Association of Angiotensin II Receptor Type 1 and Endothelin-1 Receptor Type A Agonistic Autoantibodies With Adverse Remodeling and Cardiovascular Events After Acute Myocardial Infarction

Abstract

Background: The left ventricular remodeling (LVR) process has limited the effectiveness of therapies after myocardial infarction. The relationship between autoantibodies activating AT1R-AAs (angiotensin II receptor type 1-AAs) and ETAR-AAs (autoantibodies activating endothelin-1 receptor type A) with myocardial infarction has been described. Among patients with ST-segment-elevation myocardial infarction, we investigated the relationship between these autoantibodies with LVR and subsequent major adverse cardiac events.

Methods and results: In this prospective observational study, we included 131 patients with ST-segment-elevation myocardial infarction (61±11 years of age, 112 men) treated with primary percutaneous coronary intervention. Within 48 hours of admission, 2-dimensional transthoracic echocardiography was performed, and blood samples were obtained. The seropositive threshold for AT1R-AAs and ETAR-AAs was >10 U/mL. Patients were followed up at 6 months, when repeat transthoracic echocardiography was performed. The primary end points were LVR, defined as a 20% increase in left ventricular end-diastolic volume index, and major adverse cardiac event occurrence at follow-up, defined as cardiac death, nonfatal re-myocardial infarction, and hospitalization for heart failure. Forty-one (31%) patients experienced LVR. The prevalence of AT1R-AAs and ETAR-AAs seropositivity was higher in patients with versus without LVR (39% versus 11%, P<0.001 and 37% versus 12%, P=0.001, respectively). In multivariable analysis, AT1R-AAs seropositivity was significantly associated with LVR (odds ratio [OR], 4.66; P=0.002) and represented a risk factor for subsequent major adverse cardiac events (OR, 19.6; P=0.002).

Conclusions: AT1R-AAs and ETAR-AAs are associated with LVR in patients with ST-segment-elevation myocardial infarction. AT1R-AAs are also significantly associated with recurrent major adverse cardiac events. These initial observations may set the stage for a better pathophysiological understanding of the mechanisms contributing to LVR and ST-segment-elevation myocardial infarction prognosis.

Keywords: STEMI; antibodies; immunology; prognosis; remodeling.

Figure 1. Study protocol.

AT1R‐AAs indicates autoantibodies targeting angiotensin II receptor type 1; ETAR‐AAs, autoantibodies targeting endothelin‐1 type A receptor; LV, left ventricular; MACE, major adverse cardiac event; MI, myocardial infarction; and STEMI, ST‐segment–elevation myocardial infarction.

Figure 2. Autoantibody concentration in patients with STEMI without and with LVR.

A, AT1R‐AA concentration (units per milliliter) in patients with STEMI without LVR (no remodelers) and with LVR (remodelers). B, ETAR‐AA concentration (units per milliliter) in patients with STEMI without LVR (no remodelers) and with LVR (remodelers). Values are expressed as median (interquartile range). AT1R‐AAs indicates autoantibodies activating angiotensin II receptors type 1; ETAR‐AAs, autoantibodies activating endothelin‐1 receptors type A; LVR, left ventricular remodeling; and STEMI, ST‐segment–elevation myocardial infarction.

Figure 3. Frequency of AT1R‐AAs and ETAR‐AAs seropositivity in patients with STEMI without and with LVR.

A, AT1R‐AAs seropositivity in patients with STEMI with LVR (remodelers) (left pie chart) and without LVR (no remodelers) (right pie chart) (P<0.001). B, ETAR‐AAs seropositivity in patients with STEMI with LVR (remodelers) (left pie chart) and without LVR (no remodelers) (right pie chart) (P=0.001). AT1R‐AAs indicates autoantibodies activating angiotensin II receptors type 1; ETAR‐AAs, autoantibodies activating endothelin‐1 receptors type A; LVR, left ventricular remodeling; and STEMI, ST‐segment–elevation myocardial infarction.

Figure 4. Change in LVEDVI and LVEF at 6‐month follow‐up.

A, Change in LVEDVI (milliliters per square meter) and in patients with STEMI without and with AT1R‐AAs. B, Change in LVEF (percent) in patients with STEMI without and with AT1R‐AAs. C, Change in LVEDVI (milliliters per square meter) in patients with STEMI without and with ETAR‐AAs. D, Change in LVEF (percent) in patients with STEMI without and with ETAR‐AAs. AT1R‐AAs indicates autoantibodies activating angiotensin II receptors type 1; ETAR‐AAs, autoantibodies activating endothelin‐1 receptors type A; LV, left ventricular; LVEDVI, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; and STEMI, ST‐segment–elevation myocardial infarction.

Figure 5. Frequency of AT1R‐AAs seropositivity and ETAR‐AAs seropositivity in patients with STEMI with and without MACE.

A, AT1R‐AAs seropositivity in patients with STEMI with MACE (left pie chart) and without MACE (right pie chart) (P=0.004). B, ETAR‐AAs seropositivity in patients with STEMI with MACE (left pie chart) and without MACE (right pie chart) (P=0.274). AT1R‐AAs indicates autoantibodies activating angiotensin II receptors type 1; ETAR‐AAs, autoantibodies activating endothelin‐1 receptors type A; MACE, major adverse cardiovascular event; and STEMI, ST‐segment–elevation myocardial infarction.