Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy.

BACKGROUND: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. METHODS: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. RESULTS: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. CONCLUSION: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

Cardiac transplantation in the seventh decade of life.

Twenty-five patients older than 60 years of age underwent cardiac transplantation using an immunosuppression protocol with cyclosporin and azathioprine, but without routine use of oral steroids. There were 24 men and 1 woman (age range 60 to 69 years, mean 63). The etiology of heart disease was coronary artery disease in 21 and idiopathic dilated cardiomyopathy in 4. Six patients had previous coronary artery bypass operations, 1 had undergone repair of an abdominal aneurysm and 1 had pulmonary embolism. Sixteen patients were in New York Heart Association class IV and 9 in class III. Donor mean age was 30 (14 to 46) years. Hospital stay after transplantation was 10 to 90 days (median 11). Four died within 30 days and none from 5 to 59 months (mean 22). The 1-year actuarial survival was 84%. The incidence of rejection was 2.16 episodes per patient. Only 1 patient (4%) had serious infection. Six patients received antihypertensive treatment, 3 had reversible impairment of renal function, 2 had gout and 1 had drop foot. No patient had convulsions, transient ischemic attack or cerebrovascular accident. None had significant psychological problems. The 21 patients currently alive are in New York Heart Association class I. Quality of life, assessed by the Nottingham Health Profile, showed marked improvement. It is concluded that the initial results of cardiac transplantation in the seventh decade of life are encouraging.

Combined septal perforation and cardiac rupture after myocardial infarction. Clinical features and surgical considerations of a correctable condition.

The combination of septal perforation and cardiac rupture after myocardial infarction has rarely been reported. This article describes two cases of successful surgical repair of this condition and reviews another three cases previously reported in the literature. The important clinical features were as follows: (1) acute occlusion of a single dominant coronary artery; (2) renewed chest pain before perforation or rupture; (3) electromechanical dissociation at the time of frank rupture; (4) rupture through the left ventricular free wall; (5) in three patients both complications occurred within 3 days of the infarction, and in the other two patients they developed within three weeks. The main surgical considerations are as follows: (1) femoral cannulation to prevent exsanguination before instituting cardiopulmonary bypass; (2) electrically induced fibrillation to avoid systemic embolism; (3) a left ventricular approach to repair the septal perforation followed by infarctectomy; (4) concomitant revascularization was unnecessary. In conclusion, combined septal perforation and cardiac rupture after myocardial infarction is a potentially correctable condition that requires early diagnosis and prompt surgical intervention.

Domino heart transplantation: the Papworth experience.

The use of donor hearts from heart-lung recipients, the so-called domino procedure, began at Papworth Hospital in November 1988. Between then and September 1992, 198 heart transplantations and 86 heart-lung transplantations were performed. Fifty-three heart-lung recipients donated their hearts for use in the domino procedure. Thirty-two domino hearts were transplanted at Papworth and 21 were exported to other centers. Institution of the domino procedure allowed us to perform 19% more heart transplantations (166 to 198) than would have been done had the procedure not been used. The ischemic time was significantly shorter for the domino hearts compared with organs from brain dead donors (134 minutes versus 191 minutes; p < 0.001). No difference was found in the 3-month (84% versus 83%) or 1-year (74% versus 76%) survival between domino and nondomino recipients. Other potential advantages of the domino procedure include detailed pretransplantation evaluation of the heart in live donors and the potential for human leukocyte antigen matching. Additionally many heart-lung recipients have elevated pulmonary artery pressures and a "conditioned", hypertrophied right ventricle. The use of such hearts for heart transplantation has theoretic appeal for patients with elevated pulmonary vascular resistance.

Medium-term results of combined heart and lung transplantation for emphysema.

Between December 1983 and April 1989, 222 combined heart and lung transplant operations were performed for treatment of pulmonary vascular disease and parenchymal lung disease at Harefield Hospital. Seventeen of these patients had emphysema, and 11 of them were followed up for a minimum of 1 year. There were nine male and two female patients. Their mean age was 39 (range, 32 to 54) years. Seven had alpha 1-antitrypsin deficiency. Six patients were receiving continuous oxygen therapy, and two patients were dependent on a ventilator. Postoperatively, the patients' lungs were ventilated for a median of 3 days (range, 24 hours to 2 weeks). Two patients subsequently required further periods of ventilation. Immunosuppression consisted of azathioprine and cyclosporine. Three patients also received low-dose oral steroids. There was one early death, which occurred on the second postoperative day. The remaining patients were followed up for 12 to 53 (mean, 22) months. One patient had cytomegalovirus pneumonitis 6 weeks postoperatively that responded to treatment. There was one late death at 14 months after reoperation for treatment of obliterative bronchiolitis. The overall survival was 91% at 1 year. All survivors achieved an excellent level of rehabilitation. It is concluded that the medium-term results of heart and lung transplantation for treatment of emphysema are good and that patients with alpha 1-antitrypsin deficiency may undergo transplant procedures without substitution therapy.

Increased production of beta2-microglobulin after heart transplantation.

Serum beta2-microglobulin (beta2m) levels were measured to evaluate the state of immunoactivation in stable heart transplant recipients. Serum beta2m and renal function of 29 heart transplant recipients were compared with 16 control subjects, who were age and sex matched, and 11 patients with chronic kidney failure. Serum creatinine and 24-hour urine collection for albuminuria were used as markers of renal impairment. Heart transplant recipients with normal renal function (n = 7) had significantly elevated beta2m levels compared with control subjects: 2.6 +/- 0.9 vs 1.66 +/- 0.32 microg/ml, p < or = 0.05. Heart transplant recipients with impaired renal function (n = 22) had significantly elevated beta2m compared with the chronic kidney failure group: 4.42 +/- 1.3 vs 3.49 +/- 0.66 microg/ml (p < or = 0.05); although there was no significant difference in serum creatinine levels. Albuminuria excretion was significantly elevated in the chronic kidney failure group compared with the heart transplant recipients with impaired renal function (p < or = 0.05). Elevated serum beta2m in heart transplant recipients suggests increased beta2m production, reflecting increased immunoactivation. This observation could be useful in monitoring long-term immunosuppressive therapy.

Alternative method for cardiac transplantation: surgical considerations and technical aspects.

A simplified technique for complete orthotopic cardiac transplantation is described. The potential technical difficulties and surgical considerations are discussed.

Fiberoptic-guided CO2 laser for harvesting of the internal mammary artery.

OBJECTIVE: The internal mammary artery is the preferred conduit in coronary artery bypass grafting. Although most centers use electrocautery to dissect the internal mammary artery, it has several disadvantages. The purpose of this study in a canine model was to evaluate and compare a fiberoptic CO2 laser device versus electrocautery for harvesting the internal mammary artery. MATERIAL AND METHODS: In ten mongrel dogs, both internal mammary arteries with their surrounding pedicles, were dissected from the thoracic wall, using a low-current electrocautery for one artery and a continuous wave, fiberoptic-guided CO2 laser (13 watts) for the contralateral vessel. Blood flow through the vessels was measured immediately after dissection. RESULTS: Mean flow through the laser dissected arteries was 71.3 +/- 23.7 ml/min versus 52.9 +/- 16.5 ml/min in those dissected using electrocautery. Histological examination of the chest wall specimens dissected with electrocautery showed the presence of necrosis, edema and hemorrhage surrounding the muscle, while the specimens dissected with the laser revealed only a narrow area of burn on the surgical margins of the muscle. The laser-assisted dissection was more accurate, as easy, and almost as fast as with the use of electrocautery. CONCLUSIONS: Stripping of the internal mammary artery with the fiberoptic CO2 laser offers a promising alternative to electrocautery. Owing to its greater accuracy, the laser technique may reduce the likelihood of damaging the endothelial lining of the dissected vessel. By reducing the degree of soft tissue damage, the CO2 laser may also lower the incidence of sternal wound infection and reduce postoperative chest wall pain and dysesthesia.

Primary cardiac tumours--is there a place for cardiac transplantation?

Between 1979 and 1985, seven patients (five children and two adults) were treated for primary cardiac tumours other than benign atrial myxomas. There were five malignant neoplasms (two non-classifiable sarcomas, one haemangiosarcoma, one histiocytoma and one neurofibrosarcoma) and two benign tumours (fibromas). Echocardiography, cardiac catheterisation, computed tomography and magnetic resonance imaging provided diagnostic confirmation. The two patients with fibroma are alive and well 4 and 5 years after radical resection of the tumours from the interventricular septum. The patient with a neurofibrosarcoma underwent orthotopic cardiac transplantation and is well 5.5 years postoperatively with no evidence of residual disease or recurrence. One patient died awaiting a donor heart for transplantation. Another patient who was a candidate for heart and lung transplantation was found to have an unresectable tumour at the time of operation. One patient with sarcoma who underwent a successful emergency partial resection for relief of cardiac tamponade died 18 months later from widespread metastases. The seventh patient was inoperable due to multiple secondaries. It is concluded that radical resection of large, benign, cardiac tumours can give good results and that early cardiac transplantation probably offers the only hope for patients with malignant tumours of the heart.

Heart transplantation--an update.

Cardiologists caring for heart transplant recipients must be familiar with the pharmacology, drug interactions, and drug toxicity of those agents used extensively in clinical practice (cyclosporine, prednisone, azathioprine, polyclonal and monoclonal anti-T-cell agents) and the newer treatments [methotrexate, FK-506, rapamycin, mycophenolate mofetil (RS61443), deoxyspergualin, anti-CD4 monoclonal antibodies, total lymphoid irradiation, and photophoresis]. Another important aspect of medical follow-up is the detection, differential diagnosis, and treatment of allograft dysfunction. Hemodynamic abnormalities that occur as a result of rejection or a direct drug effect must be differentiated from physiologic changes. Cardiac allograft vasculopathy is the primary impediment to the long-term survival of heart transplant recipients. Immunopathogenesis, prevention, early detection, and treatment of allograft vasculopathy should be the major focus of heart transplantation research.

Induction of controlled cardiac tamponade in the management of massive unexplained postcardiotomy bleeding. Case report and review of the literature.

Massive unexplained bleeding is a catastrophic complication of open heart surgery. The following paper describes a successful attempt to terminate such a hemorrhage by induction of controlled cardiac tamponade which caused augmentation of mediastinal pressure without hemodynamic decompensation, thereby aiding in hemostasis. This modality has not previously reported. Few events in clinical medicine are so ominous as the major unexplained hemorrhage. Diffuse bleeding from multiple transected small vessels may be controlled by mechanical techniques which apply pressure directly over the bleeding area. However, where the mediastinum is the source of bleeding, application of such a direct pressure with a closed chest, is both technically difficult and potentially risky. Reported attempts to stop bleeding by increasing the mediastinal pressure included the induction of pneumothorax, and the increase of positive end expiratory pressure (PEEP) has been published. To the best of our knowledge, a deliberate induction of controlled cardiac tamponade in order to terminate prolonged unexplained massive postcardiotomy hemorrhage has not been reported so far.

Very high frequency oscillations in the heart rate and blood pressure of heart transplant patients.

The authors studied the recently reported very high frequency (VHF) peaks in the heart rate (HR) and blood pressure (BP) power spectra of heart transplant (HT) patients. These VHF peaks appear at frequencies much higher than the respiratory frequency, in addition to the typical low-frequency and high-frequency peaks. Twenty-five recordings obtained from 13 male HT patients (0.5-65 months following surgery) were compared with recordings from 14 normal male subjects. The ECG, continuous BP and respiration were recorded during 45min of supine rest. Eight recordings from HT patients were excluded owing to arrhythmias. Spectral analysis was performed on all other recordings. VHF peaks were found in the spectra of both BP and HR in nine recordings obtained from six HT patients. In some cases, the power in the VHF peaks was markedly higher than that of the high-frequency peak. No VHF peaks were observed in eight recordings obtained from four HT patients or in recording from any of the normal subjects. No correlation was found between the incidence of VHF peaks and time after transplant. It was proved that the VHF peaks were not artifactual, and their significance within the framework of the theory of communication systems is discussed. The presence of those peaks was attributed to vagal denervation.

Does synchronization reflect a true interaction in the cardiorespiratory system?

Cardiorespiratory synchronization, studied within the framework of phase synchronization, has recently raised interest as one of the interactions in the cardiorespiratory system. In this work, we present a quantitative approach to the analysis of this nonlinear phenomenon. Our primary aim is to determine whether synchronization between HR and respiration rate is a real phenomenon or a random one. First, we developed an algorithm, which detects epochs of synchronization automatically and objectively. The algorithm was applied to recordings of respiration and HR obtained from 13 normal subjects and 13 heart transplant patients. Surrogate data sets were constructed from the original recordings, specifically lacking the coupling between HR and respiration. The statistical properties of synchronization in the two data sets and in their surrogates were compared. Synchronization was observed in all groups: in normal subjects, in the heart transplant patients and in the surrogates. Interestingly, synchronization was less abundant in normal subjects than in the transplant patients, indicating that the unique physiological condition of the latter promote cardiorespiratory synchronization. The duration of synchronization epochs was significantly shorter in the surrogate data of both data sets, suggesting that at least some of the synchronization epochs are real. In view of those results, cardiorespiratory synchronization, although not a major feature of cardiorespiratory interaction, seems to be a real phenomenon rather than an artifact.

An ultra-low dose of tetrahydrocannabinol provides cardioprotection.

UNLABELLED: Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family. Both CB1 and CB2 mRNA and proteins are present in the heart. THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro. We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults. The present study was aimed to test and characterize the cardioprotective effects of a very low dose (0.002mg/kg) of THC which is 3-4 orders of magnitude lower than the conventional doses, administered before myocardial infarction in mice in vivo. Three regimens of THC administration were tested: single THC application 2h or 48h before the induction of infarct, or 3 weeks continuous treatment before MI. All protocols of THC administration were found to be beneficial. In the case of THC treatment 2h before MI, fractional shortening was elevated (37±4% vs. 42±1%, p<0.04), troponin T leakage to the blood was reduced (14±3ng/ml vs. 10±4ng/ml, p<0.008), infarct size decreased (29±4% vs. 23±4%, p<0.02), and the accumulation of neutrophils to the infarct area declined (36±10cells/field vs. 19±4cells/field, p<0.007) in THC- compared to vehicle-pretreated mice, 24h after MI. ERK1/2 phosphorylation following infarct was also inhibited by pre-treatment with THC (p<0.01). CONCLUSION: A single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage.