II infusion had greater cardiac fibrosis and hypertrophy.	40
	Asxl1 LOF	Mice that received a BMT of Asxl1+/− HSPCs who subsequently underwent either LAD ligation or angiotensin II infusion to induce heart failure had lower ejection fraction and greater cardiac fibrosis.	160
	Jak2 V617F	Mice that received a BMT of Jak2V617F HSPCs who subsequently underwent one of two surgical procedures to induce heart failure (LAD ligation or transverse aortic constriction) had larger myocardial infarct size, poorer post-ischaemic remodeling and lower ejection fractions.	42
	Ppm1d LOF	Mice that received a BMT of HSPCs with CRISPR/Cas9-guided inactivation of Ppm1d and subsequently received an angiotensin II infusion had greater cardiac fibrosis and hypertrophy.	104
Doxorubicin-induced cardiotoxicity	Tp53 LOF	After infusion of doxorubicin, both irradiated mice that had received a BMT of Tp53+/− HSPCs and non-irradiated† mice that had received a BMT of Tp53R270H or Tp53+/− HSPCs had LV functional impairment, LV wall thinning and cardiac fibrosis.	96
Aortic aneurysms	Jak2 V617F	Apoe−/−mice that received a BMT of Jak2V617F HSPCs and subsequently received an angiotensin II infusion had greater abdominal aorta diameter and more abdominal aortic aneurysms.	161

AIM2, absent in melanoma 2; BMT, bone marrow transplant; CHIP, clonal haematopoiesis of indeterminate potential; CRISPR-Cas9, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9; CVD, cardiovascular disease; HSPCs, haematopoietic stem and progenitor cells; LAD, left anterior descending; LOF, loss-of-function; LV, left ventricular; NLRP3, Nod-like receptor family pyrin domain containing 3.

^aSee Figure 3 for details of irradiated and non-irradiated mouse models of CHIP.