Treatment of heart failure with sodium glucose co-transporter-2 inhibitors in people with type 2 diabetes mellitus: current evidence and future directions.

Diabetes is one the most common comorbidities among people with established heart failure. Interest in heart failure as an outcome among people with diabetes has emerged since it was shown that there was an association between increased risk of hospitalization for heart failure with use of thiazolidinediones and some dipeptidyl peptidase-4 inhibitors. Recently, sodium-glucose co-transporter-2 inhibitors were shown to lead to a reduction in the risk of cardiovascular death and hospitalization for heart failure in people with Type 2 diabetes mellitus and either cardiovascular risk factors or atherosclerotic cardiovascular disease. These findings appear to be consistent in people both with and without a baseline history of heart failure. Based on current evidence there are several clinical scenarios in which the use of sodium-glucose co-transporter-2 inhibitors would be justified for people with heart failure and atherosclerotic cardiovascular disease: (1) in people with a new diagnosis of Type 2 diabetes and for whom anti-hyperglycaemic management strategies are being considered; (2) in people with sub-optimal glycaemic control, regardless of baseline antihyperglycaemic therapy; and (3) in people with symptomatic heart failure (or other high-risk features such as recent hospitalization for heart failure), if glycaemic control is optimized and the individual is on a sulfonylurea or dipeptidyl peptidase-4 inhibitor; here, it may be reasonable to consider substituting one of those therapies for a sodium-glucose co-transporter-2 inhibitor. There are now a number of ongoing trials evaluating the role of sodium-glucose co-transporter-2 inhibitors as therapy for people with established heart failure (with preserved or with reduced ejection fraction) and regardless of the presence of diabetes. These trials will provide the evidence for the safety and efficacy of sodium-glucose co-transporter-2 inhibitors among people with established heart failure.

The clinical impact of an early decline in kidney function in patients following heart transplantation.

Renal dysfunction is a well-known complication following heart transplantation. We examined an early decline in kidney function as a predictor of progression to end-stage renal disease and mortality in heart transplant recipients. We performed a retrospective cohort study of 233 patients who received a heart transplant between July 1985 and July 2004, and who survived >1 month. The decline in estimated creatinine clearance (CrCl) was used to predict the outcomes of need for chronic dialysis or mortality >1-year posttransplant. The earliest time to chronic dialysis was 484 days. A 30% decline in CrCl between 1 month and 12 months predicted the need for chronic dialysis (p = 0.01), all-cause mortality (p < 0.0001) and time to first CrCl 1-year posttransplant (p = 0.02). A 30% decline in CrCl between 1 month and 3 months also independently predicted the need for chronic dialysis (p = 0.04) and time to first CrCl 1-year posttransplant (p = 0.01). In conclusion, an early drop in CrCl within the first year is a strong predictor of chronic dialysis and death >1-year postheart transplantation. Future studies should focus on kidney function preservation in those identified at high risk for progression to end-stage kidney disease and mortality.

A panel study in congestive heart failure to estimate the short-term effects from personal factors and environmental conditions on oxygen saturation and pulse rate.

OBJECTIVES: Recent studies suggest that persons with congestive heart failure (CHF) may be at higher risk for short-term effects of air pollution. This daily diary panel study in Montreal, Quebec, was carried out to determine whether oxygen saturation and pulse rate were associated with selected personal factors, weather conditions and air pollution. METHODS: Thirty-one subjects with CHF participated in this study in 2002 and 2003. Over a 2-month period, the investigators measured their oxygen saturation, pulse rate, weight and temperature each morning and recorded these and other data in a daily diary. Air pollution and weather conditions were obtained from fixed-site monitoring stations. The study made use of mixed regression models, adjusting for within-subject serial correlation and temporal trends, to determine the association between oxygen saturation and pulse rate and personal and environmental variables. Depending on the model, we accounted for the effects of a variety of personal variables (eg, body temperature, salt consumption) as well as nitrogen dioxide (NO2), ozone, maximum temperature and change in barometric pressure at 8:00 from the previous day. RESULTS: In multivariable analyses, the study found that oxygen saturation was reduced when subjects reported that they were ill, consumed salt, or drank liquids on the previous day and had higher body temperatures on the concurrent day (only the latter was statistically significant). Relative humidity and decreased atmospheric pressure from the previous day were associated with oxygen saturation. In univariate analyses, there was negative associations with concentrations of fine particulates, ozone, and sulphur dioxide (SO2), but only SO2 was significant after adjustment for the effects of weather. For pulse rate, no associations were found for the personal variables and in univariate analyses the study found positive associations with NO(2), fine particulates (aerodynamic diameter of 2.5 microm or under, PM(2.5)), SO2, and maximum temperature, although only the latter two were significant after adjustment for environmental effects. CONCLUSIONS: The findings from the present investigation suggest that personal and environmental conditions affect intermediate physiological parameters that may affect the health of CHF patients.

Novel modalities of somatostatin actions.

The first part of this contribution reviews the current knowledge about endocrine and neuromodulatory actions of somatostatin. These biological actions are exerted according to endocrine, paracrine and autocrine modes of action and involve five distinct types of membrane receptors belonging to the 'super-family' of G-protein-coupled receptors. A new concept concerning a juxtacrine mode of action has recently been introduced to refer to the intervention of cytokines and growth factors in direct, cell-to-cell communication. The evidence in favor of juxtacrine actions of somatostatin will be presented in the second part of this review and illustrated by our own results on macrophage-lymphocyte T interactions in the immune system and spermatogonia-Sertoli cell interactions in mammalian testis. Another phenomenon such as ligand-induced somatostatin receptor homo- and hetero-dimerization resulting in 'poly'-receptors (with characteristics different from those of each of the two receptors forming the complex) is also at the origin of a novel mode of somatostatin action. The latter will be illustrated by the data obtained on human pituitary adenomas with somatostatin analogs specific for either 'poly'-receptor or relevant individual receptors. The arguments in favor of the analogous mode of actions among different families of chemical messengers such as peptides, cytokines and growth factors are discussed in the concluding section. The emerging unifying concepts on such functional analogies might provide a useful basis for the development of synthetic analogs not only for bioactive peptides but also for other types of chemical messengers.

History of C2 monitoring in heart and liver transplant patients treated with cyclosporine microemulsion.

Therapeutic drug monitoring of CsA has evolved since the introduction of CsA microemulsion. The purpose of the present review is to summarize the history of CsA concentration 2 hours postdose (C2) monitoring in heart and liver transplantation. C2 has been shown to be the best single time point that correlates with the area-under-the-curve, with a correlation coefficient (r2) ranging between .83 and.93. C2 monitoring (300 to 600 ng/mL) has resulted in a significant clinical benefit in long-term heart and liver transplant patients compared to trough level (C0) monitoring. Moreover, a C2 range of 300 to 600 ng/mL resulted in a similar calcineurin inhibition compared to a C2 range of 700 to 1000 ng/mL or a C0 range of 100 to 200 ng/mL while being less injurious to renal function. In de novo liver transplant patients not receiving induction therapy, the achievement of a target C2 of 850 to 1400 ng/mL by postoperative day 3 has resulted in a low acute rejection rate. Furthermore, C2 monitoring has been associated with a lower rejection rate in hepatitis C virus (HCV)-negative patients and with an overall lesser severity of acute rejection compared to C0 monitoring. In de novo heart transplant patients who receive antithymocyte globulin induction, a lower C2 range may be sufficient to prevent rejection and renal dysfunction. Future studies should help to fine-tune the optimal C2 range in heart or liver transplant patients receiving induction therapy and different maintenance immunosuppressive combinations.

Seasonal congestive heart failure mortality and hospitalisation trends, Quebec 1990-1998.

STUDY OBJECTIVE: To describe seasonal congestive heart failure (CHF) mortality and hospitalisations in Quebec, Canada between 1990-1998 and compare trends in CHF mortality and morbidity with those in France. DESIGN: Population cohort study. SETTING: Province of Quebec, Canada. PATIENTS: Mortality data were obtained from the Quebec Death Certificate Registry and hospitalisation from the Quebec Med-Echo hospital discharge database. Cases with primary ICD-9 code 428 were considered cases of CHF. RESULTS: Monthly CHF mortality was higher in January, declined until September and then rose steadily (p<0.05). Hospital admissions for CHF declined from May until September (moving averages analysis p<0.0001). Seasonal mortality patterns observed in Quebec were similar to those observed in France. CONCLUSION: CHF mortality in Quebec is highest during the winter and declines in the summer, similar to observations in France and Scotland. This suggests that absolute temperatures may not necessarily be that important but increased CHF mortality is observed once environmental temperatures fall below a certain "threshold" temperature. Alternatively better internal heating and warmer clothing required for survival in Quebec may ameliorate mortality patterns despite colder external environments.

Accumulation of Ym1/2 protein in the mouse olfactory epithelium during regeneration and aging.

A unique feature of the olfactory system is its efficiency to produce new neurons in the adult. Thus, destruction of the olfactory receptor neurons (ORNs) using chemical (intranasal perfusion with ZnSO4) or surgical (axotomy or bulbectomy) methods, leads to an enhanced rate of proliferation of their progenitors and to complete ORNs regeneration. The aim of our study was to identify new factors implied in this regenerative process. Using an electrophoretic method, we observed the accumulation of a 42 kDa protein after axotomy in the olfactory mucosa, but not in the olfactory bulb. Its expression started after a few days following injury and increased massively during the phase of ORN regeneration. The purification and the sequence characterization revealed that this protein was Ym1/2, recently identified in activated macrophages present in various tissues during inflammation. Western blotting analysis of Ym1/2 confirmed the accumulation of this protein in the regenerating olfactory mucosa consecutively to olfactory axotomy or bulbectomy but also after ZnSO4 irrigation of the nasal cavity. In the olfactory mucosa of control mice, Ym1/2 was hardly detectable in young animals and became more and more abundant with increasing age. In injured and aged mice, Ym1/2 mainly accumulates in the cytoplasm of supporting cells as well as in other cells located throughout the olfactory epithelium. Our results suggest that Ym1/2 is involved in olfactory epithelium remodeling following several kinds of lesions of the adult olfactory mucosa and support the view of a critical role of inflammatory cues in neurodegeneration and aging.

Somatostatin inhibits stem cell factor messenger RNA expression by Sertoli cells and stem cell factor-induced DNA synthesis in isolated seminiferous tubules.

Immature porcine Sertoli cells have been reported to be targets for the regulatory peptide somatostatin (SRIF), which inhibits the basal and FSH-induced proliferation of Sertoli cells through a decrease of cAMP production. In the present study, we show that SRIF inhibits both basal and FSH-stimulated expression of the stem cell factor (SCF), a Sertoli cell-specific gene. The SRIF-mediated inhibition of forskolin-triggered, but not of 8-bromoadenosine-cAMP-triggered, SCF mRNA expression demonstrates the involvement of adenylyl cyclase in underlying peptide actions. Moreover, these effects require functional coupling of specific plasma membrane receptors to adenylyl cyclase via inhibitory G proteins, because pertussis toxin prevents SRIF-mediated inhibition of SCF mRNA expression. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assays suggest the involvement of sst2 receptors in SRIF actions on Sertoli cells. The biological relevance of these data is supported by an SRIF-mediated decrease in SCF-induced incorporation of [(3)H]thymidine in isolated seminiferous tubules. In situ hybridization and confocal microscopy show that, in seminiferous tubules only, spermatogonia display both c-kit and sst2 receptors. Taken together, these results suggest that SCF-stimulated DNA synthesis can be inhibited by SRIF in spermatogonia, but not in Sertoli and peritubular cells. Combined RT-PCR and immunohistochemical approaches point toward spermatogonia and Leydig cells as the source of testicular SRIF. These data argue in favor of paracrine/autocrine SRIF actions in testis.

Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease. METHODS: Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months. RESULTS: For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001). CONCLUSIONS: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center.

A total of 1073 infectious episodes (IEs) that occurred in 620 consecutive heart transplantation patients at Stanford Medical Center between 16 December 1980 and 30 June 1996 were reviewed. Infectious complications were a major cause of morbidity and mortality, second only to rejection as the cause of early deaths and the most common cause of late deaths. Of the IEs, 468 (43.6%) were caused by bacteria, 447 (41.7%) by viruses, 109 (10.2%) by fungi, 43 (4.0%) by Pneumocystis carinii, and 6 (0.6%) by protozoa. The largest number of IEs occurred in the lungs (301 [28.1%]). A significant reduction in the incidence of IEs and a delay in presentation after transplantation were observed; these were most likely related to the introduction of new chemoprophylactic regimens during the study period and prevention of significant disease caused by cytomegalovirus.

Severe tricuspid regurgitation after heart transplantation.

BACKGROUND: Tricuspid regurgitation (TR) is common after heart transplantation. However, the incidence of severe TR and the incidence of symptoms after echocardiographic diagnosis of severe TR have not been documented. The purpose of this study is to determine the incidence of severe TR and its clinical significance in the heart transplant population. METHODS: We reviewed echocardiograms (echo) of all heart transplant patients coming for regular echocardiographic follow-up between 1990 and 1995. We reviewed the charts of all patients who had echo diagnosis of severe TR. RESULTS: A total of 336 patients had echo follow-up during this time period. The number of months post-heart transplant to last echo was 54 +/- 50 (range, 1 to 265 months). Ninety patients had moderate TR and 23 patients had severe TR. Mean time from heart transplantation to diagnosis of severe TR was 43 +/- 38 months (range, 1 to 132). Using Cutler-Ederer analysis, at 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, 17 had charts available for review. The mean number of prior endomyocardial biopsies was 28 +/- 21 (range, 3 to 88). These patients were followed for 35 +/- 18 months after diagnosis. During this period, they developed significant heart failure and peripheral edema. Six patients eventually underwent tricuspid valve replacement. CONCLUSIONS: Moderate to severe TR commonly occurs following heart transplantation. Severe TR is associated with significant morbidity.

Somatostatin analog SMS 201995 inhibits proliferation in human leukemia T-cell line: relevance of the adenylyl cyclase stimulation.

Octreotide SMS 201995 is a stable somatostatin (SRIF) analog with potent antiproliferative actions in numerous cell types including normal T lymphocytes. It is currently used in the clinical treatment of different malignancies. However, the possible beneficial actions of octreotide in T-cell leukemia have not been addressed before, although these cells express SRIF receptors. For instance, human leukemia Jurkat T cells have been shown to express a single SRIF receptor isotype: sst3 that can be pharmacologically targeted by octreotide. In this study, we therefore studied SMS 201995 effects on in vitro [(3)H-CH3]thymidine incorporation in Jurkat T cells. Our data show that octreotide inhibits the proliferation of Jurkat cells both in the absence and in the presence of mitogens. By contrast, SRIF28, an endogenous SRIF analog sharing with SMS 201995 an almost identical affinity for somatostatin sst3 receptors, increases [(3)H-CH3]thymidine uptake in both mitogen-activated and nonactivated cells. To assess the mechanisms of the opposite actions of these two analogs on leukemia T-cell proliferation, we next studied their effects on adenylyl cyclase activity in whole Jurkat cells. At least in the presence of mitogens, SMS 201995 significantly enhances the adenylyl cyclase activity whereas SRIF28 inhibits it. Taken together these data are in accordance with the current hypothesis according to which increase and decrease in cAMP production are required to allow the inhibition and stimulation of T-cell proliferation, respectively. They also point to a potential therapeutic benefit of SMS 201995 in the management of human T-cell leukemia.

Determinants of coronary remodeling in transplant coronary disease: a simultaneous intravascular ultrasound and Doppler flow study.

BACKGROUND: Coronary remodeling plays a significant role in lumen loss in transplant allograft vasculopathy (TxCAD), but the determinants of remodeling are unknown. We assessed the relationship between remodeling and plaque topography, coronary compliance, and blood flow in TxCAD. METHODS AND RESULTS: One artery in each of 27 transplant patients was investigated with simultaneous intravascular ultrasound and coronary flow measurements (basal and hyperemic by Doppler flow wire). At 4 to 8 different cross sections (mean 5.1+/-1. 2), plaque topography (concentric or eccentric) was determined, and total vessel area, lumen area, and intimal/medial area (IMA) were measured. Mean remodeling ratio (vessel area/IMA) in eccentric lesions (E, n=28) was significantly larger than that in concentric lesions (C, n=70) (E 5.87+/-0.93 versus C 3.58+/-0.62; P<0.001), despite similar IMA (E 3.89+/-0.68 versus C 3.90+/-0.41; P=NS) and distribution of imaged segments. Remodeling ratio was consistently larger in eccentric lesions in all 3 vessel segments when analyzed separately, and mean remodeling ratio for each artery was larger in vessels with predominantly eccentric lesions. Coronary compliance ([Delta lumen area/diastolic lumen area]/Delta mean arterial pressure x 10(3)) was also significantly greater in eccentric lesions versus concentric lesions (proximal 1.00+/-0.39 versus 0.22+/-0.04; mid 0.71+/-0.17 versus 0.21+/-0.10; distal 0.43+/-0.13 versus 0. 01+/-0.08; all P<0.01). Coronary flow reserve was also significantly higher in coronary arteries with primarily eccentric lesions (E 2. 49+/-0.64 versus C 1.87+/-0.28; P<0.01). CONCLUSIONS: Vessel remodeling in transplant vasculopathy is significantly greater in eccentric lesions than in concentric lesions, possibly due to greater coronary compliance and resistive vessel function.

Sauna-induced myocardial ischemia in patients with coronary artery disease.

PURPOSE: Sauna bathing is a popular recreational activity that is generally considered to be safe. However, there have been case reports of adverse cardiac events. We sought to determine whether sauna use caused myocardial ischemia in patients with coronary artery disease. METHODS: Sixteen patients with proven coronary artery disease were submitted to three conditions (rest, exercise, and sauna bathing) with continuous electrocardiographic (ECG) monitoring and regular blood pressure measurements. During each condition, patients were injected with Tc-99 sestamibi followed by nuclear scintigraphic imaging. Perfusion defect scores were calculated in 15 patients. RESULTS: Sauna bathing was well tolerated. There was a mean (+/- SD) increase in heart rate of 32% +/- 20% in the sauna (resting mean heart rate = 60 +/- 9 beats per minute vs sauna mean heart rate = 79 +/- 11 beats per minute, P <0.001) and a 13% +/- 6% drop in systolic blood pressure (resting mean systolic blood pressure = 142 +/- 14 mm Hg vs sauna mean systolic blood pressure = 123 +/- 15 mm Hg, P <0.001). There were no arrhythmias or ECG changes in the sauna. Compared with rest, there was significant ischemia during sauna bathing (average perfusion defect score at rest = -0.44 vs average sauna score = -0.93, P <0.001). The perfusion defect score in the sauna was worse than the resting score in 14 of the 15 patients. Sauna-associated perfusion defect scores were highly correlated with exercise-induced scores (R2 = 0.65, P <0.001). CONCLUSION: In patients with stable coronary artery disease, sauna use is clinically well tolerated but is associated with scintigraphically demonstrated myocardial ischemia.