Clinical Evidence and Proposed Mechanisms of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Class Effect?

Effective treatment for heart failure with preserved ejection fraction (HFpEF) is an unmet need in cardiovascular medicine. The pathophysiological drivers of HFpEF are complex, differing depending on phenotype, making a one-size-fits-all treatment approach unlikely. Remarkably, sodium-glucose cotransporter 2 inhibitors (SGLT2is) may be the first drug class to improve cardiovascular outcomes in HFpEF. Randomised controlled trials suggest a benefit in mortality, and demonstrate decreased hospitalisations and improvement in functional status. Limitations in trials exist, either due to small sample sizes, differing results between trials or decreased efficacy at higher ejection fractions. SGLT2is may provide a class effect by targeting various pathophysiological HFpEF mechanisms. Inhibition of SGLT2 and Na+/H+ exchanger 3 in the kidney promotes glycosuria, osmotic diuresis and natriuresis. The glucose deprivation activates sirtuins - protecting against oxidation and beneficially regulating metabolism. SGLT2is reduce excess epicardial adipose tissue and its deleterious adipokines. Na+/H+ exchanger 1 inhibition in the heart and lungs reduces sodium-induced calcium overload and pulmonary hypertension, respectively.

Incidence and etiology of chylothorax after congenital heart surgery in children.

BACKGROUND: Chylothorax is a rare but serious postoperative condition with a high rate of morbidity and may lead to the mortality of children undergoing congenital heart disease (CHD) surgery. This study evaluated the specific surgical procedures associated with the higher risk of postoperative chylothorax. METHODS: We assessed 435 cases undergoing CHD surgery between April 2003 and May 2006. We detected postoperative chylothorax in 6 patients. The diagnosis of chylothorax was established based on the presence of an odorless fluid with the characteristic milky appearance of the fluid (except when the patients were fasting in the immediate postoperative period), a triglyceride level greater than 110 mg/dL or between 50 and 110 mg/dL with a pleural fluid white cell count greater than 1000, and more than 80% lymphocytes on differential when the pleural fluid was not chylous. RESULTS: Over a 37-month period, 435 (mean age = 51.6 months; 232 males) patients underwent various types of surgical procedures for CHD; 6 patients developed chylothorax after the Fontan operation; one patient died due to severe chylothorax; 3 patients were managed by nutritional modifications, diuretics, and thoracocentesis; and 2 patients required thoracic duct ligation. The Fisher exact test analysis showed a significant association between the Fontan operation and postoperative chylothorax (p value < 0.0001). CONCLUSION: Our study showed a significant association between the Fontan surgery and chylothorax.

Scar heterogeneity on cardiovascular magnetic resonance as a predictor of appropriate implantable cardioverter defibrillator therapy.

BACKGROUND: Despite the survival benefit of implantable-cardioverter-defibrillators (ICDs), the vast majority of patients receiving an ICD for primary prevention do not receive ICD therapy. We sought to assess the role of heterogeneous scar area (HSA) identified by late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) in predicting appropriate ICD therapy for primary prevention of sudden cardiac death (SCD). METHODS: From September 2003 to March 2011, all patients who underwent primary prevention ICD implantation and had a pre-implantation LGE-CMR were identified. Scar size was determined using thresholds of 4 and 6 standard deviations (SD) above remote normal myocardium; HSA was defined using 3 different criteria; as the region between 2 SD and 4 SD (HSA2-4SD), between 2SD and 6SD (HSA2-6SD), and between 4SD and 6SD (HSA4-6SD). The end-point was appropriate ICD therapy. RESULTS: Out of 40 total patients followed for 25 ± 24 months, 7 had appropriate ICD therapy. Scar size measured by different thresholds was similar in ICD therapy and non-ICD therapy groups (P = NS for all). However, HSA2-4SD and HSA4-6SD were significantly larger in the ICD therapy group (P = 0.001 and P = 0.03, respectively). In multivariable model HSA2-4SD was the only significant independent predictor of ICD therapy (HR = 1.08, 95%CI: 1.00-1.16, P = 0.04). Kaplan-Meier analysis showed that patients with greater HSA2-4SD had a lower survival free of appropriate ICD therapy (P = 0.026). CONCLUSIONS: In primary prevention ICD implantation, LGE-CMR HSA identifies patients with appropriate ICD therapy. If confirmed in larger series, HSA can be used for risk stratification in primary prevention of SCD.

Volumetric left ventricular ejection fraction is superior to 2-dimensional echocardiography for risk stratification of patients for primary prevention implantable cardioverter-defibrillator implantation.

Current guidelines recommend an implantable cardioverter-defibrillator (ICD) according to the left ventricular ejection fraction (LVEF). However, they do not mandate volumetric LVEF assessment. We sought to determine whether volumetric LVEF measurement using cardiovascular magnetic resonance imaging (CMR-LVEF) is superior to conventional LVEF measurement using 2-dimensional transthoracic echocardiography (Echo-LVEF) for risk stratifying patients referred for primary prevention ICD. Patients who underwent primary prevention ICD implantation at our institution and had undergone preimplantation CMR-LVEF from November 2001 to February 2011 were identified. Volumetric CMR-LVEF was determined from cine short-axis data sets. CMR-LVEF and Echo-LVEF were extracted from the clinical reports. The end point was appropriate ICD discharge (shock and/or antitachycardia pacing). Of 48 patients, appropriate ICD discharge occurred in 9 (19%) within 29 ± 25 months (range 1 to 99, median 20). All patients met the Echo-LVEF criteria for ICD implantation; however 25% (95% confidence interval 13% to 37%) did not meet the CMR-LVEF criteria. None (0%) of these latter patients had received an appropriate ICD discharge. Using CMR-LVEF ≤30% as a threshold for ICD eligibility, 19 patients (40%) with a qualifying Echo-LVEF would not have been referred for ICD, and none (0%) received an ICD discharge.For primary prevention ICD implantation, volumetric CMR-LVEF might be superior to clinical Echo-LVEF for risk stratification and can identify a large minority of subjects in whom ICD implantation can be safely avoided. In conclusion, if confirmed by larger prospective series, volumetric methods such as CMR should be considered a superior "gatekeeper" for the identification of patients likely to benefit from primary prevention ICD implantation.

Improved fat water separation with water selective inversion pulse for inversion recovery imaging in cardiac MRI.

PURPOSE: To develop an improved chemical shift-based water-fat separation sequence using a water-selective inversion pulse for inversion recovery 3D contrast-enhanced cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: In inversion recovery sequences the fat signal is substantially reduced due to the application of a nonselective inversion pulse. Therefore, for simultaneous visualization of water, fat, and myocardial enhancement in inversion recovery-based sequences such as late gadolinium enhancement imaging, two separate scans are used. To overcome this, the nonselective inversion pulse is replaced with a water-selective inversion pulse. Imaging was performed in phantoms, nine healthy subjects, and nine patients with suspected arrhythmogenic right ventricular cardiomyopathy plus one patient for tumor/mass imaging. In patients, images with conventional turbo-spin echo (TSE) with and without fat saturation were acquired prior to contrast injection for fat assessment. Subjective image scores (1 = poor, 4 = excellent) were used for image assessment. RESULTS: Phantom experiments showed a fat signal-to-noise ratio (SNR) increase between 1.7 to 5.9 times for inversion times of 150 and 300 msec, respectively. The water-selective inversion pulse retains the fat signal in contrast-enhanced cardiac MR, allowing improved visualization of fat in the water-fat separated images of healthy subjects with a score of 3.7 ± 0.6. Patient images acquired with the proposed sequence were scored higher when compared with a TSE sequence (3.5 ± 0.7 vs. 2.2 ± 0.5, P < 0.05). CONCLUSION: The water-selective inversion pulse retains the fat signal in inversion recovery-based contrast-enhanced cardiac MR, allowing simultaneous visualization of water and fat.

Improved multimodality data fusion of late gadolinium enhancement MRI to left ventricular voltage maps in ventricular tachycardia ablation.

Electroanatomical voltage mapping (EAVM) is commonly performed prior to catheter ablation of scar-related ventricular tachycardia (VT) to locate the arrhythmic substrate and to guide the ablation procedure. EAVM is used to locate the position of the ablation catheter and to provide a 3-D reconstruction of left-ventricular anatomy and scar. However, EAVM measurements only represent the endocardial scar with no transmural or epicardial information. Furthermore, EAVM is a time-consuming procedure, with a high operator dependence and has low sampling density, i.e., spatial resolution. Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) allows noninvasive assessment of scar morphology that can depict 3-D scar architecture. Despite the potential use of LGE as a roadmap for VT ablation for identification of arrhythmogenic substrate, its utility has been very limited. To allow for identification of VT substrate, a correlation is needed between the substrates identified by EAVM as the gold standard and LGE-MRI scar characteristics. To do so, a system must be developed to fuse the datasets from these modalities. In this study, a registration pipeline for the fusion of LGE-MRI and EAVM data is presented. A novel surface registration algorithm is proposed, integrating the matching of global scar areas as an additional constraint in the registration process. A preparatory landmark registration is initially performed to expedite the convergence of the algorithm. Numerical simulations were performed to evaluate the accuracy of the registration in the presence of errors in identifying landmarks in EAVM or LGE-MRI datasets as well as additional errors due to respiratory or cardiac motion. Subsequently, the accuracy of the proposed fusion system was evaluated in a cohort of ten patients undergoing VT ablation where both EAVM and LGE-MRI data were available. Compared to landmark registration and surface registration, the presented method achieved significant improvement in registration error. The proposed data fusion system allows the fusion of EAVM and LGE-MRI data in VT ablation with registration errors less than 3.5  mm.

Accelerated late gadolinium enhancement cardiac MR imaging with isotropic spatial resolution using compressed sensing: initial experience.

PURPOSE: To evaluate the use of low-dimensional-structure self-learning and thresholding (LOST) compressed sensing acquisition and reconstruction in the assessment of left atrial (LA) and left ventricular (LV) scar by using late gadolinium enhancement (LGE) magnetic resonance (MR) imaging with isotropic spatial resolution. MATERIALS AND METHODS: The study was approved by the local institutional review board and was compliant with HIPAA. All subjects provided written informed consent. Twenty-eight patients (eight women; mean age, 58.0 years ± 10.1) with a history of atrial fibrillation were recruited for the LA LGE study, and 14 patients (five women; mean age, 54.2 years ± 18.6) were recruited for assessment of LV myocardial infarction. With use of a pseudorandom k-space undersampling pattern, threefold accelerated three-dimensional (3D) LGE data were acquired with isotropic spatial resolution and reconstructed off-line by using LOST. For comparison, subjects were also imaged by using standard 3D LGE protocols with nonisotropic spatial resolution. Images were compared qualitatively by three cardiologists with regard to diagnostic value, presence of enhancement, and image quality. The signed rank test and Wilcoxon unpaired two-sample test were used to test the hypothesis that there would be no significant difference in image quality ratings with different resolutions. RESULTS: Interpretable images were obtained in 26 of the 28 patients (93%) in the LA LGE study. LGE was seen in 17 of 30 cases (57%) with nonisotropic resolution and in 18 cases (60%) with isotropic resolution. Diagnostic quality scores of isotropic images were significantly higher than those of nonisotropic images with coronal views (median, 3 vs 2, respectively [25th and 75th percentiles: 3, 3 vs 2, 3]; P < .001) and sagittal views (median, 3 vs 2 [25th and 75th percentiles: 3, 4 vs 2, 3]; P < .001) but lower with axial views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 3, 3]; P < .001). For the LV LGE study, all patients had interpretable images. LGE was seen in six of 14 patients (43%), with 100% agreement between both data sets. Diagnostic quality scores of high-isotropic-resolution LV images were higher than those of nonisotropic images with short-axis views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 2, 3]; P = .014) and two-chamber views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 2, 3]; P = .001). CONCLUSION: An accelerated LGE acquisition with LOST enables imaging with high isotropic spatial resolution for improved assessment of LV, LA, and pulmonary vein scar.

Accelerated contrast-enhanced whole-heart coronary MRI using low-dimensional-structure self-learning and thresholding.

We sought to evaluate the efficacy of prospective random undersampling and low-dimensional-structure self-learning and thresholding reconstruction for highly accelerated contrast-enhanced whole-heart coronary MRI. A prospective random undersampling scheme was implemented using phase ordering to minimize artifacts due to gradient switching and was compared to a randomly undersampled acquisition with no profile ordering. This profile-ordering technique was then used to acquire contrast-enhanced whole-heart coronary MRI in 10 healthy subjects with 4-fold acceleration. Reconstructed images and the acquired zero-filled images were compared for depicted vessel length, vessel sharpness, and subjective image quality on a scale of 1 (poor) to 4 (excellent). In a pilot study, contrast-enhanced whole-heart coronary MRI was also acquired in four patients with suspected coronary artery disease with 3-fold acceleration. The undersampled images were reconstructed using low-dimensional-structure self-learning and thresholding, which showed significant improvement over the zero-filled images in both objective and subjective measures, with an overall score of 3.6 ± 0.5. Reconstructed images in patients were all diagnostic. Low-dimensional-structure self-learning and thresholding reconstruction allows contrast-enhanced whole-heart coronary MRI with acceleration as high as 4-fold using clinically available five-channel phased-array coil.

Evidence for human lung stem cells.

BACKGROUND: Although progenitor cells have been described in distinct anatomical regions of the lung, description of resident stem cells has remained elusive. METHODS: Surgical lung-tissue specimens were studied in situ to identify and characterize human lung stem cells. We defined their phenotype and functional properties in vitro and in vivo. RESULTS: Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays. CONCLUSIONS: Human lungs contain identifiable stem cells. In animal models, these cells participate in tissue homeostasis and regeneration. They have the undemonstrated potential to promote tissue restoration in patients with lung disease. (Funded by the National Institutes of Health.).

Aortic arch aneurysm in a child: the role of multislice computed tomography.

A 10-year-old girl came to our cardiac clinic complaining of chest pain. She had a history of aortic arch reconstruction 9 years ago. On chest X-ray, a calcified dilated aortic arch was found. Additionally, using a multislice computed tomography scan, the dimensions of the aneurysm were better illustrated. During the reoperation, the aneurysm was resected.

The 64-multislice computed tomogram averts misdiagnosis of an anomalous origin of the left main coronary artery.

A 38-year-old woman was discovered to have a systolic murmur for an unrelated complaint. Transesophageal echocardiography showed no atrial or ventricular septal defects, but multiple large collateral vessels in inter-ventricular septum. The origin of left coronary artery was not seen at the expected site on the aortic root. The 64-multislice computed tomography confirmed the diagnosis of an anomalous origin of the left coronary artery from the pulmonary artery. Left coronary artery was revascularized with a saphenous vein graft with an uneventful recovery.

Left ventricular pseudoaneurysm demonstrated by 64-multislice computed tomography.

A 50-year-old man with a history of left ventricular aneurysmectomy was evaluated with a 64-multislice computed tomogram, which demonstrated left ventricular enlargement and a pseudoaneurysm at the apicolateral side. The images were critical to our management. We resected the pseudoaneurysm with an excellent outcome.

Effect of metal chelating agents on pentylenetetrazole-induced seizure threshold in cholestatic mice.

Zinc has been proven to be anticonvulsant in several studies which indicate that diphenylthiocarbazone (dithizone) and diethyldithiocarbamate (DEDTC), zinc chelating agents, enhance seizure activities. There is also evidence that nitric oxide (NO) generators increase zinc concentration in the brain. On the other hand, the increased level of NO in the nervous system and the consequently increased seizure threshold in cholestatic mice have been well studied. Thus, it could be hypothesized that one of the reasons for the increased seizure threshold in cholestasis is partly the enhanced endogenous zinc concentration, at least in part, due to the overproduction of NO. In this study, we examined the hypothesis that zinc chelating agents might decrease seizure activity to its pre-cholestatic level in bile duct-ligated (BDL) mice. Mice were intra-peritoneally injected with dithizone and diethyldithiocarbamate (DEDTC) before the induction of seizure by pentylenetetrazole (PTZ) and then the seizure activity was recorded. Dose response (dithizone: 5, 30, 100 and 200mg/kg; DEDTC: 25, 50 and 100mg/kg) and time course (only for dithizone: 15, 30, 60 and 120 min) studies were performed first. Then, the effects of cholestasis, with and without dithizone injection, on seizure activity were assessed. Proconvulsant effect of dithizone and DEDTC was proved to be dose dependent although time interval between dithizone and PTZ injections did not play any significant role in the seizure activity. Cholestasis decreased seizure activity and increased lag phase before seizure and both effects were decreased by dithizone injection. It is elicited that zinc may mediate the cholestasis-induced decrement in seizure activity.

Decreased right ventricular function after coronary artery bypass grafting.

Decreased right ventricular function after coronary artery bypass grafting is a common and well-known (if not well-understood) phenomenon.We prospectively evaluated right ventricular function via echocardiographic tricuspid annular motion, tricuspid annular velocity, and right ventricular strain analysis before and after coronary artery bypass grafting. We also evaluated the effect of right coronary artery disease and revascularization on post-coronary artery bypass grafting, right ventricular function, and interventricular septal motion.We performed baseline echocardiography in 250 candidates for coronary artery bypass grafting, and we repeated echocardiography in 240 of those patients 1 year after coronary artery bypass grafting. We evaluated right ventricular function via tricuspid annular motion, tricuspid annular velocity, and right ventricular strain analysis, all measured at the right ventricular free wall.Right ventricular function as evaluated by tricuspid annular motion showed a significant reduction 1 year after coronary artery bypass grafting (21.7 vs 12.1 mm; P < 0.001) compared with preoperative measurements. Right ventricular tissue velocity (14.0 vs 7.0 cm/s; P < 0.001) and right ventricular strain (20.3% vs 11.6%; P < 0.001) were also significantly reduced after coronary artery bypass grafting. Interventricular septal motion was paradoxical in 97% of the patients 1 year after coronary bypass.Right ventricular function remained depressed for as long as 1 year after coronary artery bypass grafting. These findings were independent of the state of the right coronary artery and the graft. It is likely that the interventricular septum is recruited to maintain right ventricular stroke volume after coronary artery bypass grafting.

Interaction between two predictors of functional outcome after revascularization in ischemic cardiomyopathy: left ventricular volume and amount of viable myocardium.

OBJECTIVE: In patients with ischemic cardiomyopathy and substantial amounts of dysfunctional but viable myocardium, revascularization cannot always improve the left ventricular ejection fraction. We sought to investigate the interaction between the left ventricular volume and the amount of viable myocardium to predict the left ventricular ejection fraction increase after revascularization. METHODS: Eighty-five consecutive patients with a depressed left ventricular ejection fraction (mean: 27.3% +/- 5.2%) underwent coronary artery bypass grafting after a dobutamine stress echocardiography had determined that they had at least 4 viable segments. Six months after coronary artery bypass grafting, left ventricular ejection fraction and regional wall motion were reassessed. RESULTS: Although the left ventricular ejection fraction was expected to recover more than 5% in all 85 patients after coronary artery bypass grafting, it did not improve in 15 patients (17.6%) despite the presence of viable segments. The likelihood of the left ventricular ejection fraction recovery decreased proportionally with an increase in the left ventricular end-systolic volume. The nonimprovers had a higher left ventricular end-systolic volume (164.2 +/- 22.4 mL vs 125.6 +/- 23.4 mL, P = .0001). In addition, the number of viable segments during the dobutamine stress echocardiography had a significant correlation with the ejection fraction increase after 6 months (P < .0001). Patients with 6 viable segments showed a good outcome irrespective of their left ventricular end-systolic volume. In patients with fewer than 6 viable segments, left ventricular end-systolic volume was a major factor in the prognosis: Patients with left ventricular end-systolic volume of 145 or more had a poor left ventricular ejection fraction increase and vice versa. CONCLUSION: The extent of left ventricular remodeling determines the rate of functional improvement after coronary artery bypass grafting. Patients with a high left ventricular end-systolic volume and fewer than 6 viable segments have a lower likelihood of improvement.

Side-to-side arteriovenous fistula at the elbow with perforating vein ligation.

OBJECTIVE: We postulated that ligation of a consistent perforating venous branch at the elbow would improve distention and flow in the superficial veins about the elbow. This would also lesson the likelihood of arterial steal enabling a favorable outcome following a brachial artery medial antecubital or cephalic vein arterio-venous fistula (AVF). METHODS: Pressure measurements were made from the radial artery after side-to-side brachial artery antecubital or cephalic vein AVF in 20 patients. Clamping of the perforating vein increased radial artery pressure significantly indicating that a considerable amount of flow from the side-to-side AVF was diverted into the deep system and away from the accessible superficial veins. Encouraged by this finding, we studied the outcome of brachial cephalic or brachial antecubital AVF with ligation of the deep branch in 134 patients who were not candidates for radio-cephalic AVF. The end point of the study was successful hemodialysis using the fistula. RESULTS: Of the 134 patients treated, 24 died, and 11 were lost to follow-up and were censored from analysis of fistula performance at that time point. The primary fistula success rate was 89.7% +/- 2.66% and 83.7% +/- 3.5% at 1 and 2 years by life table analysis. No patient developed significant arterial steal or venous hypertension. CONCLUSION: We recommend this simple one-stage procedure for patients requiring hemodialysis whose cephalic vein at the wrist is unsuitable.

Cyst-like lesion on mitral valve.

A 62-year-old woman presented with exertional dyspnea and fever. On physical examination, a holosystolic murmur was found. A cystic lesion was detected by echocardiography. At surgery, a membrane was seen on the anterior leaflet, which extended from the primary chordae to papillary muscle of the anterior leaflet, making a cavity. There was also fenestration in the mid portion of the anterior leaflet. Leaflet augmentation with a pericardial patch was performed.

Prediction of atrial fibrillation via atrial electromechanical interval after coronary artery bypass grafting.

BACKGROUND: We assessed the validity of the atrial electromechanical interval, measured by transthoracic tissue Doppler echocardiography, in determining patients at risk of post-coronary artery bypass graft atrial fibrillation (AF). METHODS AND RESULTS: This prospective study recruited 355 patients in sinus rhythm who were candidates for coronary artery bypass grafting. The patients underwent a preoperative transthoracic echocardiography with a tissue Doppler evaluation and were monitored with continuous ECG telemetry during their hospital stay. Sixty-eight patients had postoperative AF (19.2%), with the incident occurring 2.3+/-0.7 days after surgery. The median length of hospitalization was 7.0 days for the AF patients and 6.0 days for the non-AF patients (P<0.0001). The subjects with postoperative AF differed from the sinus rhythm patients in that the former had a lower ejection fraction (40.4+/-8.5% versus 48.4+/-9.4%), a reduced maximal A-wave transmitral Doppler flow velocity (44.3+/-4.6 versus 53.3+/-10.9 cm/s), an increased total atrial volume (68.7+/-12.6 versus 55.3+/-11.8 mL), and a prolonged atrial electromechanical interval (141.9+/-13.4 versus 100.3+/-10.3 ms, respectively; P<0.0001 for all). In addition, the AF patients were older than the sinus rhythm group (66.0+/-8.0 versus 59.8+/-8.5 years). The atrial electromechanical interval was the best independent discriminator of the history of AF. We defined a cutoff point for the atrial electromechanical interval and chose 120 milliseconds for categorization, which yielded 100% sensitivity and 94.8% specificity for the prediction of AF. CONCLUSIONS: The atrial electromechanical interval by transthoracic tissue Doppler echocardiography could be a valuable method for identifying patients vulnerable to post-coronary artery bypass graft AF.