Research progress on beta-blockers in the treatment of sepsis-induced cardiomyopathy: A mini review

Abstract

Sepsis-induced cardiomyopathy (SCM), a frequent complication of septic shock with mortality exceeding 40%, arises from catecholamine-driven cardiotoxicity, sympathetic hyperactivity, and inflammation-mediated biventricular dysfunction. Short-acting β₁-blockers (esmolol, landiolol) offer a targeted therapeutic approach by reducing heart rate (target: 80–95 bpm), myocardial oxygen demand, and proinflammatory cytokines while improving diastolic perfusion—leveraging ultra-short half-lives (t₁/₂ = 4–9 min) for rapid reversibility during instability. Clinical evidence remains divergent: a landmark single-center RCT demonstrated significant 28-day mortality reduction (49.4% vs 80.5%; p < 0.001), improved hemodynamics, and reduced vasopressor requirements in hemodynamically stabilized patients, whereas premature termination of a multicenter trial revealed harm (increased vasopressor needs, mortality trend) when initiated during persistent hypoperfusion (lactate > 2 mmol/L). Current limitations include heterogeneous trial designs, small samples, and undefined benefiting phenotypes. Thus, cautious short-acting β-blockade is supported only for selected SCM patients with hemodynamic stability (MAP ⩾65 mmHg, normalized lactate, LVEF >35%), necessitating future precision trials with AI phenotyping to guide mechanism-targeted application.

Introduction

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality in intensive care units (ICUs) worldwide. ¹ It affects approximately 8%–14% of all ICU patients, with reported mortality rates ranging from 20% to 40% in broad sepsis cohorts.^1,2 However, in the subset of patients progressing to septic shock—characterized by persistent hypotension requiring vasopressors to maintain a mean arterial pressure ⩾65 mmHg despite adequate fluid resuscitation, and serum lactate levels >2 mmol/L—mortality escalates dramatically to 40%–60%, and can exceed 70% in refractory cases or those with significant cardiac dysfunction.

Sepsis-induced cardiomyopathy (SCM) is a frequent and grave complication, contributing substantially to sepsis-related mortality.^3,4 SCM is typified by reversible biventricular dysfunction, impaired contractility, and diastolic dysfunction, often identifiable via echocardiography as a reduced left ventricular ejection fraction (LVEF <45%) or global longitudinal strain. ⁵ SCM’s clinical impact extends beyond acute illness. Pathophysiologically, it involves sympathetic hyperactivity, catecholamine cardiotoxicity, systemic inflammation, metabolic dysregulation, and microcirculatory dysfunction.^5,6 Critically, survivors of sepsis often exhibit residual cardiac impairment resembling heart failure with reduced ejection fraction (HFrEF), driven by persistent inflammation, mitochondrial dysfunction, and β-adrenergic receptor desensitization.

In this context, beta-blockers(BB), cardioselective agents like esmolol and landiolol—have emerged as potential therapeutic agents to modulate the detrimental effects of excessive sympathetic drive. This narrative mini-review aims to critically appraise and synthesize the current preclinical and clinical evidence regarding the use of beta-blockers in SCM, elucidate their underlying mechanisms of action, and discuss their clinical applicability, monitoring requirements, and future research directions.

Methods

This narrative mini-review synthesized preclinical and clinical evidence on β-blockers in SCM. PubMed/EMBASE searches used terms: (“beta-blockers” ) AND (“sepsis” OR “septic cardiomyopathy”).

Pathophysiological mechanisms of SCM

Septic cardiomyopathy arises from a complex interplay of mechanisms triggered by the host response to infection. A hallmark is profound sympathetic nervous system (SNS) hyperactivation, leading to a massive catecholamine surge (both endogenous and from vasopressors), often 20-fold above baseline levels.^7,8 This catecholamine excess induces direct cardiotoxicity via calcium overload, oxidative stress, and mitochondrial dysfunction, while persistent SNS stimulation causes myocardial β-adrenergic receptor desensitization and downregulation, impairing contractility (inotropic response) and contributing to autonomic dysfunction (sympathovagal imbalance), strongly linked to poor outcomes.^9–11 Concurrently, sepsis unleashes a storm of proinflammatory cytokines (TNF-α, IL-1β, IL-6) that directly depress myocardial contractility, promote apoptosis, and paradoxically, catecholamines can exacerbate inflammation by stimulating more cytokine release.^12,13 This inflammatory cascade, mediated centrally through pathways like NF-κB and iNOS induction, overlaps with developing immunosuppression, including impaired neutrophil function. ¹⁴ Sympathetic overdrive also shifts metabolism to a hypercatabolic state, manifesting as insulin resistance, enhanced gluconeogenesis, and lipolysis, culminating in hyperglycemia and hyperlactatemia (the latter further fueled by adrenergically stimulated anaerobic glycolysis and impaired hepatic clearance).^15,16 Furthermore, hemodynamic disturbances contribute significantly: excessive tachycardia shortens diastolic filling, compromising coronary perfusion while increasing myocardial oxygen demand, potentially precipitating ischemia. ¹⁷ Microvascular dysfunction, characterized by impaired flow, endothelial injury, and associated coagulopathy, exacerbates tissue hypoxia. ¹⁸ Direct catecholamine effects and inflammatory mediators also promote myocardial fibrosis and cell death pathways. ¹⁹

Current challenges in defining SCM mechanisms center around evolving diagnostic criteria and understanding its variable natural history. A key point of contention remains the precise definition of SCM itself. While left ventricular systolic dysfunction measured by LVEF decline is most commonly cited, its sensitivity and specificity are debated. There’s increasing recognition of the importance of diastolic dysfunction and right ventricular impairment, but standardized definitions integrating these facets are lacking. Furthermore, the natural history of SCM is incompletely understood. Myocardial dysfunction often appears early and transiently (myocardial stunning) but may also present late in sepsis or persist long-term. The factors determining whether dysfunction is reversible (resolving inflammation, metabolic correction) or progresses to chronic fibrosis and cardiomyopathy (driven by unresolved catecholamine toxicity or persistent inflammatory/ischemic insults) require further elucidation. Distinguishing the acute, adaptive responses from maladaptive processes leading to permanent damage remains a critical research focus.

Therapeutic effects and mechanisms of beta-blockers

BBs deliver established mortality benefits in chronic cardiovascular disease—reducing all-cause death by 34% in HFrEF through sympathetic blockade and by 30%–40% in post-MI CAD via anti-ischemic/antiarrhythmic effects. However, their role in septic cardiomyopathy (SCM) is complex.

Mechanistically, beta-blockers mitigate septic cardiomyopathy by suppressing sympathetic overactivation (reducing catecholamines, HR, and myocardial O₂ demand), concurrently modulating inflammation (inhibiting NF-κB/iNOS while enhancing Akt/eNOS pathways) and potentially restoring β-receptor sensitivity, though this must be balanced against risks of myocardial depression.^20,21 Clinically, agents like esmolol optimize coronary perfusion via targeted HR reduction (80–95 bpm), prolonging diastolic filling to improve stroke volume without compromising output; notably, while diastolic dysfunction may benefit from BBs, ivabradine’s contractility-sparing HR control offers a physiologically advantageous alternative in unstable cases despite sharing the limitation of unproven mortality impact, underscoring tachycardia’s role as a biomarker rather than causal driver.^20,22

Hemodynamically, BBs paradoxically increase afterload (via unopposed α-mediated vasoconstriction) yet augment preload (through prolonged diastole), creating significant treatment tension: HR control improves myocardial oxygen balance but risks reducing cardiac output in tenuous patients, thus confining prognostic benefit (short-term mortality reduction) to rigorously selected cohorts (LVEF >35%–40%, adequate MAP/volume) in trials, yet unresolved mechanisms and absent long-term outcomes data necessitate precision-guided trials before broader adoption. Selective β1-blockers (esmolol, landiolol) attenuate systemic inflammation by lowering catecholamine levels and suppressing proinflammatory cytokines (IL-1, IL-6, TNF-α, HMGB-1) while enhancing anti-inflammatory mediators (IL-10, IL-1ra). ²⁰ Esmolol reduces NF-κB and iNOS expression while boosting eNOS activity, thereby improving vascular function. ²⁰ Landiolol similarly decreases proinflammatory cytokines in serum and lung tissue. Beta-blockers also restore sympathovagal balance, activating cholinergic anti-inflammatory pathways to mitigate cytokine storms. Notably, β2-blockade may exacerbate inflammation, whereas β1-blockade or β2-agonism promotes anti-inflammatory effects. ²³

BBs mitigate endothelial dysfunction in septic CM by counteracting catecholamine-induced oxidative stress and inflammation, thereby improving NO-dependent vasodilation, reducing vascular permeability, and ameliorating microcirculatory flow. This endothelial stabilization attenuates myocardial hypoperfusion and oxidative injury, potentially preserving contractile function during sepsis; however, direct clinical evidence in septic CM remains limited compared to theoretical mechanisms. Esmolol reduces vasopressor requirements in septic shock without compromising hemodynamic stability. ²⁴ This contrasts with traditional vasopressors, which may worsen cardiac dysfunction.

Cardiac MRI reveals myocardial edema acutely impairs diastolic function in SCM, while late gadolinium enhancement-documented fibrosis drives persistent ventricular stiffening.^25,26 Although beta-blockers theoretically suppress edema/fibrosis via catecholamine and TGF-β pathway modulation, current cMRI data indicate paradoxical worsening in specific subgroups, necessitating phenotype-guided titration to avoid fluid overload in hypovolemic patients or high-extracellular volume phenotypes (Figure 1).

Figure 1.

Beta-blockers reduce sympathetic overactivation. Figure 1 was drawn in https://app.biorender.com/.

Clinical evidence and future perspectives of beta-blockade in SCM

The potential of BB to modulate the deleterious adrenergic storm in SCM has moved from theoretical concept to a promising, albeit cautiously applied, therapeutic strategy (Table 1). A growing body of varying quality clinical evidence supports this approach, demanding a critical appraisal of individual study merits, limitations, and implications for future investigation.

Table 1.

Summary of Clinical Trials on Beta-Blockers in Sepsis-Induced Cardiomyopathy.

Study (Year)	Design	Patients (n) a	Intervention	Key eligibility criteria	Main outcomes
Morelli et al. (2013) 22	Single-center RCT	154 (77 vs. 77)	Esmolol (titrated to HR 80–95 bpm)	Septic shock + tachyarrhythmia (HR ⩾95 bpm), requiring NE dose ⩽0.1 µg/kg/min after fluid resuscitation	Reduced 28-day mortality: 49.4% vs. 80.5% (p <0.001)Increase LV stroke volume & LVEFReduced Norepinephrine requirements
Kondo et al. (2019) 28	Meta-analysis	~800	Landiolol (HR target <100–110 bpm)	Mixed sepsis/SCM with tachyarrhythmia	Reduced arrhythmiasIncreased LVEFReduced Vasopressor requirementsNo consistent mortality benefit
BACTRIC Trial (2024) 31	Multicenter RCT b	252 (126 vs. 126)	Landiolol + Hydrocortisone vs. Hydrocortisone alone	Septic shock + lactate >2 mmol/L without strict HR criteria	Increased Vasopressor requirementsIncreased SOFA scores at Day 7Increased 28-day mortality trendReduced Stroke volume & cardiac index Terminated early for harm

Abbreviations: BB = Beta-blocker; HR = Heart rate; LVEF = Left ventricular ejection fraction; NE = Norepinephrine; SCM = Sepsis-induced cardiomyopathy; SOFA = Sequential Organ Failure Assessment.

a

Patient numbers reflect intervention vs. control groups.

b

BACTRIC: Evaluated hydrocortisone ± landiolol; landiolol arm showed harm despite similar baseline SOFA scores.

The single-center, open-label RCT by Morelli et al. investigated the efficacy of titrated esmolol infusion (targeting heart rate 80–95 bpm) versus standard care in highly selected patients with septic shock. ²² Esmolol treatment demonstrated significant benefits, markedly reducing heart rate, lowering norepinephrine requirements, improving left ventricular stroke volume and LVEF, and crucially, yielding a striking reduction in 28-day mortality (49.4% in controls vs. 80.5% in the esmolol group, p <0.001) without increasing adverse events such as hypotension or vasopressor escalation; mortality benefit was most evident in patients achieving the target heart rate. ²⁷ The trial’s major strengths lie in being the first large RCT to report such a profound positive mortality outcome, and providing compelling pathophysiological plausibility by linking heart rate reduction directly to improved hemodynamics. However, key limitations include: highly selective inclusion criteria limiting generalizability to less severe sepsis or lower-adrenergic-drive patients; open-label vasopressor titration risking clinician bias favoring norepinephrine reduction in the esmolol group; and insufficient mechanistic depth (lacking investigation of specific SCM endpoints beyond LVEF or underlying pathways like inflammation/metabolism beyond HR/NE alterations).

Subsequent clinical studies, predominantly employing the ultra–short-acting β1-blocker landiolol, confirm the feasibility of heart rate control in sepsis (target HR <100–110 bpm), yielding reduced arrhythmias, improved LVEF, and lower vasopressor requirements—with meta-analyses indicating a mortality trend.^28,29 Pharmacokinetically, landiolol’s ultra-short half-life (t½ = 4 min) enables rapid titration and reversibility (±5 min), mitigating persistent hypotension/bradycardia risks that complicate long-acting agents (carvedilol t½ = 7–10 h) during hemodynamic instability. ³⁰ However, current evidence faces critical limitations: small open-label trials with heterogeneous protocols; overreliance on surrogate endpoints; inconsistent mortality signals; undefined benefiting phenotypes; and landiolol’s restricted availability. Critically, no data demonstrate superior efficacy of short-acting vs. long-acting β-blockers in SCM, underscoring their selection is safety-driven, not efficacy-based.

A large multi-center RCT, assessed hydrocortisone versus hydrocortisone plus low-dose landiolol in septic shock patients with persistent lactate elevation (>2 mmol/L). ³¹ Early trial termination occurred due to harm in the landiolol group, marked by significantly higher vasopressor requirements over 6 days, worsened SOFA scores at day 7, a trend toward increased 28-day mortality, and absence of organ protection benefits. While its multi-center RCT design is methodologically robust, critical limitations include enrollment without strict heart rate thresholds (median HR ~105 bpm, lower than Morelli’s cohort), very early BB initiation within shock onset (potential instability), and complex concurrent/sequential hydrocortisone administration complicating interpretation. The profound cardiac index/stroke volume decrease in the landiolol arm highlights an inadequate hemodynamic status for BB initiation, underscoring the essentiality of cautious, low-dose titration. This trial provides a vital counterpoint to previous positive studies, demonstrating potential harm in suboptimal contexts and emphasizing non-universal applicability, thereby necessitating stringent hemodynamic screening protocols for beta-blocker use.

This study’s key limitations include heterogeneous trial designs with highly selective patient criteria and fundamental gaps in understanding β-blockers’ precise mechanisms. These limitations prevent consistent outcomes, limit generalizability, and hinder identification of responsive phenotypes, thus impeding clinical translation.

Conclusion

Current evidence cautiously supports BB benefits in selected SCM patients, yet heterogeneous trial designs, conflicting mortality signals, and fundamental knowledge gaps critically limit translation to clinical practice. ³² Three barriers dominate: (1) absence of universal SCM diagnostic criteria, (2) predominant focus on short-term outcomes (28-day mortality) overlooking long-term cardiac remodeling, and (3) undetermined mechanisms whereby BBs modulate myocardial inflammation, calcium dynamics, or mitochondrial repair in humans—constraining optimization beyond hemodynamics. Crucially, multicenter trials face irreducible challenges: hemodynamic instability and inter-center variability in patient selection (baseline cardiac index, volume status, vasopressor requirements) obstruct protocol standardization and safe BB initiation. Future research must therefore pivot toward precision-guided frameworks employing AI-driven phenotyping and validated hemodynamic biomarkers to identify responsive subpopulations, enabling mechanism, targeted BB application rather than empiric adoption.