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Purpose of Review: Diabetes mellitus (DM) is a major comorbidity of heart failure (HF). Comparing the similarities and differences in disease characteristics and treatment between the HF patients with and without DM, this review was to investigate whether and how the novel class of sodium-glucose transport protein 2 inhibitors (SGLT2i) would benefit both populations. Recent Findings: Despite the obviously different clinical profiles, patients of HF with reduced ejection fraction (HFrEF) should be treated the same with guideline directed medical therapy, irrespective of DM status. Upon the mounting evidence that supported its use in diabetic patients at high risk of HF, recent large clinical trials demonstrated that SGLT2i could further reduce HF hospitalization or cardiovascular mortality and improve quality of life in diabetic and non-diabetic HFrEF patients who were optimally managed. Summary: SGLT2i expands the foundation of HFrEF therapy. Whether it is equally effective in HF with preserved ejection fraction awaits more evidence. [ABSTRACT FROM AUTHOR]

Clinicians often have a difficulty in determining the presence of mitral regurgitation (MR)-related symptoms because of subjectivity. However, there are few actual measurement data for echocardiographic left ventricular (LV) and left atrial (LA) size related to the severity of MR and the relationship between MR-related symptoms and these echocardiographic parameters. Among patients enrolled in the Asian Valve Registry, we investigated 778 consecutive patients with primary MR showing sinus rhythm. Symptoms were determined by New York Heart Association grade (≤ II or ≥ III). MR severity was mild in 106, moderate in 285, and severe in 387 patients. LA volume index, LV end-diastolic diameter, and LV mass index increased with increasing MR grade [LA volume index: 47.9 (mild), 56.2 (moderate), and 64.9 ml/m2 (severe) (p < 0.001), LV end-diastolic diameter: 51.2, 54.5, 58.1 mm (p < 0.001), and LV mass index: 101, 109, 123 g/m2 (p < 0.001)]. Regarding moderate and severe MR, 70 patients (10.4%) were symptomatic. In multivariable analysis, for being symptomatic in moderate and severe MR patients, LV mass index (odds ratio [OR] per 10 g/m2 increment; 1.09; 95% confidence interval [CI]: 1.005–1.18, p = 0.040), ejection fraction (OR per 1% increment; 0.96, 95%CI: 0.93–0.98, p < 0.001), female gender (OR 2.28; 95% CI: 1.31–3.98, p = 0.004), and heart rate (OR per 1 bpm increment; 1.03; 95%CI: 1.01–1.05, p = 0.007) were independent factors. LV and LA parameters on echocardiography worsened as MR severity progressed. Larger LV mass index and lower ejection fraction were independent determinant factors for MR-related symptoms. We should also pay attention to LV hypertrophy in patients with primary MR. [ABSTRACT FROM AUTHOR]

Background: Mitral and aortic valves are coupled via fibrous tissue. This coupling is considered to be important for cardiac function before and after mitral valve surgery. The relationship between mitral-aortic coupling and different types of mitral regurgitation (MR) is not completely understood. Methods and results: Real-time three-dimensional transesophageal echocardiography (RT3D-TEE) was performed in 133 subjects: 30 normal subjects, 15 patients with Carpentier type I MR (annular dilatation and congenital cleft), 40 type II (mitral valve prolapse), 20 type IIIa (rheumatic) and 28 type IIIb (ischemic mitral regurgitation). Custom software was used to track mitral (MA) and aortic annuli (AoA) in 3D space throughout cardiac cycle, allowing measurement of changes in mitral and aortic valve morphology. Normal mitral-aortic coupling is characterized by reciprocal changes in the annular areas throughout cardiac cycle, with systolic reduction of the angle between the two annular planes. In Carpentier type II patients, not only MA but also AoA areas were increased ( P < 0.05 vs normal), but the reciprocal pattern of mitral-aortic coupling was preserved. In both type I IMR and IIIb patients, MA and AoA areas were both increased ( P < 0.05 vs normal) and the reciprocal behavior of mitral-aortic coupling was lost. Only MA area was increased in type IIIa patients. The extent of mitral-aortic angle reduction during systole was diminished in all 4 Carpentier groups ( P < 0.05 vs normal). Conclusions: Mitral valve diseases may affect normal mitral-aortic coupling and aortic valve function. Different patterns of abnormal mitral-aortic coupling are associated with different Carpentier types of MR. [ABSTRACT FROM AUTHOR]

The normal data of left ventricular (LV) synchronicity by real-time 3-dimensional echocardiography (RT3DE) are lacking. We assessed the normal range/cutoff values of LV dyssynchrony parameters by RT3DE. For this purpose, RT3DE was performed in 130 healthy subjects, aged 53 ± 12 years. Time to the point of minimal regional systolic volume (Tmsv) was measured from time-volume curves in each segment. Standard deviation (SD) and maximal difference (Dif) of Tmsv were calculated from 16 (6 basal/6 mid/4 apical), 12 (6 basal/6 mid), and 6 (basal) LV segments together with the corresponding parameters adjusted by R-R interval. The data show non-significant difference between Tmsv-16-SD (9.24 ± 3.54 ms) and Tmsv-12-SD (8.80 ± 3.82 ms); with a correlation between two by both unadjusted (ms; r = 0.87) and adjusted (%R-R; r = 0.84) methods ( P < 0.001). Heart rate correlated negatively with Tmsv ( r = −0.13 to −0.34, P < 0.05-0.001) but had no effect on parameters adjusted for %R-R. Age and gender did not affect any of these parameters. Inter-observer variability was 3.3-4.6 % for 16, 4.8-9.1 % for 12, and 14.4-19.7 % for 6 segments. Thus, RT3DE is a reliable technique for detecting LV systolic dyssynchrony whereas the heart rate, but not age and gender, affects Tmsv parameters. Dyssynchrony parameters by 16 or 12 segments are superior to 6 segments in yielding comprehensive information and lower variability. [ABSTRACT FROM AUTHOR]

Stroke in patients with atrial fibrillation (AF) is often associated with substantial morbidity and mortality. Oral anticoagulation remains the first-line approach to stroke prevention in such individuals; however, for a considerable proportion of patients, traditional treatment using warfarin is limited by a number of factors, such as the inconvenience of frequent therapeutic monitoring and the risk of haemorrhage. The development of new oral anticoagulants with improved efficacy and safety profiles has provided viable options for oral anticoagulation therapy in patients with nonvalvular (nonrheumatic AF). Nonetheless, in patients who have an increased risk of major haemorrhage, a nonpharmacological approach to antithrombotic therapy remains an attractive alternative. The left atrial appendage (LAA) has been found to be the source of >90% of thrombi in patients with nonvalvular AF; thus, prevention of thrombus formation via transcatheter mechanical LAA occlusion is a novel therapeutic target for stroke prevention in this patient population. In this Review, we present the rationale for LAA occlusion in patients with AF, the available occlusion devices and their clinical evidence to date. We also discuss the roles of various imaging techniques in device implantation and the management strategy for associated procedural complications. [ABSTRACT FROM AUTHOR]

Purpose: Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases that impairs endothelial function. We investigated whether the impaired endothelial function can be restored by the eNOS transcription enhancer AVE3085 in porcine coronary arteries. The effects of AVE3085 against Hcy on eNOS-NO function were studied and further investigations were conducted to reveal the role of arginase and the signaling pathway of eNOS activation in the effect of AVE3085 on endothelial dysfunction caused by Hcy. Methods: Myograph study of vasorelaxation, electrochemical measurement of NO, RT-PCR and Western blot analysis of eNOS, iNOS expression, and eNOS phosphorylation were performed. Arginase activity was determined by urea production and O 2.− generation by lucigenin-enhanced chemiluminenscence. Results: Exposure to Hcy for 24 h attenuated bradykinin-induced relaxation and NO release, downregulated eNOS mRNA expression and protein expressions of eNOS and p-eNOS Ser1177 whereas it upregulated iNOS expression. AVE3085 restored NO release and relaxation, enhanced eNOS but decreased iNOS expression. Inhibition of protein kinase Akt or PI3 kinase attenuated the effect of AVE3085 on relaxation and eNOS phosphorylation. Arginase activity and O 2.− production were inhibited by AVE3085 in Hcy-exposed vessels. Conclusions: AVE3085 prevents Hcy-induced endothelial dysfunction in coronary arteries by preservation of NO production and suppression of O 2.− generation. Preservation of NO is attributed to upregulation of eNOS expression, activation of eNOS via phosphorylation of Ser1177 through a PI3 kinase/Akt-dependent pathway, and inhibition of arginase. Reduction of O 2.− generation results from reversal of eNOS uncoupling and inhibition of arginase and iNOS. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that significant left ventricular dysfunction may arise in right-sided septal or paraseptal accessory pathways (APs) with Wolff-Parkinson-White syndrome, even in the absence of recurrent or incessant tachycardia. During 1 year and 9 months, we identified four consecutive female children with median age of 8 years diagnosed as having dilated cardiomyopathy (DCM) combined with overt right-sided APs several years ago. Incessant or recurrent tachycardia as the cause of DCM could be excluded. Anti-heart failure chemotherapy did not produce satisfactory effects. The patients underwent radiofrequency ablations (RFCAs). This report describes the clinical and echocardiographic characteristics of the cases before and after the ablation. Dyssynchronous ventricular contraction was observed in all patients. The locations of the APs were the right-sided anteroseptum and the free wall ( n = 2 each). All patients received successful RFCAs. Their physical activities and growth improved greatly, and the echocardiographic data demonstrated that their left ventricular (LV) contraction recovered to synchrony shortly after the ablation and that their LV function recovered to normal gradually during the follow-up. Conclusions: A causal relationship between overt ventricular preexcitation and the development of DCM is supported by the complete recovery of LV function and reversed LV remodeling after the loss of ventricular preexcitation. Preexcitation-related dyssynchrony was probably the crucial mechanism. Not only right-sided septal or paraseptal but also free wall overt APs may induce LV dysfunction and even DCM. AP-induced DCM is an indication for ablation with a good prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Oral direct factor Xa inhibitors and oral direct thrombin inhibitors are new oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). We systematically reviewed their risk of major bleeding and efficacy in thromboembolism reduction in AF. Methods: Eligible randomized controlled trials evaluating NOACs for stroke prevention in AF patients were identified from a systematic search of MEDLINE, EMBASE and the Cochrane database. Risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a Mantel-Haenzel random-effects model. Results: A total of 13 studies ( n = 61,406) were included. Oral direct factor Xa inhibitors were more effective in reducing stroke and systemic embolism compared to controls (RR 0.71, 95 % CI 0.54-0.92, P = 0.009) or vitamin K antagonists (VKAs) (RR 0.84, 95 % CI 0.74-0.94, P = 0.002), with no significant difference in major and clinically relevant non-major (CRNM) bleeding (against controls: RR 0.94, 95 % CI 0.75-1.18, P = 0.60; against VKAs: RR 0.90, 95 % 0.69-1.17, P = 0.44). Oral direct thrombin inhibitors were associated with an improved major and CRNM bleeding profile (both comparisons: RR 0.88, 95 % CI 0.78-0.98, P = 0.02) and a significant reduction in stroke and systemic embolism (against controls: RR 0.79, 95 % CI 0.66-0.93, P = 0.006; against VKAs: RR 0.78, 95 % CI 0.66-0.93, P = 0.006). Conclusions: Oral direct factor Xa inhibitors and oral direct thrombin inhibitors are more effective in reducing stroke and systemic embolism without increasing the risk of major bleeding compared to traditional oral anticoagulants. This favorable risk-benefit balance should be further confirmed by long-term, large-scale safety studies. [ABSTRACT FROM AUTHOR]

Although there is little debate over the fact that cardiac resynchronization therapy (CRT) can benefit the majority of patients selected with routine indications, the precise mechanism for improvement may be considered controversial. Among patients selected with New York Heart Association functional class III or IV symptoms, left ventricular ejection fraction ≤35% and electrocardiographic QRS widening of at least 120-130 ms, approximately 60-80% of patients improved depending on the definition of response used. Although a reasonable assumption is that electrocardiographic QRS widening is a surrogate for delays in regional ventricular mechanical activation, a large volume of data has demonstrated that there is a subset of patients with widened QRS complexes who have no significant mechanical dyssynchrony. The reason for dissociation of electrical dispersion and mechanical dyssynchrony is unknown presently, but many studies have demonstrated the association of dyssynchrony with favorable outcome following CRT. Perhaps more importantly, several imaging studies (principally by echocardiography) have shown the lack of baseline mechanical dyssynchrony to be as a marker for a less favorable outcome after CRT. Recently, the lack of dyssynchrony before CRT has been shown to be associated with a significantly lower long-term probability of freedom from death, heart transplantation, or left ventricular assist device placement. As further mechanistic evidence for the relationship of mechanical dyssynchrony and LV functional response to CRT, it has been suggested that patients who failed to improve their tissue Doppler measures of dyssynchrony after CRT have a lower chance of reverse remodeling. This topic has been muddled by technical difficulties in measurement of mechanical dyssynchrony by all imaging approaches, the confounding variable of scar in ischemic disease, and the widely variable definitions of response used by different investigators. However, the weight of evidence from a pathophysiological basis to the recent long-term patient outcome data strongly support the notion that resynchronization is the principle mechanism of benefit from CRT. [ABSTRACT FROM AUTHOR]

Purpose: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS and it is recognized as a risk factor for endothelial dysfunction in cardiovascular diseases. We investigated the effect of AVE3085, a newly developed transcription enhancer of eNOS, on ADMA-induced endothelial dysfunction in coronary arteries with underlying mechanisms explored. Methods: Porcine coronary small arteries (diameter 600-800 μm) were studied in a myograph for endothelium-dependent relaxation to bradykinin and endothelium-independent relaxation to sodium nitroprusside. Protein expressions of eNOS and phosphorylated-eNOS (p-eNOS and p-eNOS), and nitrotyrosine formation were determined by Western blot. NO release was directly measured with a NO microsensor. Productions of O and peroxynitrite (ONOO) were determined by lucigenin- and luminol- enhanced chemiluminescence respectively. Results: Exposure to ADMA significantly decreased the bradykinin-induced vasorelaxation and reduced the protein expression of p-eNOS whereas increased the expression of p-eNOS and nitrotyrosine. Pre-incubation with AVE3085 restored the bradykinin-induced relaxation, reversed the decrease of p-eNOS, and lowered the level of p-eNOS and nitrotyrosine. NO release in response to bradykinin was significantly reduced by ADMA and such reduction was restored by AVE3085. AVE3085 also prevented the elevation of O and ONOO levels in coronary arteries exposed to ADMA. Conclusions: AVE3085 prevents ADMA-induced endothelial dysfunction in coronary arteries. The protective effect of AVE3085 may be attributed to increased NO production resulting from enhanced eNOS activation, and decreased oxidative stress that involves inhibition of O generation by eNOS recoupling. The present study suggested the therapeutic potential of AVE3085 in endothelial dysfunction in cardiovascular disorders. [ABSTRACT FROM AUTHOR]

The ONTARGET and TRANSCEND clinical trials were designed to investigate the cardioprotective effects of telmisartan 80 mg and ramipril 10 mg, alone and in combination, in patients at high risk of cardiovascular disease. Cardiac MRI enables investigation of mechanistic effects of these agents on cardiac structural and functional variables. Here, we report the design, analysis protocol, reproducibility and relevant quality control procedures, and baseline patient characteristics of the ONTARGET/TRANSCEND cardiac MRI substudy. MRI was undertaken in 330 subjects enrolled in ONTARGET, and 38 subjects in TRANSCEND, across eight centers in six countries. Analyses were performed by two independent analysts using guide-point modeling. Cases with discrepancies in LV mass (LVM) of >5% were independently reanalyzed. Cases with discrepancies in end-diastolic volume (EDV) of >5%, or end-systolic volume (ESV) of >12%, were then reconciled by consensus. Baseline characteristics were broadly similar to the main ONTARGET/TRANSCEND trials, except for a higher frequency of coronary artery disease and Asian ethnicity in the substudy. Reproducibility of MRI analyses (mean ± SD) were 2.8 ± 3.7 ml in EDV, −0.3 ± 3.6 ml in ESV, 3.1 ± 3.3 ml in SV, 1.1 ± 1.8% in EF, and 0.4 ± 4.5 g in LVM. Subgroup analyses revealed increased ESV and LVM, and reduced EF, in subjects with a history of either coronary artery disease or myocardial infarction. The ONTARGET/TRANSCEND cardiac MRI substudy protocol provides for a reliable assessment of the effects of telmisartan and ramipril, alone and in combination, on cardiac structural and functional parameters over a 2-year follow-up period. [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy is a standard therapy for heart failure patients with cardiac dyssynchrony. The implantable device provides a convenient and continuous platform for heart failure monitoring. Information such as heart rate variability and activity status retrieved from the device allows physicians to more comprehensively evaluate these high-risk patients. Several registries and prospective observational studies have evaluated the value of intrathoracic impedance monitoring in predicting exacerbation of heart failure. With its sensitivity and positive predictive power, the fluid index—derived from the raw intrathoracic impedance—may alert clinicians to subclinical or clinical heart failure deterioration. Uncertainty remains as to whether the additional device-derived information will translate into clinical benefit by reducing the number of hospitalizations for heart failure. An ongoing randomized controlled clinical trial is expected to clarify the role of the device-based pulmonary fluid index in the management of heart failure. [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy is a standard therapy for selected patients with heart failure. With advances in technology and storage capacity, the device acts as a convenient platform to provide valuable information about heart failure status in these high-risk patients. Unlike other modalities of investigation which may only allow one-off evaluation, heart failure status can be monitored by device diagnostics including heart rate variability, activity status, and intrathoracic impedance in a continuous basis. These parameters do not just provide long-term prognostic information but also may be useful to predict upcoming heart failure exacerbation. Prompt and early intervention may abort decompensation, prevent hospitalization, improve quality of life, and reduce health care cost. Moreover, this information may be applied to titrate the dosage of medication and monitor response to heart failure treatment. This review will focus on the prognostic and predictive values of heart failure status monitoring provided by these devices. [ABSTRACT FROM AUTHOR]

Implantation of left ventricular leads (LV) for biventricular pacing remains a technological challenge and failure of the procedure is not uncommon. We described a 58 year-old patient with heart failure and intraventricular conduction delay where difficulty is encountered when cannulating the coronary sinus by the guiding catheter. By placing a guiding catheter in the inferior portion of the right atrium, a coronary guidewire, preloaded with an over-the-wire lead system, was used to reach the lateral cardiac vein. This may help to reduce the implant failure rate and avoid other more invasive means of LV lead implantation. [ABSTRACT FROM AUTHOR]