The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy.

Effect of the Ligation and Reperfusion Timeframe on Maximal Ischemia-Reperfusion Injury in Diverse Rat Models.

Background: Little is known about the effect that different time sequences for coronary ligation and reperfusion have on ischemic-reperfusion (IR) injury. Objective: To investigate the relationship between the extent of IR injury and the timeframe for coronary ligation/reperfusion in three animal models. Methods: Three rat models were used: normal Sprague-Dawley rats, diabetes mellitus (DM) rats, and fat rats. The rats in each model were divided into four groups based on the coronary ligation period (L): 30, 60, 120, and 180 min, and then divided into seven sub-groups based on the reperfusion period (R): 0, 30, 60, 120, 180, 270, and 360 min. R0 was the IR injury baseline for each sub-group. The hearts were harvested and stained with Evans blue and 2,3,5-triphenyl tetrazolium chloride dye to distinguish the different myocardial injury areas: area at risk (AAR) and myocardial necrosis. The difference between each subgroup and baseline (R0) for the necrotic area/AAR was calculated. Results: In the normal rats, the highest IR injury differences compared with the baseline group occurred at L120, with a reperfusion time of > 180 min. The highest IR injury difference compared to the baseline group occurred at L30, with a reperfusion time of > 180 min in the DM rats and at L60R270, L120R180 in the fat rats. Conclusions: IR injury, as induced by different coronary ligation and reperfusion time intervals, had diverse expression profiles in the different animal models. Optimal animal models with optimal coronary ligation/reperfusion protocols to achieve maximal IR injury will affect the results and interpretation of future studies.

Catheter Ablation Compared with Medical Therapy for Atrial Fibrillation with Heart Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Background: The optimal strategy for patients with coexisting atrial fibrillation (AF) and heart failure (HF) was not settled. Our purpose was to conduct a systematic review and meta-analysis of randomized controlled trials to evaluate the effect of catheter ablation compared with medical therapy for AF on mortality, HF hospitalization, left ventricular (LV) function, and quality of life among patients with HF and AF. Materials and Methods: We searched Pubmed (1966 to September 20, 2019), EMBASE (1966 to September 20, 2019), the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov for randomized controlled trials with a comparison of catheter ablation for AF with medical therapy among patients with coexisting AF and HF. Risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI) was used as a measure of the effect of catheter ablation versus medical therapy on endpoints. Our final analysis included 6 randomized control trials with 775 patients. Results: Pooled results from the random-effects model showed that compared with medical therapy for AF, catheter ablation was associated with reduced all-cause mortality (RR 0.52, 95%Cl, 0.35 to 0.76) and HF hospitalization (RR 0.56, 95%Cl, 0.44 to 0.71), as well as increased LV ejection fraction (LVEF), distance walked in six minutes, and improvements in quality of life. Conclusions: This updated meta-analysis showed that compared to medical therapy, catheter ablation for AF was associated with significant benefits in several key clinical and biomarker endpoints, including reductions in all-cause mortality and HF hospitalization.

Is it possible to expect left ventricular ejection fraction improvement in patients with known advanced heart diseases in the case of right atrial flutter treated by ablation?

BACKGROUND: Atrial flutter (AFL)-related tachycardia-induced cardiomyopathy (TICM) is a treatable cause of heart failure (HF). This study aims to explore the effect of AFL ablation on left ventricular (LV) function in right AFL patients with or without advanced heart diseases. METHODS: Between January 2013 and December 2019, 149 patients underwent ablation for persistent AFL. Among them, 60 patients with persistent right atrial (RA) flutter had symptomatic HF and elevated natriuretic peptide levels. Group 1 consisted of 35 patients without advanced heart diseases, and group 2 consisted of 25 patients with prior history of ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM) or surgery for valvular heart disease (VHD). Follow-up echocardiography was performed 6 months later. Improvement of LV performance was defined as LV ejection fraction (EF) increase ≥50% of baseline EF without clinical HF symptoms or LVEF recovery to ≥60%. RESULTS: Group 2 had larger LV end-diastolic volume (LVEDV) and LV end-systolic volume than group 1. At follow-up, group 2 had larger LV end-systolic volume than group 1. Group 1 had more increase in LVEF than group 2 (21.7 ± 15.2% vs 4.1 ± 13.2%; P < .001). A receiver operating characteristic curve was constructed to determine the discrimination threshold of baseline LVEDV (137 mL) in the overall study group for improvement of LV performance after ablation (P = .005). CONCLUSIONS: Successful ablation for right AFL could achieve more reversal of LV dysfunction in patients without advanced heart diseases. Pre-ablation LVEDV ≥ 137 mL was associated with no improvement of LV performance after ablation.

An Examination System to Detect Deep Vein Thrombosis of a Lower Limb Using Light Reflection Rheography.

Deep vein thrombosis (DVT) of lower limbs can easily arise from prolonged sitting or standing. Elders and pregnant women are most likely to have this disease. When the embolus of DVT comes to pass the lung, it will become a life-threatening disease. Thus, for DVT disease, early detection and the early treatment are needed. The goal of this study was to develop an examination system to be used at non-medical places to detect the DVT of lower limbs with light reflection rheography (LRR). Consisting of a wearable device and a mobile application (APP), the system is operated in a wireless manner to control the actions of sensors and display and store the LRR signals on the APP. Then, the recorded LRR signals are processed to find the parameters of DVT examination. Twenty subjects were recruited to perform experiments. The veins of lower limbs were occluded by pressuring the cuff up to 100 mmHg and 150 mmHg to simulate the slight and serious DVT scenarios, respectively. Six characteristic parameters were defined to classify whether there was positive or negative DVT using the receiver operating characteristic curves, including the slopes of emptying and refilling curves in the LRR signal, and the changes of venous pump volume. Under the slight DVT scenario (0 mmHg vs. 100 mmHg), the first three parameters, m10, m40, and m50, had accuracies of 72%, 69%, and 69%, respectively. Under the serious DVT scenario (0 mmHg vs. 150 mmHg), m10, m40, and m50 achieved accuracies of 73%, 76%, and 73%, respectively. The experimental results show that this proposed examination system may be practical as an auxiliary tool to screen DVT in homecare settings.

Sarcomeres Morphology and Z-Line Arrangement Disarray Induced by Ventricular Premature Contractions through the Rac2/Cofilin Pathway.

The most common ventricular premature contractions (VPCs) originate from the right ventricular outflow tract (RVOT), but the molecular mechanisms of altered cytoskeletons of VPC-induced cardiomyopathy remain unexplored. We created a RVOT bigeminy VPC pig model (n = 6 in each group). Echocardiography was performed. The histopathological alternations in the LV myocardium were analyzed, and next generation sequencing (NGS) and functional enrichment analyses were employed to identify the differentially expressed genes (DEGs) responsible for the histopathological alternations. Finally, a cell silencing model was used to confirm the key regulatory gene and pathway. VPC pigs had increased LV diameters in the 6-month follow-up period. A histological study showed more actin cytoskeleton disorganization and actin accumulation over intercalated disc, Z-line arrangement disarray, increased ß-catenin expression, and cardiomyocyte enlargement in the LV myocardium of the VPC pigs compared to the control pigs. The NGS study showed actin cytoskeleton signaling, RhoGDI signaling, and signaling by Rho Family GTPases and ILK Signaling presented z-scores with same activation states. The expressions of Rac family small GTPase 2 (Rac2), the p-cofilin/cofilin ratio, and the F-actin/G-actin ratio were downregulated in the VPC group compared to the control group. Moreover, the intensity and number of actin filaments per cardiomyocyte were significantly decreased by Rac2 siRNA in the cell silencing model. Therefore, the Rac2/cofilin pathway was found to play a crucial role in the sarcomere morphology and Z-line arrangement disarray induced by RVOT bigeminy VPCs.

Inhibition of Notch Signaling Alleviated Diabetic Macrovasculopathy in an In Vitro Model.

BACKGROUND: Interactions between endothelial cells and vascular smooth muscle cells (VSMCs) through the Notch signal pathway causing diabetic microvasculopathy have been reported. OBJECTIVES: The purpose of this study was to investigate whether the effect of high glucose on VSMCs through the Notch-2 signaling pathway could induce extracellular matrix (ECM) accumulation, VSMC proliferation and migration and thus directly mediate diabetic macrovasculopathy. METHODS: Rat smooth muscle cells (SV40LT-SMC Clone HEP-SA cells) were cultured in different concentrations of D-glucose to evaluate the impact of high glucose on ECM accumulation including fibronectin and collagen I measured by Western blot analysis, and on VSMC proliferation and migration evaluated by MTT assay and wound healing assay. The expression of Notch-2 intra-cellular domain (Notch-2 ICD) protein was also checked in high glucose-stressed VSMCs. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, was used to modulate the Notch-2 signaling pathway. RESULTS: High glucose (D-glucose 25 mM) induced fibronectin and collagen I expressions in VSMCs, promoted VSMC proliferation/migration, and enhanced the expression of Notch-2 ICD. DAPT inhibited Notch-2 signal to abolish the expressions of fibronectin and collagen I in VSMCs, and also prevented the proliferation/migration of VSMCs under high glucose (D-glucose 25 mM) stress. CONCLUSIONS: Our study suggests that high glucose can enhance the Notch-2 signaling pathway thereby directly mediating diabetic macrovasculopathy. Blocking the Notch-2 signaling pathway decreased fibronectin and collagen I expressions secreted by VSMCs, and reduced the proliferation and migration of VSMCs under high glucose stress. Inhibition of Notch-2 signaling represents a promising target for treating diabetic macrovasculopathy.

Shorter Leukocyte Telomere Length Is Associated With Atrial Remodeling and Predicts Recurrence in Younger Patients With Paroxysmal Atrial Fibrillation After Radiofrequency Ablation.

BACKGROUND: Telomere length is a biologic aging marker. This study investigated leukocyte telomere length (LTL) as a new biomarker to predict recurrence after paroxysmal atrial fibrillation (PAF) ablation.Methods and Results:A total of 131 participants (26 healthy individuals and 105 symptomatic PAF patients) were enrolled. PAF patients (54.1±10.8 years) who received catheter ablation therapy were divided into 2 groups: recurrent AF (n=25) and no recurrent AF after catheter ablation (n=80). Peripheral blood mononuclear cells were collected from all subjects to measure LTL. Under 50 years old, LTL in healthy individuals (n=17) was longer than in PAF patients (n=31; 7.34±0.58 kbp vs. 6.44±0.91 kbp, P=0.01). In PAF patients, LTL was positively correlated with left atrial bipolar voltage (R=0.497, P<0.001), and negatively correlated with biatrial scar area (R=-0.570, P<0.001) and left atrial diameter (R=-0.214, P=0.028). LTL was shorter in the patients with recurrent AF than in those without recurrent AF after catheter ablation (5.68±0.82 kbp vs. 6.66±0.71 kbp; P<0.001). On receiver operating characteristic curve analysis, LTL cut-off <6.14 kbp had a specificity of 0.68 and sensitivity of 0.79 to predict recurrent AF after catheter ablation. CONCLUSIONS: Young PAF patients (≤50 years) had shorter LTL. Shorter LTL was associated with a degenerative atrial substrate and recurrence after catheter ablation in younger PAF patients.

Late fractionated potentials in catheter ablation for right ventricular outflow tract ventricular arrhythmias.

BACKGROUND: Endocardial late fractionated potentials during sinus rhythm mapping may reflect abnormal "subendocardial" substrates associated with right ventricular outflow tract (RVOT) ventricular arrhythmias (VAs). The aim of this study was to explore the clinical outcomes of catheter ablation guided by these late fractionated potentials for RVOT VAs in patients without structural heart disease. METHODS: From January 2016 to March 2018, 28 patients underwent catheter ablation for RVOT premature ventricular contractions (PVCs) or ventricular tachycardia (VT), guided by the EnSite NavX or Velocity V5.0 three-dimensional mapping system (Abbott, St. Paul, MN, USA). Among them, 10 patients (35.7%) were found to have endocardial late fractionated potentials during sinus rhythm mapping (Group 1). Group 2 was composed of 18 patients in whom no endocardial late fractionated potentials were seen. The burden of VAs, acute procedural success, and 3-month clinical outcomes were analyzed. RESULTS: The average duration of late fractionated potentials after the end of QRS during sinus rhythm mapping in group 1 was 45.00 ± 17.15 ms. Baseline demographics and morphology and burden of PVCs were similarly distributed between both groups. Group 1 had higher acute procedural success compared to group 2 (100% vs 66.7%; P = .039). Moreover, at 3-month follow-up, group 1 had lower total PVCs (49 (1-5986) versus 4316 (1-23231); P = .048), PVC burden (0% (0-5.9) vs 4.3% (0-18.9); P = .055), and higher clinical success (100% vs 55.6%; P = .025) compared to group 2. CONCLUSION: The identification and elimination of endocardial late fractionated potentials during sinus rhythm mapping could improve the acute success and short-term outcomes of ablation for RVOT VAs.

Common pulmonary vein on the recurrence of atrial tachyarrhythmia after pulmonary vein isolation.

AIMS: Catheter ablation has become an effective treatment modality for atrial fibrillation (AF). However, the relationship between common pulmonary vein (PV) and recurrent atrial tachyarrhythmia (ATA) after PV isolation (PVI) remains controversial. This study aimed to explore the function of common PV on the risk of recurrent ATA after PVI. METHODS: We identified a total of 191 patients who received radiofrequency catheter ablation for paroxysmal AF at our hospital between July 2010 and December 2017 for retrospective chart review. We collected the following data for analysis: results of preprocedural computed tomography, including the anatomy of PV and left atrial (LA) volume; the incidence of early- and late-onset recurrence of ATA. We compared these characteristics between the two groups defined by the presence or absence of the late-onset recurrence of ATA. RESULTS: Compared to the no ATA recurrence group, the ATA recurrence group had larger LA size, larger LA end-diastolic and systolic volumes, larger maximal diameter of PV, higher prevalence of common PV, and higher incidence of early-onset recurrence of ATA. In multivariate logistic regression analyses, presence of common PV and early-onset recurrence were independently associated with late-onset recurrence of ATA. Compared to patients without common PV, patients with common PV had larger diameter of PV and higher incidence of late-onset recurrent ATA. CONCLUSION: In patients with paroxysmal AF, early-onset recurrence of ATA and the presence of common PV were independently associated with late-onset recurrent ATA after radiofrequency catheter ablation.

Additional cavotricuspid isthmus block ablation may not improve the outcome of atrial fibrillation ablation.

AIMS: Pulmonary vein isolation (PVI) is an effective procedure for atrial fibrillation (AF). The role of additional cavotricuspid isthmus (CTI) block ablation remains controversial in AF patients without atrial flutter (AFL). Therefore, this study aimed to explore the clinical outcome of additional CTI block ablation in patients without AFL. METHODS: Between January 2013 and December 2017, a total of 139 patients who did not have documented AFL and who underwent catheter ablation for AF were recruited. Fifty-seven patients were classified in additional CTI block ablation group and 82 patients were classified in without CTI group. The incidence of early-onset and late-onset atrial arrhythmia recurrence was compared between the two groups. RESULTS: The additional CTI group had a higher prevalence of persistent or long-standing AF and larger left atrial volume. The additional CTI group had a higher incidence of late-onset atrial arrhythmia recurrence (38.6% vs 12.2%; P < .001). When compared to without CTI group, additional CTI therapy did not have a better outcome in terms of freedom of atrial arrhythmia in subgroup analysis. The incidence of early-onset and late-onset atrial arrhythmia recurrence did not differ between additional CTI group and without CTI group in paroxysmal AF patients and nonparoxysmal AF patients after propensity scoring matching. CONCLUSION: CTI block ablation in addition to PVI for AF patients without a history of AFL or inducible AFL during ablation may not improve the clinical outcome of AF ablation in the patients with larger LA volume, nonparoxysmal AF, or post-PVI inducible AF.

Idi1 and Hmgcs2 Are Affected by Stretch in HL-1 Atrial Myocytes.

BACKGROUND: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. METHODS: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). RESULTS: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the "superpathway of cholesterol biosynthesis" were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). CONCLUSIONS: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.

Predictors of Left Ventricle Remodeling: Combined Plasma B-type Natriuretic Peptide Decreasing Ratio and Peak Creatine Kinase-MB.

Background: Previous studies reported that patients who had an acute myocardial infarction (AMI) have found that measuring B-type natriuretic peptide (BNP) during the subacute phase of left ventricular (LV) remodeling can predict the possible course of LV remodeling. This study assessed the use of serial BNP serum levels combined with early creatine kinase-MB (CK-MB) to predict the development of significant LV remodeling in AMI patients. Methods: Nighty-seven patients with new onset AMI were assessed using serial echocardiographic studies and serial measurements of BNP levels, both performed on day-2 (BNP1), day-7 (BNP2), day-90 (BNP3), and day-180 (BNP4) after admission. LV remodeling was defined as >20% increase in biplane LV end-diastolic volume on day-180 compared to baseline (day-2). Results: Patients were divided into LV remodeling [LVR(+)] and non LV remodeling [LVR(-)] groups. No first-week BNP level was found to predict remodeling. However, the two groups had significantly different day-90 BNP level (208.1 ± 263.7 pg/ml vs. 82.4 ± 153.7 pg/ml, P = 0.039) and significantly different 3-month BNP decrease ratios ( R BNP13) (14.4 ± 92.2% vs. 69.4 ± 25.9%, P < 0.001). The appropriate cut-off value for R BNP13 was 53.2% (AUC = 0.764, P < 0.001). Early peak CK-MB (cut-off 48.2 ng/ml; AUC = 0.672; P = 0.014) was another independent predictor of remodeling. Additionally, combining peak CK-MB and R BNP13 offered an excellent discrimination for half-year remodeling when assessed by ROC curve (AUC = 0.818, P < 0.001). Conclusion: R BNP13 is a significant independent predictor of 6-month LV remodeling. The early peak CK-MB additionally offered an incremental power to the predictions derived from serial BNP examinations.

Deciphering the gene expression profile of peroxisome proliferator-activated receptor signaling pathway in the left atria of patients with mitral regurgitation.

BACKGROUND: Differentially expressed genes in the left atria of mitral regurgitation (MR) pigs have been linked to peroxisome proliferator-activated receptor (PPAR) signaling pathway in the KEGG pathway. However, specific genes of the PPAR signaling pathway in the left atria of MR patients have never been explored. METHODS: This study enrolled 15 MR patients with heart failure, 7 patients with aortic valve disease and heart failure, and 6 normal controls. We used PCR assay (84 genes) for PPAR pathway and quantitative RT-PCR to study specific genes of the PPAR pathway in the left atria. RESULTS: Gene expression profiling analysis through PCR assay identified 23 genes to be differentially expressed in the left atria of MR patients compared to normal controls. The expressions of APOA1, ACADM, FABP3, ETFDH, ECH1, CPT1B, CPT2, SLC27A6, ACAA2, SMARCD3, SORBS1, EHHADH, SLC27A1, PPARGC1B, PPARA and CPT1A were significantly up-regulated, whereas the expression of PLTP was significantly down-regulated in the MR patients compared to normal controls. The expressions of HMGCS2, ACADM, FABP3, MLYCD, ECH1, ACAA2, EHHADH, CPT1A and PLTP were significantly up-regulated in the MR patients compared to patients with aortic valve disease. Notably, only ACADM, FABP3, ECH1, ACAA2, EHHADH, CPT1A and PLTP of the PPAR pathway were significantly differentially expressed in the MR patients compared to patients with aortic valve disease and normal controls. CONCLUSIONS: Differentially expressed genes of the PPAR pathway have been identified in the left atria of MR patients compared with patients with aortic valve disease and normal controls.

Bundled preparation of skin antisepsis decreases the risk of cardiac implantable electronic device-related infection.

AIMS: To evaluate the efficacy of bundled skin antiseptic preparation to prevent cardiac implantable electronic device (CIED) infections. METHODS AND RESULTS: From January 2010 to November 2013, 665 consecutive patients were divided into two groups according to the strategy of skin preparation. In Period 1 (January 2010 to June 2012), 395 patients received the standard skin antiseptic preparation. In Period 2 (July 2012 to November 2013), 270 patients received a triple-step skin antiseptic preparation, 'bundled skin antiseptic preparation', consisting of applying 75% alcohol over anterior chest on the night before the index day, povidone-iodine 10 min before operation, and the standard skin antiseptic preparation before incision. During follow-up, the occurrence of CIED infection was recorded. Multiple logistic regression analysis was used to determinate the risk factors of CIED infection. During a mean follow-up of 26.9 ± 16.2 months, 20 episodes of CIED infection developed in 19 patients (2.9%), and the incidence of minor and major infection episodes was 2.2% and 0.8%, respectively. Patients with the bundled skin antiseptic preparation had a significantly lower incidence of CIED infection, compared with patients with the standard preparation (0.7 vs. 4.3%, P = 0.007). In multivariate analysis, pocket haematoma (P = 0.020), atrial fibrillation (P = 0.033), and complex procedures (P = 0.047) were independent predictors for CIED infection. In contrast, the bundled skin antiseptic preparation was a significant predictor against CIED infection (P = 0.014). CONCLUSION: Pocket haematoma was the most important risk factor for CIED infection. The bundled skin antiseptic preparation strategy significantly reduced the risk of minor CIED infection.

Left ventricle remodeling predicts the recurrence of ventricular tachyarrhythmias in implantable cardioverter defibrillator recipients for secondary prevention.

BACKGROUND: Implantable cardioverter defibrillator (ICD) is an effective treatment for secondary prevention of ventricular tachycardia/ventricular fibrillation (VT/VF). Left ventricular (LV) remodeling may develop before ICD implant and over time. However, it remains unclear how LV remodeling affects subsequent risk for recurrence VT/VF in ICD recipients under optimal medical therapy. METHODS: From May of 2004 to June of 2015, 144 patients received ICD implantation for secondary prevention were enrolled in this study. All information interrogated from ICD devices during follow-up or ICD therapy history (anti-tachycardia pacing and shock therapy) were reviewed and validated the occurrences of VT/VF. RESULTS: At a mean follow-up of 1110.5 ± 860.6 days, 53 patients (36.8%) had recurrence of VT/VF episodes and 91 patients had no recurrence of VT/VF episode after ICD implant. Left ventricular end-diastolic volume (LVEDV) > 163.5 mL had significant predictive value for VT/VF recurrence (area under the curve: 0.602, p = 0.041). Moreover, the percentage of patients with LVEDV >163.5 mL was significantly higher in patients with recurrent VT/VF than patients without recurrent VT/VF (62.3 vs 40.0%, p = 0.010). Left ventricular ejection fraction ≤ 30% (p = 0.031), LVEDV > 163.5 mL (p = 0.012) and QRS width > 125 msec (p = 0.049) were significant predictors for VT/VF recurrence by univariate Cox regression analysis. However, only LVEDV > 163.5 mL (hazard ratio: 2.549, 95% confidence interval: 1.249 ~ 5.201, p = 0.010) and QRS width > 125 msec (hazard ratio: 2.173, 95% confidence interval: 1.030 ~ 4.586, p = 0.042) were independent predictors for recurrence of VT/VF after multivariable adjustment. CONCLUSION: LV remodeling and QRS width > 125 msec were independent predictors for VT/VF recurrence in secondary prevention ICD recipients under optimal medical therapy, independent of LV ejection fraction.

Optimal Duration of Coronary Ligation and Reperfusion for Reperfusion Injury Study in a Rat Model.

BACKGROUND: Reperfusion injury (RI) has an important impact on the clinical prognosis for patients with acute myocardial injury who had their coronary blood flow reestablished. However, no studies to date have investigated the timeframe of coronary occlusion and reperfusion effects on RI. METHODS: A total of 100 rats were divided into 4 groups based on the coronary ligation period: 30, 60, 120, and 180 min, and each group was further divided into 5 subgroups with different reperfusion periods: 0, 30, 60, 120, and 180 min. R0 was the baseline of each subgroup. All animals received the same protocols for designed ligation and reperfusion periods. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to distinguish different myocardial injury areas: area at risk (AAR) and myocardial necrosis. The differences of the ratios of the necrotic area to AAR between each subgroup and baseline were further averaged to calculate an overall value of each heart. RESULTS: The relative RI percentages showed significant differences (0.8 ± 2.3%, 4.9 ± 3.3%, 10.8 ± 3.1%, and 20.3 ± 3.6% respectively, p < 0.001) at different time points of reperfusion but not at different time points of ligation (p = 0.593). The effects of different time courses in RI showed that the L120R180 group (43.4 ± 2.3%) had the highest RI difference with the baseline group. CONCLUSIONS: Maximal RI occurred at the timeframe of L120R180 in our animal model. This result may be utilized to assess the substantial benefits of RI therapies in an experimental rat model setting.

Mitochondrial apoptotic pathway activation in the atria of heart failure patients due to mitral and tricuspid regurgitation.

Apoptosis occurs in atrial cardiomyocytes in mitral and tricuspid valve disease. The purpose of this study was to examine the respective roles of the mitochondrial and tumor necrosis factor-α receptor associated death domain (TRADD)-mediated death receptor pathways for apoptosis in the atrial cardiomyocytes of heart failure patients due to severe mitral and moderate-to-severe tricuspid regurgitation. This study comprised eighteen patients (7 patients with persistent atrial fibrillation and 11 in sinus rhythm). Atrial appendage tissues were obtained during surgery. Three purchased normal human left atrial tissues served as normal controls. Moderately-to-severely myolytic cardiomyocytes comprised 59.7±22.1% of the cardiomyocytes in the right atria and 52.4±12.9% of the cardiomyocytes in the left atria of mitral and tricuspid regurgitation patients with atrial fibrillation group and comprised 58.4±24.8% of the cardiomyocytes in the right atria of mitral and tricuspid regurgitation patients with sinus rhythm. In contrast, no myolysis was observed in the normal human adult left atrial tissue samples. Immunohistochemical analysis showed expression of cleaved caspase-9, an effector of the mitochondrial pathways, in the majority of right atrial cardiomyocytes (87.3±10.0%) of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial cardiomyocytes (90.6±31.4%) and left atrial cardiomyocytes (70.7±22.0%) of mitral and tricuspid regurgitation patients with atrial fibrillation. In contrast, only 5.7% of cardiomyocytes of the normal left atrial tissues showed strongly positive expression of cleaved caspase-9. Of note, none of the atrial cardiomyocytes in right atrial tissue in sinus rhythm and in the fibrillating right and left atria of mitral and tricuspid regurgitation patients, and in the normal human adult left atrial tissue samples showed cleaved caspase-8 expression, which is a downstream effector of TRADD of the death receptor pathway. Immunoblotting of atrial extracts showed that there was enhanced expression of cytosolic cytochrome c, an effector of the mitochondrial pathways, but no expression of membrane TRADD and cytosolic caspase-8 in the right atrial tissue of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial and left atrial tissues of mitral and tricuspid regurgitation patients with atrial fibrillation. Taken together, this study showed that mitochondrial pathway for apoptosis was activated in the right atria in sinus rhythm and in the left and right atria in atrial fibrillation of heart failure patients due to mitral and tricuspid regurgitation, and this mitochondrial pathway activation may contribute to atrial contractile dysfunction and enlargement in this clinical setting.

Enhanced expression of ROCK in left atrial myocytes of mitral regurgitation: a potential mechanism of myolysis.

BACKGROUND: Severe mitral regurgitation (MR) may cause myolysis in the left atrial myocytes. Myolysis may contribute to atrial enlargement. However, the relationship between Rho-associated kinase (ROCK) and myolysis in the left atrial myocytes of MR patients remain unclear. METHODS: This study comprised 22 patients with severe MR [12 with atrial fibrillation (AF) and ten in sinus rhythm]. Left atrial appendage tissues were obtained during surgery. Normal left atrial tissues were purchased. Immunofluorescence histochemical and immunoblotting studies were performed. RESULTS: The expression of ROCK2 in the myolytic left atrial myocytes of MR AF patients (p = 0.009) and MR sinus patients (p = 0.011) were significantly higher than that of the normal subjects. Similarly, the expression of ROCK1 in the myolytic left atrial myocytes of MR AF patients was significantly higher than that of the normal subjects (p = 0.010), and the expression of ROCK1 in the myolytic left atrial myocytes of MR sinus patients was higher than that of the normal subjects (p = 0.091). Immunofluorescence study revealed significant co-localization and juxtaposition of ROCK2 and cleaved caspase-3 in the left atrial myocytes both in the MR AF group (Pearson's coefficient = 0.74 ± 0.03) and the MR sinus group (Pearson's coefficient = 0.73 ± 0.02). Similarly, immunofluorescence study revealed significant co-localization and juxtaposition of ROCK1 and cleaved caspase-3 in the left atrial myocytes both in the MR AF group (Pearson's coefficient = 0.65 ± 0.03) and the MR sinus group (Pearson's coefficient = 0.65 ± 0.03). Correlation analysis demonstrated that there was a significant direct relationship between the expression of ROCK2 in the myolytic left atrial myocytes and left atrial diameter in the MR patients (p = 0.041; r = 0.440). Moreover, the ratio of phosphorylated myosin-binding subunit of myosin light chain phosphatase (pMBS)/total MBS of left atrial tissues was significantly higher in the MR AF group (p < 0.04) and the MR sinus group (p < 0.04) compared with the normal control group. CONCLUSIONS: The enhanced expression of ROCKs might be involved in the myolysis of the left atrial myocytes of MR patients.

Platelet Glycoprotein IIb/IIIa Inhibitor Tirofiban Ameliorates Cardiac Reperfusion Injury.

There are many published articles on the effects of the antithrombolytic function of platelet glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa inhibitors) in myocardial infarction. However, few studies have explored the effects and optimal concentration of tirofibans in diminishing the extent of myocardial reperfusion injury (RI).Rats received 120 minutes of coronary ligation and 180 minutes of reperfusion. The rats were then divided into 7 groups based on the concentration of tirofiban administered intravenously 30 minutes prior to coronary reperfusion to the end of reperfusion. The ratio of myocardial necrotic area to area at risk (AAR), and myocardial malondialdehyde (MDA) and plasma myeloperoxidase (MPO) activities were measured. The apoptotic index (AI) was the percentage of myocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) out of all myocytes stained by 4', 6-diamidino-2-phenylindole (DAPI).The ratio of myocardial necrotic area to AAR significantly decreased in all tirofiban subgroups. The MDA activity for tirofiban concentrations of 2 and 5 ug/kg/minute showed a slight reduction. MPO activity was significantly decreased at a tirofiban concentration of 2 ug/kg/minute. The AI was significantly decreased at a tirofiban concentration of ≥ 0.4 ug/kg/minute.The results indicate that a tirofiban can significantly ameliorate the cardiac RI and myocyte apoptosis in rats.