Fluoroquinolones increase susceptibility to aortic aneurysm and aortic dissection: Molecular mechanism and clinical evidence

Abstract

Aortic aneurysm (AA) and aortic dissection (AD) are prevalent severe cardiovascular diseases that result in catastrophic complications and unexpected deaths. Owing to the lack of clinically established and effective medications, the only treatment options are open surgical repair or endovascular therapy. Most researchers have focused on the development of innovative medications or therapeutic targets to slow the progression of AA/AD or lower the risk of malignant consequences. Recent studies have shown that the use of fluoroquinolones (FQs) may increase susceptibility to AA/AD to some extent, especially in patients with aortic dilatation and those at a high risk of AD. Therefore, it is crucial for doctors, particularly those in cardiovascular specialties, to recognize the dangers of FQs and adopt alternatives. In the present review, the main clinical observational studies on the correlation between FQs and AA/AD in recent years are summarized, with an emphasis on the relative physiopathological mechanism incorporating destruction of the extracellular matrix (ECM), phenotypic transformation of vascular smooth muscle cells, and local inflammation. Although additional data are required, it is anticipated that the rational use of FQs will become the standard of care for the treatment of aortic diseases.

Keywords

aortic aneurysm aortic dissection extracellular matrix fluoroquinolones vascular smooth muscle cell

Introduction

Aortic aneurysm (AA) and aortic dissection (AD) are the most lethal aortic diseases in adults.¹ In Western countries, 1–2%² of deaths are caused by AA, which is a persistent localized dilatation of the aorta. As its most serious complication, AA rupture frequently results in deadly hemorrhage, with a prehospital mortality rate of up to 80%.³ It is reported that 60% of all AAs are abdominal aortic aneurysms (AAAs).^4,5 AD is the separation of the aortic media caused by aortic intimal tears or aortic wall hemorrhage. The mortality rate can reach 90% if treatment is delayed.⁶ Recent studies have indicated that fluoroquinolones (FQs), in addition to their antibacterial abilities, can cause structural damage to the aorta. The associated mechanisms involve extracellular matrix degradation (ECM) and remodeling, increased phenotypic transformation and loss of vascular smooth muscle cells (VSMCs), inflammatory response, and oxidative stress in the arterial wall. Considering the increasing expansion of FQ use, FQ therapy is anticipated to become a nonnegligible aggravating factor in AA and AD.⁷ However, current understanding suggests that the aortic risk of FQs is not frequently recognized. From initial observational studies to subsequent animal and cell tests, research in related fields has increased worldwide in recent years. In this review article, the latest research results have been summarized to expand the clinical pharmacological reference guidance.

Characteristics and clinical observation of fluoroquinolones (FQs)

Overview of FQs

FQs are one of the most widely used antibiotics worldwide owing to their broad antibacterial spectrum, good oral bioavailability, and wide tissue penetration.⁷ FQs exert antibacterial effects mainly by targeting bacterial DNA topoisomerase IV and gyrase.⁸ The most frequently prescribed FQs are ciprofloxacin, norfloxacin, ofloxacin, levofloxacin, enrofloxacin, danofloxacin, and moxifloxacin.⁸ Ciprofloxacin is the most commonly used FQ.⁹ Initially, use of FQs was associated with an increased incidence of tendinopathy and retinal detachment. The results showed that FQs enhanced the expression of matrix metalloproteinase (MMP) (Mmp1/13,¹⁰ Mmp2,¹¹ and Mmp3¹²) in tendon tissue and Mmp2/9 in corneal tissue.¹³ Type I collagen (COL) and β1-integrin production decreased and degradation increased.^10,11 This leads to structural damage and reconstruction of ECM. In addition, FQs exacerbate the damage and oxidative stress to the mitochondria and other organelles of tendon cells, resulting in tendon cells malfunctioning and increased apoptosis.^10,14 Excessive ECM degradation mediated by MMPs and parenchymal cell death were also closely related to the occurrence and development of AA/AD.^15,16

Clinical observation studies on FQs and susceptibility to aortic aneurysum and dissection (AA/AD)

In a nested case–control analysis in Taiwan, Lee et al. discovered a greater than twofold increase in the risk of AA or AD within a 60-day risk period for FQ exposure. This risk was more pronounced in patients older than 70 years and in women, and was substantially related to a longer term of exposure.¹⁷ Previous data have shown that the occurrence of AAAs is two to five times more prevalent in men aged > 65 years than in women.¹⁸ In the International Registry of Acute Aortic Dissection (IRAD) registry, 65% of patients with AD were men.¹⁹ However, the results of this study showed that AD incidence in women (relative risk [RR], 1.83; 95% CI, 1.27–2.64) appeared to be higher than that of men (RR, 1.61; 95% CI, 1.28–2.03); hence, women were more susceptible to FQs.

Another cross-case study involving 1,213 AA/AD patients by the same investigators compared the distribution of FQ exposure in the same patients 60 days (risk period) before the AA/AD event and 60–180 days (reference period) before the AA/AD event. In the main case crossover analysis, exposure to fluoroquinolone was more frequent during the hazard periods than during the referent periods (1.6% vs 0.6%; odds ratio [OR], 2.71; 95% CI, 1.14–6.46).²⁰ However, antibiotic use is frequently accompanied by infection, which is associated with an increased risk of AA/AD.²¹ Pathogenic bacteria can cause mycotic aneurysms (MAs) through the blood stream, spread to adjacent lesions, or direct infection by trauma.²² Thoracic and abdominal aortic MAs comprise 0.7%–4.5% of all AAs.²³ Gram-positive bacteria (e.g., Staphylococcus, Enterococcus, Streptococcus, and Bacillus cereus) and gram-negative bacilli (including Salmonella and Haemophilus influenzae) are the main pathogenic bacteria that cause aortic infections. Therefore, FQs must be compared with other types of antibiotics (such as penicillin and cephalosporins) in case–control studies to exclude the effect of MA on authenticity as much as possible. Otherwise, the aortic risk associated with FQs may have been overestimated. In another longitudinal observational study conducted in Ontario, Canada, the use of FQs was associated with a higher risk of AA within 30 days of exposure (hazard ratio [HR], 2.24; 95% CI, 2.02–2.49) among 1,744,360 adults over 65 years of age who were tracked. This risk was comparable to that posed by hypertension (HR, 2.20; 95% CI, 2.09–2.31) and remained significant when compared with that of amoxicillin (HR, 1.50; 95% CI, 1.32–1.70).²⁴ Similarly, a nationwide historical cohort study from Sweden found a 66% greater risk of AA/AD in the aged (> 50 years) during the 60 days following oral FQs compared to that with amoxicillin.²⁵

These findings also prompted the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to issue safety warnings regarding FQs and to identify ciprofloxacin, levofloxacin, and moxifloxacin as significantly associated with AA/AD.^26–29 Relevant warnings are listed in Table 1. In patients with chronic obstructive pulmonary disease, these medications are not indicated as first-line treatments for acute sinusitis, bacterial infections, or urinary tract infections because the risks outweigh the benefits.³⁰ A US retrospective analysis found that use of FQs increased the risk of adult aneurysms, iliac artery aneurysms, and other abdominal aneurysms compared to that with multiple antibiotics.³¹ The use of FQs was associated with aortic mortality and resulted in a higher risk of death from any cause (HR 1.61; 95% CI, 1.50–1.73).³² A meta-analysis also showed that compared to amoxicillin, azithromycin, doxycycline, or no antibiotics, FQs were associated with a higher risk of developing AA/AD within 30/60 days.³³ These studies emphasized the correlation between the use of FQs and the occurrence and adverse effects of AA/ADs. Although infection increases the risk of AA/AD, the use of FQs further increases this risk.

Table 1.

US Food and Drug Administration and European Medicines Agency warnings for fluoroquinolones.

Date	Regulatory entity	Related warning content	Method of administration
Jul 26, 2016	FDA²⁶	FQs should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections.	Systemic use (i.e., taken by mouth or by injection)
May 10, 2017	FDA²⁶	The patient cases do not support reports that FQs may result in bulges or tears in the aorta blood vessel called aortic aneurysm and aortic dissection.	Systemic use
Sep 5, 2018	EMA²⁷	The Pharmacovigilance Risk Assessment Committee (PRAC) agrees letter warning to professionals about the FQ-related risk of aortic aneurysm and dissection.	Not mentioned
Dec 20, 2018	FDA²⁸	FQs can increase the occurrence of rare but serious events of ruptures or tears in the main artery of the body – the aorta.	Systemic use
Oct 29, 2020	EMA²⁹	Connective tissue disorders (e.g., Marfan syndrome or Ehlers–Danlos syndrome) predisposing to the FQ-related risk of heart valve regurgitation/incompetence.	Systemic and inhaled use

EMA, European Medicines Agency; FDA, Food and Drug Administration; FQ, fluoroquinolones.

However, other studies have reported contradictory results. In a recent cohort study based on a Taiwanese population, there was no connection between FQs and an increased incidence of AA/AD in patients with urinary tract infections (UTIs) compared with first- or second-generation cephalosporins.³⁴ However, this study had several limitations. Patients with UTIs usually do not undergo a comprehensive aortic evaluation, and there were surveillance biases in this study. Additionally, the number of events in the subgroup analysis was relatively limited. Nevertheless, this study also suggests that the major objective for patients with UTIs is the administration of adequate medications and infection management. Dong et al. analyzed 21,651,176 adult patients in the Taiwan Population Health Insurance claims database and found patients with sepsis (OR, 3.16; 95% CI, 2.63–3.78) and abdominal infection (OR, 2.99; 95% CI, 2.45–3.65) had the highest AA/AD risk increase if they received FQs within 60 days.³⁵ However, FQs did not demonstrate an increased risk of AA/AD when compared with amoxicillin–clavulanic acid or ampicillin–sulbactam (OR, 1.01; 95% CI, 0.82–1.24), and the results were stable when compared with those using extended spectrum cephalosporins (OR, 0.88; 95% CI, 0.70–1.11). Although various corrections have been made for detection and monitoring biases in contemporary studies, no definite causal relationship has been derived from these observational studies. Hence, additional randomized clinical studies with larger sample sizes and stringent control for other factors should be performed. In addition, the long-term use of FQs remains common in patients with multidrug-resistant tuberculosis (MDRTB) and chronic bacterial prostatitis.³⁶ Future studies should consider the impact of long-term FQ exposure on aortic disorders. Additional study characteristics are presented in Table 2.

Table 2.

Clinical studies of aortic aneurysm or aortic dissection (AA/AD) risk associated with fluoroquinolones (FQs).

Comparison	Study design	Region	Comparator antibiotics exposure	Study participants, n		Mean age (SD or range)		Men, %		FQ use	Risk window,days	AA/AD risk,95% CI	Ref.
Comparison	Study design	Region	Comparator antibiotics exposure	Study group	Control group	Study group	Control group	Study group	Control group	FQ use	Risk window,days	AA/AD risk,95% CI	Ref.
AA/AD vs non-AA/AD	Nested case–control study	Taiwan	–	1512	147,700	AA 74.7 (11.7) AD 66.2 (14.5)	71.0 (13.7)	AA 74.1 AD 71.5	72.9	⩾ 3 days^a	60	RR 2.43, 1.83–3.22	Lee et al. 2015¹⁷
AA/AD vs non-AA/AD	Case-crossover study	Taiwan	–	1213	1213	70.6 (13.8)	70.5 (13.7)	72.5	72.5	⩾ 3 days	60	OR 2.52, 1.44–4.44	Lee et al. 2018²⁰
FQ use vs non-FQs	Population-based longitudinal cohort study	Ontario, Canada	AMX	657,950	1,086,410	65.0	65.0	48.6	48.9	RX	30	HR 3.13, 2.98–3.28	Daneman et al. 2015²⁴
FQ use vs AMX use	Nationwide historical cohort study	Sweden	AMX	360,088	360,088	67.9 (10.8)	68.0 (10.4)	45.0	45.0	RX	60	HR 1.66, 1.12–2.46	Pasternak et al. 2018²⁵
AA/AD vs non-AA/AD	Nested case–control study	Taiwan	AMC, SAM	28,948	289,480	67.4 (15.0)	67.4 (15.0)	71.4	71.4	⩾ 3 days	60	OR 1.01, 0.82–1.24	Dong et al. 2020³⁵
FQs vs comparator antibiotics	Cohort study	United States	AMC, AZM, CLX, CLI, SMX/TMP	9,053,961	38,542,584	47.0 (36.0–57.0)	43.0 (31.0–54.0)	38.7	40.5	RX	90	HR 1.20, 1.17–1.24	Newton et al. 2021³¹
FQ use vs non-FQs	Cohort study	Taiwan	AMX	14,853	682,318	73.1 (63.4–79.9)	68.5 (55.7–77.3)	69.7	72.0	⩾ 3 days	60	HR 1.80, 1.50–2.15	Chen et al. 2021³²
FQs vs comparator antibiotics	Cohort study	Taiwan	First- or second-generation cephalosporins	28,568	28,568	(⩾ 18.0)	(⩾ 18.0)	28.2	28.1	RX	365	HR 0.86, 0.59–1.27	Chen et al. 2022³⁴

FQs are drugs that contain any of the following active compounds: ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin, norfloxacin, lomefloxacin, moxifloxacin, gemifloxacin, enoxacin, or pefloxacin.

Dash (–) indicates data are missing or not available.

RX indicates that patients received at least one FQ during follow up.

In this study, use of FQ was assumed whenever there was any order for a reimbursement code of oral FQ with a prescription length of 3 days or longer.

AMC, amoxicillin–clavulanate; AMX, amoxicillin; AZM, azithromycin; CLI, clindamycin; CLX, cephalexin; OR, odds ratio; RR, rate ratio; SAM, ampicillin-sulbactam; SMX/TMP, sulfamethoxazole/trimethoprim.

FQ-related structural damage to the aorta

The aorta wall is primarily composed of various types of cells and ECM.³⁷ Anatomically, the aortic wall can be divided into three layers arranged in concentric circles: the intima, media, and adventitia.³⁸ The three layers are separated by internal and external elastic lamina. The endothelial cells lining the inner surface of the aortic wall constitute the majority of the cellular composition.³⁹ The media is the thickest and is predominantly composed of multilayer VSMCs and elastic lamellae.⁴⁰ The adventitia comprises adipocytes, fibroblasts, and blood arteries that supply the tissue.⁴¹ The media consists of dozens of annular VSMCs and annular elastic lamellae arranged in a concentric circular structure.⁴² The function and number of cells in the aorta wall and the composition of ECMs determine the structure and strength of the aortic wall, which in turn affects the risk of aortic dilation or dissection.^37,43 According to recent investigations, FQs can disrupt the aortic ECM, induce VSMC damage and phenotypic alterations, and cause local aortic inflammation (Table 3).

Table 3.

In vitro and animal experiments associated with fluoroquinolone-related aortic aneurysm or aortic dissection.

FQs used	Dose and route of FQs	Organisms, molding method	Effect			Mechanism				Ref.
FQs used	Dose and route of FQs	Organisms, molding method	Diameter	Dissection	Rupture rate	Degradation of ECM	VSMC	Inflammation	Others	Ref.
CPFX	100 mg/kg/day, gavage for 4 weeks	C57BL/6J mice aged 4 weeks, high-fat diet 8 weeks + Ang II (1000 ng/min/kg) IH, 4 weeks	↑	↑	↑	MMP-9 ↑ MMPs activity ↑ LOX ↓	Inhibit proliferation, induce death	ROS ↑	–	LeMaire et al. 2018⁴⁹
CPFX	0~200 µg/mL, co-culture for 24 h	Human arterial smooth muscle cells	–	–	–	MMP-1/9 ↑ MMPs activity ↑ LOX ↓ TIMP-1 ↓	Inhibit proliferation, induce death	ROS ↑	STING signaling pathway ↑	LeMaire et al. 2018⁴⁹
CPFX	100 mg/kg/day, IP for 2 weeks or 4 weeks	Male SD rat aged 2–4 months, extraluminal application of 0.5 M CaCl₂	↑	↑	–	–	–	–	–	Çulpan et al. 2022⁵⁷
CPFX	100 mg/kg/day, gavage for 4 weeks	8-week-old mice with Marfan syndrome (Fbn1^C1041G+)	↑	↑	↑	LOX ↓MMP2/9 ↑	–	–	–	LeMaire et al. 2022⁵⁰
CPFX	40 mg/kg/day, IP for 2 weeks	Male C57BL/6 mice aged 3 weeks, BAPN (1 mg/g/day) PO, 4 weeks	↑	↑	↑	MMP-9 ↑ TIMP-2 ↓	OPN ↑ SM22α ↓ Induce apoptosis	–	–	Xiang et al. 2023⁴⁸
CPFX	100 and 200 µg/mL, co-culture for 24 h	Human arterial smooth muscle cells	–	–	–	MMP-2/9 ↑ TIMP-1/2 ↓ COL I/IV ↓	OPN ↑ SM22α ↓ Induce apoptosis	IL-6 ↑ IL-1β ↑ ROS ↑	ERK1/2 and P38 MAPK signaling pathway ↑	Xiang et al. 2023⁴⁸
MFX	30 and 100 mg/kg/day, gavage for 3 weeks	C57BL/6J mice aged 4 weeks, high-fat diet 8 weeks + Ang II (1000 ng/min/kg) IH, 4 weeks	↑	↑	↑	OPN ↑ MMP-2 ↓	SM22α ↓ Induce death	–	–	Inada et al. 2022⁵¹

An upward arrow (↑) represents an increase in severity of aortic disease or in the quantity of molecules; a downward arrow (↓) means reduction.

Dash (–) indicates data are missing or not available.

BAPN, beta-aminopropionitrile; COL, collagen; CPFX, ciprofloxacin; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; FQs, fluoroquinolones; IH, subcutaneous injection; IL, interleukin; IP, intraperitoneal injection; LOX, lysyl oxidase; MAPK, mitogen-activated protein kinase; MFX, moxifloxacin; MMP, matrix metalloproteinase; OPN, osteopontin; ROS, reactive oxygen species; SD, Sprague Dawley; SM22α, smooth muscle protein 22-alpha; STING, stimulator of interferon genes; TIMP, tissue inhibitor of metalloproteinase; VSMC, vascular smooth muscle cell.

Disruption of the ECM

ECM is the predominant noncellular component of the aorta, and its components and structure are in a dynamic balance between constant renewal, degradation, and remodeling.⁴⁴ Collagen and elastin are the primary ECM components responsible for maintaining mechanical properties of the aorta wall, accounting for 30% and 35% of its dry weight, respectively.⁴⁵ In addition, overexpression of MMP degrades collagen and elastin, resulting in structural damage to the ECM.⁴⁶ As shown in Figure 1, when the ECM is damaged or its structure is altered, aortic strength and elasticity are diminished.⁴⁷ As a result, the aorta is more susceptible to permanent dilatation or rupture of the lining as it opposes the pulse of blood, with particularly pronounced variations in blood pressure.

Figure 1.

Fluoroquinolones (FQs) are associated with structural damage of the aorta. The aorta consists of three layers; from the inside out are the intima, the media, and the adventitia. There is an elastic lamina between each layer. The media consists of dozens of annular VSMCs and annular elastic lamellae arranged in a concentric circle structure. VSMCs are the highest proportion of cells in the media. Under the influence of FQs, VSMCs switch to other phenotypes from contractile phenotype. Among them, macrophage-like VSMCs secrete massive cytokines, recruit circulating macrophages and lymphocytes into the arterial wall, and aggravate the local inflammatory response. MMPs secreted by macrophages and macrophage-like VSMCs degrade collagen and elastin abundant in ECM, thus causing the degradation and disappearance of elastic lamellae. Moreover, under the influence of FQs, massive VSMCs died in the media, and the level of TIMP, LOX, and COL I/IV decreased, which further reduced the contractility and strength of the arterial wall. Together, these factors contribute to an increased susceptibility to AA/AD.

Ciprofloxacin (200 µg/mL) decreased the mRNA levels of COL I/IV in cultured human arterial smooth muscle cells (SMCs).⁴⁸ Ciprofloxacin (100 mg/kg/day) increases the activity of MMPs and the level of MMP-9⁴⁹ in the aortic wall of mice with AA and AD. Ciprofloxacin (100 mg/kg/day) significantly promotes the deterioration of aortic elastic fiber structure in rats with Marfan syndrome and considerably elevates the expression of Mmp2 and Mmp9.⁵⁰ Given that osteopontin (OPN) can induce the expression of MMP2/9, Inada et al. found that moxifloxacin (30 and 100 mg/kg/day) increased the expression of Opn in the aorta of angiotensin II-treated mice. Therefore, MMP2 overexpression and elastin breakdown are induced by FQs.⁵¹ MMP activity is regulated by endogenous tissue inhibitors of MMPs (TIMPs). An imbalance in MMP/TIMP can cause excessive ECM degradation.⁵² The expression of TIMP1/2 of VSMCs in a human aortic microphysiological model was significantly down-regulated after ciprofloxacin (200 µg/mL) treatment.⁴⁸ Furthermore, ciprofloxacin exposure significantly reduced TIMPs and collagen secretion in aortic myoblasts, resulting in a significant increase in the MMP-9/TIMP-2 ratio.⁵³

Ciprofloxacin not only directly or indirectly induces the enhancement of MMPs, but also destroys the structural stability of the ECM fibrin. Lysyl oxidase (LOX) is an amine oxidase involved in the assembly and stability of elastic fiber.^54,55 Ciprofloxacin (100 mg/kg/day) reduced LOX levels in the aortic wall of aortic aneurysm and dissection (AA/AD) mice, promoted AA/AD formation, and increased susceptibility to aortic rupture.⁴⁹ Disruption of the ECM can lead to progressive enlargement of the aortic diameter. In clinical practice, the maximal AAA diameter is the most commonly used measure to assess the risk of AAA rupture.⁵⁶ In a recent study, Çulpan et al. observed that ciprofloxacin (100 mg/kg/day) significantly increased the abdominal aortic diameter in a CaCl₂-induced AAA model in Sprague Dawley (SD) rats, which was linked to the duration of ciprofloxacin treatment.⁵⁷ However, short-term (4 weeks) use of FQs did not appear to cause significant expansion of the diameter of the normal aorta, but significantly aggravated the destruction of the aortic wall in the presence of risk factors (angiotensin II or elastase induction). Therefore, these results suggest that FQs disrupt the aortic ECM by inducing excessive ECM degradation and reducing the structural stability of fibrin, which significantly promote the progression of AA/AD and increase susceptibility to AA rupture.

VSMC damage and phenotypic transformation

Most VSMCs are located in the media, which is the primary cellular component of the aortic wall. Its status and quantity are closely related to the function of the aorta.⁵⁸ Ciprofloxacin can induce damage and increased apoptosis of aortic cells in mice, and the expression of apoptotic genes (such as Bcl2, Bax, Caspase-3) is significantly up-regulated. Ciprofloxacin decreases the activity of normal human aortic VSMCs in a dose-dependent manner and promotes cell death. It has been reported to cause subcellular nuclear and mitochondrial DNA damage in aortic VSMCs, followed by mitochondrial dysfunction and the production of reactive oxygen species.⁴⁹ Xiang et al. found that ciprofloxacin (200 µg/mL) induced mitochondrial dysfunction in human aortic VSMCs and promoted apoptosis via the P38 and ERK1/2 MAPK pathways.⁴⁸

Previously, VSMCs were classified as contractile and synthetic/proliferative phenotypes. As the primary type of VSMCs, contractile VSMCs not only maintain the integrity of the aortic wall, but also provide them with abundant tension and active elasticity to avoid excessive expansion of the aorta in response to blood pressure.^47,59 Under the action of multiple injury factors inside and outside the blood vessels, the number of contractile VSMCs is excessively reduced owing to apoptosis, or the phenotypic transformation of VSMCs is caused by impaired mitochondrial function, which leads to decreased strength of the aortic wall, and VSMCs cannot complete the recovery of artery shape after cardiac pulse injection through contraction. This results in an overexpansion of the blood vessel wall and its eventual rupture.⁶⁰ Synthetic VSMCs have weak contractility but robust proliferative and secretory properties, including collagen, elastin, laminin, gelatin, and proteoglycan.⁴⁷ Synthetic VSMCs also play a pivotal role in preserving the vascular wall integrity. The dynamic balance between these two phenotypes is the basis of maintaining the physiological function of the aortic wall. In recent years, however, with the application of lineage tracing techniques and single-cell analysis techniques, researchers have newly defined macrophage-like, mesenchymal-like, fibroblast-like, and osteogenic VSMCs in addition to the above two phenotypes.⁶¹ Macrophage-like VSMCs have a certain phagocytic capability and release MMPs and chemokines, which can exacerbate the local inflammatory response and cause excessive degradation of elastin, thereby accelerating the progression of AA/AD. Recent studies have demonstrated that ciprofloxacin exposure significantly increases apoptosis and decreases cell activity in the aortic structure of mice with Marfan syndrome.⁵³ Ciprofloxacin (200 µg/mL) decreases the expression level of contractile markers smooth muscle 22 alpha (SM22α) and calponin 1 (CNN1) in human arterial SMCs. Moxifloxacin inhibits Sm22 expression in the aorta of angiotensin II-treated C57 male rats. The decreased expression of contractile phenotypic markers suggests the transformation of VSMCs to synthesis, and the secretion of OPN and MMP-2 leads to remodeling of the aortic wall structure.^48,51 Al-Neklawy et al. conducted pathological staining of sections from rats treated with ciprofloxacin, revealing multiple tissue losses in the tunica media, disordered arrangement of VSMCs, abnormal reduction in the number of VSMCs, and most notably, an increase in eosinophilic VSMCs, which may be the result of VSMCs injury. The diminished immunohistochemical staining of α-smooth muscle actin (αSMA) in the ciprofloxacin-treated group was indicative of phenotypic transition of VSMCs.⁶² Moreover, as a DNA topoisomerase inhibitor, ciprofloxacin can cause nuclear and mitochondrial DNA damage and induce mitochondrial dysfunction and reactive oxygen production, thereby promoting the phenotypic transformation of VSMCs.⁴⁹ There are currently a small number of studies examining whether FQs influence the phenotypic transformation of VSMCs, and lineage tracing and single-cell analysis techniques are uncommon in this field. It is anticipated that inhibition of the transformation of VSMCs into macrophage-like phenotypes will become a crucial therapeutic target for AA/AD. More relevant and in-depth research in this field in the future is recommended.

Aortic inflammatory response

It has been established that inflammatory responses play a crucial role in the onset and progression of AA and AD.⁶³ A substantial number of chronic inflammatory cells, such as lymphocytes, macrophages, mast cells, and neutrophils infiltrate the tunica media and adventitia of AA and AD, which are essential for aortic injury and repair. Circulating neutrophils are involved in the early stages of AAA formation, but their numbers do not differ significantly in the late stages.⁶³ Mononuclear macrophages are the most abundant inflammatory cell type, and infiltrating macrophages can be polarized into either M1 or M2 subtypes. Stimulated by tissue inflammatory factors, M1-type macrophages produce proteolytic enzymes such as MMPs to participate in tissue remodeling, and secrete a variety of chemokines to recruit more monocytes/macrophages and lymphocytes into the aortic wall, forming a positive feedback loop.⁶⁴ In contrast, M2-type macrophages exert an antiinflammatory function, mainly by secreting cytokines such as interleukin (IL)-4, IL-10, and IL-13.⁶⁵ In AA and AD, the M1/M2 balance is disrupted, which triggers the onset or progression of local inflammation. It has been shown that the depletion of CD11c⁺ antigen-presenting cells (DCs) can significantly reduce the maximum AAA diameter.⁶⁶ Mast cell-derived proteases, such as trypsin, synergistically increase MMP expression and VSMCs apoptosis synergistically.⁶⁷ Notably, there is a positive correlation between the number of mast cells and the maximum AAA diameter.⁶⁸ As both CD4⁺ T cells and CD8⁺ T cells accumulate in AAA samples, studies have shown that IFN-γ released by CD8⁺ T cells can promote the recruitment of macrophages, thus increasing the expressions of proteolytic enzymes and chemokines.⁶⁹

IL-6 and IL-β1 are important proinflammatory cytokines that recruit monocytes into the arterial wall and are closely associated with AAA and preruptured AAA.⁷⁰ Ciprofloxacin induces the increased expression of proinflammatory factors (IL-6 and IL-1β) and reactive oxygen species in aortic SMCs.⁴⁹ In a recent study, Çulpan et al. discovered that ciprofloxacin administration (100 mg/kg/day) resulted in severe inflammatory changes and structural damage to the aortic wall in a AAA model of SD rats induced by CaCl₂.⁵⁷ Inflammation influences the risk of aortic dilation and rupture and is involved in aortic remodeling. However, few studies have investigated fluoroquinolone-induced inflammatory responses in AA and AD. It is necessary to further study the number and type of inflammatory cells and the expression level of inflammatory factors in the aortic wall following FQ exposure, as this is believed to be an important mechanism by which FQs promote the advancement of AA and AD.

Mechanisms for future study

Changes in endothelial cell function also play important roles in the occurrence and development of AA/AD.^71,72 Endothelial cells secrete vasoactive chemicals, participate in the interchange of fluids, form barriers, and contribute to coagulation and inflammation. Endothelial cells and the inner elastic membrane beneath them jointly form a vascular endothelial barrier that is compromised when endothelial cells die in significant numbers or when their function is impaired. Through the impaired intima, inflammatory cells penetrate the tunica media and release proinflammatory substances, resulting in additional degeneration of the tunica media. Hence, the occurrence and development of aneurysms and dissections is inevitable. Angiogenesis is prevalent in aneurysm tissues, and is most evident along the ruptured edge of an AA, indicating that it is associated with the evolution of AA.⁷³ In addition, angiogenic response is associated with inflammatory infiltration, which promotes aneurysm wall degeneration and rupture.⁷⁴ Possible mechanisms affecting the progression of AAA or dissection include the formation of neutrophil extracellular traps (NETs), loss of structural cells because of copper toxicity, and organelle destruction. However, to date, no relevant studies have been conducted. Exploration of the aforementioned directions is expected to further reveal the relevant mechanism of FQ-related AA/AD.

Summary

As the global population ages, researchers have predicted that the disease burden of AA/AD will continue to increase over the next decade.^75,76 Recent basic studies have shown that FQs can increase susceptibility to AA/AD and aggravate its progression through multiple pathways (ECM degradation and remodeling, increased phenotypic transformation and loss of VSMCs, and vascular wall inflammation). However, the relevant mechanisms are still not well studied. Currently, except for reducing the use of FQs, there is no effective method for inhibiting the occurrence of FQ-related AA/AD. The phenotypic transformation of VSMCs, recruitment of inflammatory cells, changes in endothelial cell function, and neovascularization require further investigation. As FQs are one of the most widely used antibiotics, the use of alternative medicines or shorter courses to reduce unnecessary FQs treatments can help reduce the global burden of AA/AD. Based on the available evidence, we believe that health care professionals should be fully aware of the aortic risks associated with FQs. When FQs are prescribed, patients should stop taking them and seek medical attention if AA/AD-related symptoms occur. In patients with AA/AD, aortic dilatation, AA/AD high-risk patients (such as those with Marfan syndrome, Loys–Dietz syndrome, contractile-Goldman syndrome, familial thoracic aortic aneurysm, and dissection), and older adults, the benefit-risk should be carefully evaluated and FQs replaced with other antibiotics whenever possible. If FQ use is unavoidable in high-risk populations, aortic-related imaging should be considered during and after use of FQs. The use of FQs has saved the lives of numerous infected individuals. For low-risk patients with AA/AD, the use of appropriate FQs for infection control remains a first-line consideration, and optimal antiinfective therapy should not be delayed because of concerns regarding AA/AD.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81870354), Scientific Research Project of Shanxi Provincial Health Commission (Grant No. 202203021211031), and Graduate Education Innovation Program of Shanxi Provincial Education Institution (Grant No. 2022Y383).

ORCID iDs

Xuezhen Xuan

Honglin Dong

References

Tan

Luo

, et al. SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS. J Am Heart Assoc 2013; 2: e000269.

Schwaerzer

Kalyanaraman

Casteel

, et al. Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B₁₂ analog. Nat Commun 2019; 10: 3533.

Chen

Wang

Cao

, et al. Mechanisms underlying the inhibitory effects of probucol on elastase-induced abdominal aortic aneurysm in mice. Br J Pharmacol 2020; 177: 204–216.

Roth

Johnson

Abajobir

, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol 2017; 70: 1–25.

Bhak

Wininger

Johnson

, et al. Factors associated with small abdominal aortic aneurysm expansion rate. JAMA Surg 2015; 150: 44–50.

Suki

Zhang

. Avalanches and power law behavior in aortic dissection propagation. Sci Adv 2020; 6: eaaz1173.

Haddad Kashani

Schmelcher

Sabzalipoor

, et al. Recombinant endolysins as potential therapeutics against antibiotic-resistant staphylococcus aureus: Current status of research and novel delivery strategies. Clin Microbiol Rev 2017; 31: e00071-17.

Bhatt

Chatterjee

. Fluoroquinolone antibiotics: Occurrence, mode of action, resistance, environmental detection, and remediation – A comprehensive review. Environ Pollut 2022; 315: 120440.

Bojanić

Marković-Peković

Škrbić

, et al. Recent initiatives in the Republic of Srpska to enhance appropriate use of antibiotics in ambulatory care: Their influence and implications. Front Pharmacol 2018; 9: 442.

10.

Sendzik

Shakibaei

Schäfer-Korting

, et al. Synergistic effects of dexamethasone and quinolones on human-derived tendon cells. Int J Antimicrob Agents 2010; 35: 366–374.

11.

Tsai

Hsu

Chen

, et al. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen. J Orthop Res 2011; 29: 67–73.

12.

Corps

Harrall

Curry

, et al. Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1β in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum 2002; 46: 3034–3040.

13.

Sharma

Velpandian

Baska Singh

, et al. Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats. Toxicol Mech Methods 2011; 21: 6–12.

14.

Pouzaud

Bernard-Beaubois

Thevenin

, et al. In vitro discrimination of fluoroquinolones toxicity on tendon cells: Involvement of oxidative stress. J Pharmacol Exp Ther 2004; 308: 394–402.

15.

Fletcher

Syed

MBJ

Aitman

, et al. Inherited thoracic aortic disease: New insights and translational targets. Circulation 2020; 141: 1570–1587.

16.

Zhang

Liu

, et al. Polycystin-1 downregulation induced vascular smooth muscle cells phenotypic alteration and extracellular matrix remodeling in thoracic aortic dissection. Front Physiol 2020; 11: 548055.

17.

Lee

Chen

, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med 2015; 175: 1839–1847.

18.

Harrison

Smith

Jones

, et al. Interleukin-6 receptor pathways in abdominal aortic aneurysm. Eur Heart J 2013; 34: 3707–3716.

19.

Erbel

Aboyans

Boileau

, et al. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014; 35: 2873–2926.

20.

Lee

Hsieh

, et al. Oral fluoroquinolone and the risk of aortic dissection. J Am Coll Cardiol 2018; 72: 1369–1378.

21.

Lopes

Almeida

Dias

, et al. Infectious thoracic aortitis: A literature review. Clin Cardiol 2009; 32: 488–490.

22.

Oderich

Panneton

Bower

, et al. Infected aortic aneurysms: Aggressive presentation, complicated early outcome, but durable results. J Vasc Surg 2001; 34: 900–908.

23.

Wilson

Bower

Creager

, et al. Vascular graft infections, mycotic aneurysms, and endovascular infections: A Scientific Statement from the American Heart Association. Circulation 2016; 134: e412–e460.

24.

Daneman

Redelmeier

. Fluoroquinolones and collagen associated severe adverse events: A longitudinal cohort study. BMJ Open 2015; 5: e010077.

25.

Pasternak

Inghammar

Svanström

. Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study. BMJ 2018; 360: k678.

26.

U.S. Food & Drug Administration. FDA Drug Safety Communication: FDA updates warnings for oral and injectablefluoroquinolone antibiotics due to disabling side effects, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-updates-warnings-oral-and-injectable-fluoroquinolone-antibiotics (2018, accessed July 15, 2023).

27.

Arlett

. Pharmacovigilance in 2018, https://www.ema.europa.eu/en/documents/other/presentation-pharmacovigilance-2018-p-arlett_en.pdf (2018, accessed July 15, 2023).

28.

U.S. Food & Drug Administration. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients, https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics (2018, accessed July 15, 2023).

29.

European Medicines Agency. Direct Healthcare Professional Communication – Systemic and inhaled fluoroquinolones: risk of heart valve regurgitation/incompetence, https://www.ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communication-dhpc-systemic-inhaled-fluoroquinolones-risk-heart-valve/incompetence_en.pdf (2020, accessed July 15, 2023).

30.

Bennkdalekdaleett

Bennett

Witherspoon

, et al. An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency. Expert Opin Drug Saf 2019; 18: 1055–1063.

31.

Newton

Akerman

Strassle

, et al. Association of fluoroquinolone use with short-term risk of development of aortic aneurysm. JAMA Surg 2021; 156: 264–272.

32.

Chen

Chan

Chien-Chia Wu

, et al. Effects of fluoroquinolones on outcomes of patients with aortic dissection or aneurysm. J Am Coll Cardiol 2021; 77: 1875–1887.

33.

Chen

Patterson

Simpson

, et al. Do fluoroquinolones increase aortic aneurysm or dissection incidence and mortality? A systematic review and meta-analysis. Front Cardiovasc Med 2022; 9: 949538.

34.

Chen

Yang

Yeh

, et al. Association between aortic aneurysm and aortic dissection with fluoroquinolones use in patients with urinary tract infections: A population-based cohort study. J Am Heart Assoc 2022; 11: e023267.

35.

Dong

Chang

Wang

, et al. Association of infections and use of fluoroquinolones with the risk of aortic aneurysm or aortic dissection. JAMA Intern Med 2020; 180: 1587–1595.

36.

Mirzayev

Viney

Linh

, et al. World Health Organization recommendations on the treatment of drug-resistant tuberculosis, 2020 update. Eur Respir J 2021; 57: 2003300.

37.

Branchetti

Poggio

Sainger

, et al. Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovasc Res 2013; 100: 316–324.

38.

Maegdefessel

. Non-coding RNA contribution to thoracic and abdominal aortic aneurysm disease development and progression. Front Physiol 2017; 8: 429.

39.

Selçuk

Sungu

Parlakpinar

, et al. Evaluation of the cardiovascular effects of varenicline in rats. Drug Des Devel Ther 2015; 9: 5705–5717.

40.

Zhang

, et al. MicroRNA-15a-5p induces pulmonary artery smooth muscle cell apoptosis in a pulmonary arterial hypertension model via the VEGF/p38/MMP-2 signaling pathway. Int J Mol Med 2020; 45: 461–474.

41.

Touyz

Alves-Lopes

Rios

, et al. Vascular smooth muscle contraction in hypertension. Cardiovasc Res 2018; 114: 529–539.

42.

Olson

Soriano

. PDGFRβ signaling regulates mural cell plasticity and inhibits fat development. Dev Cell 2011; 20: 815–826.

43.

Liu

Zhang

Wang

, et al. Obstructive sleep apnea syndrome promotes the progression of aortic dissection via a ROS- HIF-1α-MMPs associated pathway. Int J Biol Sci 2019; 15: 2774–2782.

44.

Nallanthighal

Heiserman

Cheon

. The role of the extracellular matrix in cancer stemness. Front Cell Dev Biol 2019; 7: 86.

45.

Metcalf

Linders

, et al. Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expression. Mol Genet Metab 2010; 99: 396–407.

46.

Longo

Xiong

Greiner

, et al. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002; 110: 625–632.

47.

Wang

LeMaire

Chen

, et al. Increased collagen deposition and elevated expression of connective tissue growth factor in human thoracic aortic dissection. Circulation 2006; 114: I200–205.

48.

Xiang

Abudupataer

Liu

, et al. Ciprofloxacin exacerbates dysfunction of smooth muscle cells in a microphysiological model of thoracic aortic aneurysm. JCI Insight 2023; 8: e161729.

49.

LeMaire

Zhang

Luo

, et al. Effect of ciprofloxacin on susceptibility to aortic dissection and rupture in mice. JAMA Surg 2018; 153: e181804.

50.

LeMaire

Zhang

, et al. Ciprofloxacin accelerates aortic enlargement and promotes dissection and rupture in Marfan mice. J Thorac Cardiovasc Surg 2022; 163: e215–e226.

51.

Inada

Koga

Yamada

, et al. Moxifloxacin induces aortic aneurysm and dissection by increasing osteopontin in mice. Biochem Biophys Res Commun 2022; 629: 1–5.

52.

Maguire

Pearce

SWA

Xiao

, et al. Matrix metalloproteinase in abdominal aortic aneurysm and aortic dissection. Pharmaceuticals (Basel) 2019; 12: 118.

53.

Guzzardi

Teng

Kang

, et al. Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy. J Thorac Cardiovasc Surg 2019; 157: 109–119.e2.

54.

Erler

Bennewith

Cox

, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 2009; 15: 35–44.

55.

Tsang

Knutsen

Billington

Jr , et al. Copper-binding domain variation in a novel murine lysyl oxidase model produces structurally inferior aortic elastic fibers whose failure is modified by age, sex, and blood pressure. Int J Mol Sci 2022; 23: 6749.

56.

Martufi

Forneris

Nobakht

, et al. Case study: Intra-patient heterogeneity of aneurysmal tissue properties. Front Cardiovasc Med 2018; 5: 82.

57.

Çulpan

Keçeci

Sandıkçı

, et al. Duration of ciprofloxacin use is important in the development of abdominal aortic aneurysm in a rat model. Anatol J Cardiol 2022; 26: 810–817.

58.

Osman

Liu

, et al. TEAD1 (TEA domain transcription factor 1) promotes smooth muscle cell proliferation through upregulating SLC1A5 (solute carrier family 1 member 5)-mediated glutamine uptake. Circ Res 2019; 124: 1309–1322.

59.

Kostina

Zverev

Grebennik

, et al. Aortic graft at coronary artery bypass surgery as a source of human aortic smooth muscle cells. Cell Transplant 2017; 26: 1663–1668.

60.

Christensen

Mulvany

. Location of resistance arteries. J Vasc Res 2001; 38: 1–12.

61.

Feil

Fehrenbacher

Lukowski

, et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 2014; 115: 662–667.

62.

Al-Neklawy

El-Nefiawy

Rady

. Does oral ciprofloxacin affect the structure of thoracic aorta in adult and senile male albino rats? A clue to fluoroquinolones-induced risk of aortic dissection. Anat Cell Biol 2022; 55: 79–91.

63.

Eliason

Hannawa

Ailawadi

, et al. Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation. Circulation 2005; 112: 232–240.

64.

Komohara

Fujiwara

Ohnishi

, et al. Contribution of macrophage polarization to metabolic diseases. J Atheroscler Thromb 2016; 23: 10–17.

65.

Crosby

Kronenberg

. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol 2018; 18: 559–574.

66.

Krishna

Moran

Jose

, et al. Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth. Clin Sci (Lond) 2019; 133: 2203–2215.

67.

Wang

Shi

. Mast cell chymase and tryptase in abdominal aortic aneurysm formation. Trends Cardiovasc Med 2012; 22: 150–155.

68.

Tsuruda

Kato

Hatakeyama

, et al. Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ Res 2008; 102: 1368–1377.

69.

Zhou

Yan

Cannon

, et al. CD43-mediated IFN-γ production by CD8+ T cells promotes abdominal aortic aneurysm in mice. J Immunol 2013; 190: 5078–5085.

70.

Middleton

Lloyd

Bown

, et al. The pro-inflammatory and chemotactic cytokine microenvironment of the abdominal aortic aneurysm wall: A protein array study. J Vasc Surg 2007; 45: 574–580.

71.

Verstraeten

Fedoryshchenko

Loeys

. The emerging role of endothelial cells in the pathogenesis of thoracic aortic aneurysm and dissection. Eur Heart J 2023; 44: 1262–1264.

72.

Luo

Kong

Zhao

, et al. Endothelial HDAC1-ZEB2-NuRD complex drives aortic aneurysm and dissection through regulation of protein S-sulfhydration. Circulation 2023; 147: 1382–1403.

73.

Choke

Thompson

Dawson

, et al. Abdominal aortic aneurysm rupture is associated with increased medial neovascularization and overexpression of proangiogenic cytokines. Arterioscler Thromb Vasc Biol 2006; 26: 2077–2082.

74.

Wang

Xiong

, et al. Quercetin downregulates cyclooxygenase-2 expression and HIF-1α/VEGF signaling-related angiogenesis in a mouse model of abdominal aortic aneurysm. Biomed Res Int 2020; 2020: 9485398.

75.

Huang

Wang

Shen

, et al. Projection of global burden and risk factors for aortic aneurysm – timely warning for greater emphasis on managing blood pressure. Ann Med 2022; 54: 553–564.

76.

Bossone

Eagle

. Epidemiology and management of aortic disease: Aortic aneurysms and acute aortic syndromes. Nat Rev Cardiol 2021; 18: 331–348.