Abstract
Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
Highlights
Licensee MDPI, Basel, Switzerland.Recent literature shows that depression is an independent risk factor for cardiac events [1]
Echocardiographic assessment of left ventricular dimensions and function under baseline conditions revealed no overt differences between 5-Htt genotypes at 2–3 months of age (Figure 2A,B and Supplementary Table S1)
5-HTT−/− mice relative to age-matched controls and 2–3-month-old 5-HTT−/− mice (n = 8–18 per age group and genotype). (C–E) Hemodynamic measurements from 7-month-old mice demonstrated slightly diminished cardiac output (C), increased pressure at the peak rate of left ventricular filling (D) and decreased peak systolic ejection rate (E) in 5-HTT−/− mice as compared to 5-HTT+/+ littermates (n = 5–6/genotype). (F) Myocardial collagen content did not differ between 5-Htt genotypes (n = 6/genotype)
Summary
Recent literature shows that depression is an independent risk factor for cardiac events [1]. Depression results in reduced compliance regarding lifestyle factors and prescribed medication, which might aggravate the underlying cardiac disease [2] and is associated with increased mortality [3]. Major depression and anxiety disorders are common comorbidities in patients with chronic heart failure (CHF), which could be the final common pathway of the coronary artery disease. Interdisciplinary Network for Heart Failure (INH) registry depression at study entry was frequent [4], and an independent predictor of mortality in CHF patients [5]
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