Statin Therapy Induces Gut Leakage and Neuromuscular Disjunction in Patients With Chronic Heart Failure

Abstract

Statins are commonly used to limit the risk of cardiovascular diseases, including ischemic heart attack and stroke. However, treatment often leads to myopathy and muscle weakness. Therefore, a better understanding of underlying pathomechanism is needed to improve the clinical outcomes. Here, we assessed the physical performance, including handgrip strength (HGS), gait speed (GS), and short physical performance battery, in 172 patients diagnosed with chronic heart failure (CHF) treated with (n = 50) or without (n = 122) statin and 59 controls. The plasma biomarkers, including sarcopenia marker C-terminal agrin fragment-22 (CAF22), intestinal barrier integrity marker zonulin, and C-reactive protein (CRP), were measured and correlated with the physical performance of patients. The HGS, short physical performance battery scores, and GS were significantly compromised in patients with CHF versus controls. Irrespective of etiology, significant elevation of plasma CAF22, zonulin, and CRP was observed in patients with CHF. There were strong inverse correlations of CAF22 with HGS (r 2 = 0.34, P , 0.0001), short physical performance battery scores (r 2 = 0.08, P = 0.0001), and GS (r 2 = 0.143, P , 0.0001). Strikingly, CAF22 and zonulin were positively correlated with each other (r 2 = 0.10, P = 0.0002) and with the level of CRP in patients with CHF.Further investigations revealed a significant induction of CAF22, zonulin, and CRP in patients with CHF taking statin versus nonstatin group. Consistently, HGS and GS were significantly lower in the statin versus nonstatin CHF patients' group. Collectively, statin therapy adversely affects the neuromuscular junction and intestinal barrier, which potentially induces systemic inflammation and physical disability in patients with CHF. Further prospective confirmation of the findings is required in a well-controlled study.

Oral Cardiac Drug–Gut Microbiota Interaction in Chronic Heart Failure Patients: An Emerging Association

“…Indeed, it has been suggested that Statin users have compositionally differing microbiotas from non-users [89]. Notably, Statin therapy activates the inflammation process through gut leakage that leads to adverse effects, especially on the neuromuscular junction [90].…”

Statins in patients with established heart failure: Time for reflection

“…11,12 An increase in lipoprotein polysaccharide and trimethylamine-N-oxide and a decrease in short-chain fatty acid have been suggested to have important adverse effects in patients with HF including an increase in systemic inflammation; an increase in myocardial and renal fibrosis; an increase in platelet activation and thrombosis; an increase in major depression; and an increase in cognitive dysfunction including Alzheimer's disease. 11,12 Although the suggestion from the study by Ahmad et al 8 that statins increase intestinal permeability has important clinical implications, it should be pointed out that the study was observational, and the number of patients with HF relatively small (n = 172), the number on a statin even smaller (n = 50), and that patients were not on a sodium glucose transport inhibitor or mineralocorticoid receptor antagonist, both of which can alter the intestinal microbiome and are part of the recommended "4-pillar" therapy of patients with HF. Thus, there is need for further prospective adequately powered, placebo-controlled randomized trials to confirm these findings.…”