Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning.

AIMS: Post-ovariectomy (OVX) changes in hormones induce obesity and white adipose tissue (WAT) inflammation. Increased energy expenditure via WAT browning is a novel therapeutic strategy for treating obesity. Naringenin (NAR) reduces inflammation and lipogenesis in obesity and attenuates estrogen deficiency-associated metabolic disorders; however, its role in WAT browning remains unclear. MATERIALS AND METHODS: We investigated NAR ability to inhibit estrogen deficiency-associated obesity in vivo using a rat model and in vitro using 3T3-L1 adipocytes. KEY FINDINGS: NAR significantly decreased the body weight and WAT mass of rats. O2 consumption, CO2 production, and energy expenditure were significantly lower in the OVX group than in the sham group, but NAR treatment reversed these effects of OVX. NAR treatment markedly improved glucose intolerance and lipid profiles as well as leptin, adiponectin, and irisin levels. NAR upregulated markers of browning and mitochondrial biogenesis in inguinal WAT. Moreover, it enhanced markers of mitochondrial fusion and inhibited fission via activating the AMP-activated protein kinase pathway. Similar results were observed in 3T3-L1 adipocytes. Moreover, NAR-induced mitochondrial biogenesis and fusion were suppressed by dorsomorphin (an AMP-activated protein kinase inhibitor). SIGNIFICANCE: NAR alleviates obesity and metabolic dysfunction through the induction of WAT browning achieved via the modulation of AMP-activated protein kinase-regulated mitochondrial dynamics in WATs. NAR supplementation may therefore represent a potential intervention for preventing postmenopausal adipose tissue dysregulation.

PGC-1α-mediated angiogenesis prevents pulmonary hypertension in mice.

Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell-specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α-mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.

A Pacing-Controlled Procedure for the Assessment of Heart Rate-Dependent Diastolic Functions in Murine Heart Failure Models.

Heart failure with preserved ejection fraction (HFpEF) is a condition characterized by diastolic dysfunction and exercise intolerance. While exercise-stressed hemodynamic tests or MRI can be used to detect diastolic dysfunction and diagnose HFpEF in humans, such modalities are limited in basic research using mouse models. A treadmill exercise test is commonly used for this purpose in mice, but its results can be influenced by body weight, skeletal muscle strength, and mental state. Here, we describe an atrial-pacing protocol to detect heart rate (HR)-dependent changes in diastolic performance and validate its usefulness in a mouse model of HFpEF. The method involves anesthetizing, intubating, and performing pressure-volume (PV) loop analysis concomitant with atrial pacing. In this work, a conductance catheter was inserted via a left ventricular apical approach, and an atrial pacing catheter was placed in the esophagus. Baseline PV loops were collected before the HR was slowed with ivabradine. PV loops were collected and analyzed at HR increments ranging from 400 bpm to 700 bpm via atrial pacing. Using this protocol, we clearly demonstrated HR-dependent diastolic impairment in a metabolically induced HFpEF model. Both the relaxation time constant (Tau) and the end-diastolic pressure-volume relationship (EDPVR) worsened as the HR increased compared to control mice. In conclusion, this atrial pacing-controlled protocol is useful for detecting HR-dependent cardiac dysfunctions. It provides a new way to study the underlying mechanisms of diastolic dysfunction in HFpEF mouse models and may help develop new treatments for this condition.

Perivascular adipose tissue in vascular pathologies-a novel therapeutic target for atherosclerotic disease?

Most blood vessels are surrounded by adipose tissues known as perivascular adipose tissue (PVAT). Emerging experimental data have implicated the potential involvement of PVAT in the pathogenesis of cardiovascular disease: PVAT might be a source of inflammatory mediators under pathological conditions such as metabolic disorders, chronic inflammation, and aging, leading to vascular pathologies, while having vasculo-protective roles in a healthy state. PVAT has been also gaining attention in human disease conditions. Recent integrative omics approaches have greatly enhanced our understanding of the molecular mechanisms underlying the diverse functions of PVAT. This review summarizes recent progress in PVAT research and discusses the potential of PVAT as a target for the treatment of atherosclerosis.

The emerging role of estrogen's non-nuclear signaling in the cardiovascular disease.

Sexual dimorphism exists in the epidemiology of cardiovascular disease (CVD), which indicates the involvement of sexual hormones in the pathophysiology of CVD. In particular, ample evidence has demonstrated estrogen's protective effect on the cardiovascular system. While estrogen receptors, bound to estrogen, act as a transcription factor which regulates gene expressions by binding to the specific DNA sequence, a subpopulation of estrogen receptors localized at the plasma membrane induces activation of intracellular signaling, called "non-nuclear signaling" or "membrane-initiated steroid signaling of estrogen". Although the precise molecular mechanism of non-nuclear signaling as well as its physiological impact was unclear for a long time, recent development of genetically modified animal models and pathway-selective estrogen receptor stimulant bring new insights into this pathway. We review the published experimental studies on non-nuclear signaling of estrogen, and summarize its role in cardiovascular system, especially focusing on: (1) the molecular mechanism of non-nuclear signaling; (2) the design of genetically modified animals and pathway-selective stimulant of estrogen receptor.

Low-carbohydrate diets containing plant-derived fat but not animal-derived fat ameliorate heart failure.

Cardiovascular disease (CVD) is a global health burden in the world. Although low-carbohydrate diets (LCDs) have beneficial effects on CVD risk, their preventive effects remain elusive. We investigated whether LCDs ameliorate heart failure (HF) using a murine model of pressure overload. LCD with plant-derived fat (LCD-P) ameliorated HF progression, whereas LCD with animal-derived fat (LCD-A) aggravated inflammation and cardiac dysfunction. In the hearts of LCD-P-fed mice but not LCD-A, fatty acid oxidation-related genes were highly expressed, and peroxisome proliferator-activated receptor α (PPARα), which regulates lipid metabolism and inflammation, was activated. Loss- and gain-of-function experiments indicated the critical roles of PPARα in preventing HF progression. Stearic acid, which was more abundant in the serum and heart of LCD-P-fed mice, activated PPARα in cultured cardiomyocytes. We highlight the importance of fat sources substituted for reduced carbohydrates in LCDs and suggest that the LCD-P-stearic acid-PPARα pathway as a therapeutic target for HF.

Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.

Using the Cre-loxP system, we generated the first mouse model in which estrogen receptor-α non-nuclear signaling was inactivated in endothelial cells. Estrogen protection against mechanical vascular injury was impaired in this model. This result indicates the pivotal role of endothelial estrogen receptor-α non-nuclear signaling in the vasculoprotective effects of estrogen.

NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.

BACKGROUND: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1ß (interleukin-1ß) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1ß production to induce adaptive hypertrophy in the stressed heart. METHODS: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1ß antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1ß and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. RESULTS: Genetic disruption of NLRP3 resulted in significant loss of IL-1ß production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1ß production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1ß-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic ß-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1ß production, and adaptive cardiac hypertrophy during pressure overload. CONCLUSIONS: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

Endoplasmic reticulum stress-activated nuclear factor-kappa B signaling pathway induces the upregulation of cardiomyocyte dopamine D1 receptor in heart failure.

Dopamine D1 receptor (D1R), coded by the Drd1 gene, is induced in cardiomyocytes of failing hearts, triggering heart failure-associated ventricular arrhythmia, and therefore could be a potential therapeutic target for chronic heart failure. The regulation of D1R expression, however, is not fully understood. Here, we explored the molecular mechanism by which cardiomyocyte D1R is induced in failing hearts. We performed motif analysis for the promoter region of the Drd1 gene using the transcription factor affinity prediction (TRAP) method and identified nuclear factor-kappa B (NF-κB) as a candidate transcriptional factor regulating the expression of the Drd1 gene. We next employed murine models of heart failure from chronic pressure overload by transverse aortic constriction (TAC), and assessed myocardial Drd1 expression levels and NF-κB activity, as well as endoplasmic reticulum (ER) stress, which has been implicated in the pathogenesis of heart failure. Drd1 induction in TAC hearts was dependent on the severity of heart failure, and was associated with NF-κB activation and ER stress, as assessed by p65 phosphorylation and the expression of ER stress-related genes, respectively. We further tested if Drd1 was induced by ER stress via NF-κB activation in cultured neonatal rat ventricular myocytes. Tunicamycin activated NF-κB pathway in an ER stress-dependent manner and increased Drd1 expression. Importantly, inhibition of NF-κB pathway by pretreatment with Bay11-7082 completely suppressed the tunicamycin-induced upregulation of Drd1, suggesting that NF-κB activation is essential to this regulation. Our study demonstrates the pivotal role for the ER stress-induced NF-κB activation in the induction of D1R in cardiomyocytes. Intervention of this pathway might be a potential new therapeutic strategy for heart failure-associated ventricular arrhythmia.

Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Cyclic GMP and PKG Signaling in Heart Failure.

Cyclic guanosine monophosphate (cGMP), produced by guanylate cyclase (GC), activates protein kinase G (PKG) and regulates cardiac remodeling. cGMP/PKG signal is activated by two intrinsic pathways: nitric oxide (NO)-soluble GC and natriuretic peptide (NP)-particulate GC (pGC) pathways. Activation of these pathways has emerged as a potent therapeutic strategy to treat patients with heart failure, given cGMP-PKG signaling is impaired in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Large scale clinical trials in patients with HFrEF have shown positive results with agents that activate cGMP-PKG pathways. In patients with HFpEF, however, benefits were observed only in a subgroup of patients. Further investigation for cGMP-PKG pathway is needed to develop better targeting strategies for HFpEF. This review outlines cGMP-PKG pathway and its modulation in heart failure.

The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure.

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α+/+ hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α-/- hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG-PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.

Takotsubo Syndrome Occurring after mRNA COVID-19 Vaccination in a Patient with Graves' Disease.

Cardiovascular events such as myocarditis following mRNA COVID-19 vaccination are increasing. We present a 67-year-old postmenopausal woman with Takotsubo Syndrome and Graves' disease after mRNA COVID-19 vaccination. She developed chest pain and shortness of breath one week after vaccination. An electrocardiogram revealed ST elevation in the precordial leads. Coronary angiography revealed the absence of obstructive coronary artery disease, and the left ventriculography showed a typical feature with apical ballooning. Laboratory workup showed the elevation of free T4 and thyrotropin receptor antibodies. It was presumed that Takotsubo Syndrome and Graves' disease were probably related to the COVID-19 mRNA vaccination. The patient was treated with low-dose bisoprolol, diuretics, carbimazole, and steroid and discharged uneventfully. The mRNA COVID-19 vaccination is still safe and effective to defend against COVID-19 pandemic. However, clinicians should be aware of the possible cardiovascular adverse events other than myocarditis following vaccination.

Sex Differences and Regulatory Actions of Estrogen in Cardiovascular System.

Great progress has been made in the understanding of the pathophysiology of cardiovascular diseases (CVDs), and this has improved the prevention and prognosis of CVDs. However, while sex differences in CVDs have been well documented and studied for decades, their full extent remains unclear. Results of the latest clinical studies provide strong evidence of sex differences in the efficacy of drug treatment for heart failure, thereby possibly providing new mechanistic insights into sex differences in CVDs. In this review, we discuss the significance of sex differences, as rediscovered by recent studies, in the pathogenesis of CVDs. First, we provide an overview of the results of clinical trials to date regarding sex differences and hormone replacement therapy. Then, we discuss the role of sex differences in the maintenance and disruption of cardiovascular tissue homeostasis.

Preexisting heart failure with reduced ejection fraction attenuates renal fibrosis after ischemia reperfusion via sympathetic activation.

Although chronic heart failure is clinically associated with acute kidney injury (AKI), the precise mechanism that connects kidney and heart remains unknown. Here, we elucidate the effect of pre-existing heart failure with reduced ejection fraction (HFrEF) on kidney via sympathetic activity, using the combining models of transverse aortic constriction (TAC) and unilateral renal ischemia reperfusion (IR). The evaluation of acute (24 h) and chronic (2 weeks) phases of renal injury following IR 8 weeks after TAC in C57BL/6 mice revealed that the development of renal fibrosis in chronic phase was significantly attenuated in TAC mice, but not in non-TAC mice, whereas no impact of pre-existing heart failure was observed in acute phase of renal IR. Expression of transforming growth factor-ß, monocyte chemoattractant protein-1, and macrophage infiltration were significantly reduced in TAC mice. Lastly, to investigate the effect of sympathetic nerve activity, we performed renal sympathetic denervation two days prior to renal IR, which abrogated attenuation of renal fibrosis in TAC mice. Collectively, we demonstrate the protective effect of pre-existing HFrEF on long-term renal ischemic injury. Renal sympathetic nerve may contribute to this protection; however, further studies are needed to fully clarify the comprehensive mechanisms associated with attenuated renal fibrosis and pre-existing HFrEF.

Prevalence and characteristics of mitral valve prolapse in military young adults in Taiwan of the CHIEF Heart Study.

The prevalence of mitral valve prolapse (MVP) among middle- and older-aged individuals is estimated to be 2-4% in Western countries. However, few studies have been conducted among Asian individuals and young adults. This study included a sample of 2442 consecutive military adults aged 18-39 years in Hualien, Taiwan. MVP was defined as displacement of the anterior or posterior leaflet of the mitral valve to the mid portion of the annular hinge point > 2 mm in the parasternal long-axis view of echocardiography. Cardiac chamber size and wall thickness were measured based on the latest criteria of the American Society of Echocardiography. The clinical features of participants with MVP and those without MVP were compared using a two-sample t test, and the cardiac structures were compared using analysis of covariance with adjustment for body surface area (BSA). Eighty-two participants were diagnosed with MVP, and the prevalence was 3.36% in the overall population. Compared with those without MVP, participants with MVP had a lower body mass index (kg/m2) (24.89 ± 3.70 vs. 23.91 ± 3.45, p = 0.02) and higher prevalence of somatic symptoms related to exercise (11.0% vs. 4.9%, p = 0.02) and systolic click in auscultation (18.3% vs. 0.6%, p < 0.01). In addition, participants with MVP had greater left ventricular mass (gm) and smaller right ventricular wall thickness (mm) and dimensions (mm) indexed by BSA than those without MVP (149.12 ± 35.76 vs. 155.38 ± 36.26; 4.66 ± 0.63 vs. 4.40 ± 0.68; 26.57 ± 3.99 vs. 25.41 ± 4.35, respectively, all p-values < 0.01). In conclusion, the prevalence and clinical features of MVP in military young adults in Taiwan were in line with those in Western countries. Whether the novel MVP phenotype found in this study has any pathological meaning needs further investigation.

Factors associated with left ventricular reverse remodelling after percutaneous coronary intervention in patients with left ventricular systolic dysfunction.

Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function (LVEF < 50% at initial left ventriculography) were included in the analysis. LVRR was defined as LV end-systolic volume reduction ≥ 15% and improvement of LVEF ≥ 10% at 6 months follow-up left ventriculography. Patients were divided into LVRR (n = 63) and non-LVRR (n = 223) groups. Multivariate logistic regression analysis revealed that unprotected left main coronary artery (LMCA) intervention was significantly associated with LVRR (P = 0.007, odds ratios [OR] 4.70, 95% confidence interval [CI] 1.54-14.38), while prior PCI (P = 0.001, OR 0.35, 95% CI 0.19-0.66), presence of in-stent restenosis (P = 0.016, OR 0.32, 95% CI 0.12-0.81), and presence of de-novo stenosis (P = 0.038, OR 0.36, 95% CI 0.14-0.95) were negatively associated with LVRR. These data suggest the potential prognostic benefit of unprotected LMCA intervention for LVRR and importance of angiographic follow-up in patients with CAD and LV systolic dysfunction.