Sex differences in cardiac remodeling post myocardial infarction with acute cigarette smoking

Abstract

Background: Whether cigarette smoking affects the heart post-myocardial infarction (MI) in a sex-dependent way remains controversial. Using a mouse model, we investigated cardiac remodeling under the influence of acute cigarette smoke (CS) exposure following ischemic injury in both sexes.

Methods: Ten cigarettes were smoked twice daily for 2 weeks followed by MI and then 1 additional week post permanent LAD ligation. Cardiac function, histology, and infarct size were assessed, and inflammatory markers quantified by RT-PCR. Statistical comparisons were performed using an unpaired t test or ANOVA followed by Tukey post hoc test.

Results: We observed that cigarette smoking exacerbated both left and right ventricular remodeling only in males at an early stage of post-MI. Females did not display a significant structural and/or functional alteration within 7 days of cardiac remodeling post-MI upon CS exposure. Worsened right ventricular remodeling in males was independent of pulmonary congestion. CS-exposed males exhibited enhanced increases in left ventricular end systolic and diastolic volumes, as well as reductions in ejection fraction and fractional area changes of left ventricular base. At day 7, infarct size was increased by cigarette smoking in males only, which was accompanied by enhanced collagen deposition in both the infarcted and peri-infarcted areas. Both IL-6 and TNF-α mRNA expression significantly increased in CS-exposed MI male group only at day 7 post-MI suggestive of prolonged inflammation.

Conclusions: These findings indicate that CS exposure worsens the progression of cardiac remodeling post-MI in male sex in a significant manner compared to female sex at least at early stages.

Keywords: Cardiac fibrosis; Cigarette smoke; Inflammation; Left ventricular remodeling; Right ventricular remodeling; Sex differences.

Fig. 1

Blood pressure measurement after 2 weeks of cigarette smoke (CS) exposure prior to surgery. After 2 weeks of CS exposure, systolic blood pressure did not show a significant alteration from baseline in either sex compared to their control counterparts MIF: MI female group (n = 8); MIM: MI male group (n = 10); SMIM-BL: smoking Male group before starting CS exposure (n = 12); SMIF-BL: smoking Female group before starting CS exposure (n = 9); SMIM-2 W: 2 weeks of CS exposure for smoking male group (n = 11); SMIF-2 W: 2 weeks of CS exposure for smoking female group (n = 8)

Fig. 2

Effects of myocardial infarction (MI) and cigarette smoke (CS) on left ventricular volumes in males and females. Following MI surgery, both sexes displayed progressive LV dilatation through 7 days. A Left ventricular end-diastolic volume (LVEDV) of the CS-exposed and CS-naïve groups were compared at the day before surgery (BL/2 W), day 1, and day 7 post-MI. While LVEDV in both female groups was comparable at all timepoints, CS-exposed MI male group differed significantly from CS-naive MI male group at day 7. B Left ventricular end-systolic volume (LVESV) of the CS-exposed and CS-naive groups were compared at the day before surgery (day − 1), day 1, and day 7 post-MI. While LVESV in both female groups was comparable at all timepoints of assessment, CS-exposed MI male group differed significantly from CS-naïve MI males at day 7. N = 8 (MIF), 6 (MIM), 8 (SMIF), and 6 (SMIM). MI: myocardial Infarction; MIF: MI females group; MIM: MI male group; SMIF: smoking MI females group; SMIM: smoking MI males group; D-1: baseline the day before LAD ligation for MI group or the day before LAD ligation but after 2 weeks of CS exposure for smoking MI group; D1: day 1 after MI; D7: day 7 after MI, LV: left ventricular. p ≤ 0.05 (*), p ≤ 0.01 (**), and p ≤ 0.001 (***); ANOVA

Fig. 3

Effects of myocardial infarction (MI) and cigarette smoke (CS) on fractional area change and ejection fraction (EF) of LV in males and females. Following MI surgery, left ventricular systolic function progressively deteriorated during 7 days of follow-up. A Left ventricular EF of the CS-exposed and CS-naive groups were compared at the day before surgery (day − 1), day 1 and day 7 post-MI. While EF in both female groups was comparable at all timepoints of assessment, CS-exposed MI male group differed significantly from CS-naive MI males at day 1 and day 7 post-MI. B Fractional area change of LV base was found significantly reduced in CS-exposed MI male group in comparison with CS-naïve MI males at day 1 post-MI. No significant difference was found between female groups. N = 8 (MIF), 6 (MIM), 8 (SMIF), and 6 (SMIM). MI: myocardial Infarction; MIF: MI females group; MIM: MI male group; SMIF: smoking MI females group; SMIM: smoking MI males group; D-1: baseline the day before LAD ligation for MI group or the day before LAD ligation but after 2 weeks of CS exposure for smoking MI group; D1: day 1 after MI; D7: day 7 after MI, LV: left ventricular. p ≤ 0.05 (*), p ≤ 0.01 (**), and p ≤ 0.001 (***); ANOVA (A) and t test (B)

Fig. 4

Comparison of infarct sizes among the groups. A No group showed significant difference with regard to echocardiographic measurements of infarct size at day 1 post-MI. B Only CS-exposed MI male group showed significantly larger infarcted area in the heart tissue at day 7 post-MI compared to their CS-naïve counterpart. N = 8 (MIF), 6 (MIM), 8 (SMIF), and 6 (SMIM). MI myocardial infarction, MIF MI female group, MIM MI male group, SMIF smoking MI female group, SMIM smoking MI male group. p ≤ 0.01 (**); t test

Fig. 5

Effect of myocardial infarction (MI) and cigarette smoke (CS) on left ventricular (LV) and right ventricular (RV) mass in males and females. A Smoke exposure did not have a significant effect on LV mass of both sexes post-MI. In female groups, LV mass significantly increased post-MI regardless of smoke exposure. However, in male groups, only CS-exposed MI mice showed significantly increased LV mass. B Although smoking male mice had a greater RV mass on average post-MI, none of the four groups showed significant RV mass increase. N = 7 (CF), 7 (CM), 8 (MIF), 6 (MIM), 8 (SMIF), and 6 (SMIM). CM/CF control male/female, MI myocardial infarction, MIF MI female group, MIM MI male group, SMIF smoking MI female group, SMIM smoking MI male group. p ≤ 0.05 (*); ANOVA

Fig. 6

Effect of cigarette smoke (CS) on right ventricular (RV) areas and lung edema in males and females. A CS-exposed MI male group had greater RV areas compared to CS-naive MI males. Female groups had comparable RV area post-MI irrespective of smoke exposure. B No group developed significant pulmonary fluid accumulation. N = 7 (CF), 7 (CM), 8 (MIF), 6(MIM), 8 (SMIF), and 6 (SMIM). CM/CF control male/female, MI myocardial infarction, MIF MI female group, MIM MI male group, SMIF smoking plus MI female group, SMIM smoking plus MI male group. p ≤ 0.01 (**); t test (A) and ANOVA (B)

Fig. 7

Effect of cigarette smoke (CS) on collagen content of the infarcted and peri-infarcted areas in males and females. Collagen accumulation in both infarcted and peri-infarct area (IA and PIA, respectively) showed significance enhancement in CS-exposed MI male mice only. a = MIF (n = 15), b = MIM (n = 15), c = SMIF (n = 15), and d = SMIM (n = 15). MI myocardial infarction, MIF MI female group, MIM MI male group, SMIF smoking plus MI female group, SMIM smoking plus MI male group. p ≤ 0.05 (*) and p ≤ 0.001 (***); t test

Fig. 8

Effect of cigarette smoke (CS) on IL-6 and TNF-α proinflammatory markers fold change at day 7 post-MI. A CS-exposed MI male group had greater IL-6 mRNA expression levels compared to CS-naive MI males. Female groups had comparable IL-6 mRNA expression levels post-MI irrespective of smoke exposure. No difference across sexes was observed (B) CS-exposed MI male group had greater TNF-α mRNA expression levels compared to control males and CS-exposed MI female group. Female groups had comparable TNF-α mRNA expression levels post-MI irrespective of smoke exposure. N = 3 in each group. CTL control, MI myocardial infarction, MICS smoking plus MI. *p < 0.05; ANOVA