Diabetes Mellitus Heart Failure Research Articles

Impact of Diabetes Mellitus on Heart Failure Patients: Insights from a Comprehensive Analysis and Machine Learning Model Using the Jordanian Heart Failure Registry.

Heart failure (HF) is a common final pathway of various insults to the heart, primarily from risk factors including diabetes mellitus (DM) type 2. This study analyzed the clinical characteristics of HF in a Jordanian population with a particular emphasis on the relationship between DM and HF. This prospective study used the Jordanian Heart Failure Registry (JoHFR) data. Patients with HF were characterized by DM status and HF type: HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). Demographics, clinical presentations, and treatment outcomes were collected. Statistical analyses and machine learning techniques were carried out for the prediction of mortality among HF patients: Recursive Feature Elimination with Cross-Validation (RFECV) and Synthetic Minority Over-sampling Technique with Edited Nearest Neighbors (SMOTEENN) were employed. A total of 2007 patients with HF were included. Notable differences between diabetic and non-diabetic patients are apparent. Diabetic patients were predominantly male, older, and obese (p < 0.001 for all). A higher incidence of HFpEF was observed in the diabetes cohort (p = 0.006). Also, diabetic patients had significantly higher levels of cholesterol (p = 0.008) and LDL (p = 0.003), reduced hemoglobin levels (p < 0.001), and more severe renal impairment (eGFR; p = 0.006). Machine learning models, particularly the Random Forest Classifier, highlighted its superiority in mortality prediction, with an accuracy of 90.02% and AUC of 80.51%. Predictors of mortality included creatinine levels >115 µmol/L, length of hospital stay, and need for mechanical ventilation. This study underscores notable differences in clinical characteristics and outcomes between diabetic and non-diabetic heart failure patients in Jordan. Diabetic patients had higher prevalence of HFpEF and poorer health indicators such as elevated cholesterol, LDL, and impaired kidney function. High creatinine levels, longer hospital stays, and the need for mechanical ventilation were key predictors of mortality.

Maladaptive response following glucose overload in GLUT4-overexpressing H9C2 cardiomyoblasts.

Glucose overload drives diabetic cardiomyopathy by affecting the tricarboxylic acid pathway. However, it is still unknown how cells could overcome massive chronic glucose influx on cellular and structural level. Expression profiles of hyperglycemic, glucose transporter-4 (GLUT4) overexpressing H9C2 (KE2) cardiomyoblasts loaded with 30 mM glucose (KE230L) and wild type (WT) cardiomyoblasts loaded with 30 mM glucose (WT30L) were compared using proteomics, real-time polymerase quantitative chain reaction analysis, or Western blotting, and immunocytochemistry. The findings suggest that hyperglycemic insulin-sensitive cells at the onset of diabetic cardiomyopathy present complex changes in levels of structural cell-related proteins like tissue inhibitor of metalloproteases-1 (1.3 fold), intercellular adhesion molecule 1 (1.8 fold), type-IV-collagen (3.2 fold), chaperones (Glucose-Regulated Protein 78: 1.8 fold), autophagy (Autophagosome Proteins LC3A, LC3B: 1.3 fold), and in unfolded protein response (UPR; activating transcription factor 6α expression: 2.3 fold and processing: 2.4 fold). Increased f-actin levels were detectable with glucose overload by immnocytochemistry. Effects on energy balance (1.6 fold), sirtuin expression profile (Sirtuin 1: 0.7 fold, sirtuin 3: 1.9 fold, and sirtuin 6: 4.2 fold), and antioxidant enzymes (Catalase: 0.8 fold and Superoxide dismutase 2: 1.5 fold) were detected. In conclusion, these findings implicate induction of chronic cell distress by sustained glucose accumulation with a non-compensatory repair reaction not preventing final cell death. This might explain the chronic long lasting pathogenesis observed in developing heart failure in diabetes mellitus.

Impacto pronóstico de metformina en pacientes con diabetes mellitus tipo 2 e insuficiencia cardiaca aguda. Análisis combinado de los registros EAHFE y RICA

IntroductionPatients with diabetes mellitus (DM) and heart failure (HF) have a worse prognosis despite therapeutic advances in both diseases. Sodium-glucose co-transporter type 2 and GLP-1 receptor agonists have shown cardiovascular benefits and have been positioned as the first step in the treatment of DM in patients with HF or high cardiovascular risk. However, in the pivotal trials the majority of patients receives concomitant treatment with metformin. Randomized clinical trials have not yet been developed to assess the prognostic impact of metformin at the cardiovascular level. Our objective was to analyze whether patients with DM and acute HF who receive treatment with metformin at the time of discharge may have had a better prognosis at one year of follow-up. MethodsProspective cohort trial using the combined analysis of the 2 main Spanish HF registries: the Epidemiology of Acute Heart Failure in Emergency Departments registry –EAHFE– and the National Registry of Patients with Heart Failure –RICA–. Results33% (1453) of a total of 4403 patients with DM type 2 received treatment with metformin. This group presented significantly lower mortality after one year of treatment (22 vs. 32%; Log Rank test, p<0.001). In the adjusted analysis of mortality, patients receiving treatment with metformin had lower mortality at one year of follow-up regardless of the rest of the variables (RR 0.814; 95% CI: 0.712–0.930; p<0.01). ConclusionsPatients with DM type 2 and acute HF who received metformin had a better prognosis after one year of follow-up, so we believe that this drug should continue to be a fundamental pillar in the treatment of these patients.

Prognostic impact of metformin in patients with type 2 diabetes mellitus and acute heart failure: Combined analysis of the EAHFE and RICA registries

IntroductionPatients with diabetes mellitus (DM) and heart failure (HF) have a worse prognosis despite therapeutic advances in both diseases. Sodium-glucose co-transporter type 2 and GLP-1 receptor agonists have shown cardiovascular benefits and they have been positioned as the first step in the treatment of DM in patients with HF or high cardiovascular risk. However, in the pivotal trials the majority of patients receive concomitant treatment with metformin. Randomized clinical trials have not yet been developed to assess the prognostic impact of metformin at the cardiovascular level. Our objective has been centered in analyzing whether patients with DM and acute HF who receive treatment with metformin at the time of discharge may have a better prognosis at one year of follow-up. MethodsProspective cohort trial using the combined analysis of the two main Spanish HF registries, the EAHFE Registry (Epidemiology of Acute Heart Failure in Emergency Departments) and the RICA (National Registry of Patients with Heart Failure). Results33% (1453) of a total of 4403 patients with DM type 2 received treatment with metformin. This group presents significantly lower mortality after one year of treatment (22 versus 32%; Log Rank test P < 0.001). In the adjusted analysis of mortality, patients receiving treatment with metformin have lower mortality at one year of follow-up regardless of the rest of the variables (RR 0,814; 95%IC 0,712–0,930; P < 0.01). ConclusionsPatients with DM type 2 and acute HF who receive metformin have a better prognosis after one year of follow-up, so we believe that this drug should continue to be a fundamental pillar in the treatment of these patients.

Outcomes of Patients With Diabetes Versus Patients Without Diabetes Hospitalized With Acute Heart Failure

The objective is to define the clinical echocardiographic characteristics and cardiovascular outcome in patients with acute heart failure (HF) with versus without diabetes mellitus (DM). Demographic, clinical, laboratory, and echocardiographic data were collected in Olmsted County adults hospitalized for acute HF between 2005 and 2008. Analyses were performed for mortality and acute HF hospitalization outcomes stratified by diabetic status, systolic function, and diastolic function. There were 912 subjects who met inclusion criteria, and mean age was 79 (SD 13.1) years with 53% women. Prevalence of DM was 42% in the study population, and those with DM had worse diastolic function and increased mortality and HF rehospitalization. Among those with DM and acute HF, reduced left ventricular ejection fraction and worse diastolic function conferred increased HF rehospitalization (p=0.010 and p=0.022, respectively). In conclusion, DM is common in those hospitalized for acute HF and is associated with worse long-term clinical outcomes. The subgroup of DM with acute HF and left ventricular systolic dysfunction or diastolic dysfunction had worse HF rehospitalization outcomes.

Diabetes Mellitus and Heart Failure

Diabetes mellitus (DM) is a major risk factor for new-onset heart failure (HF) and vice versa. The pathogenesis of new-onset HF in DM is complex and has been largely attributed to the toxic cardiovascular effects of hyperglycemia and relevant metabolic abnormalities (diabetic cardiomyopathy) as well as the frequently coexisting morbidities such as hypertension (HTN), coronary artery disease (CAD), and diabetic nephropathy. In patients with type 1 DM (T1DM), HF develops in the setting of a dysregulated immune response, whereas in most patients with type 2 DM (T2DM), against a background of overweight/obesity. HF prevention in DM is feasible with rigorous treatment of cardiovascular risk factors and selective antidiabetic agents. Conversely, development of new-onset T2DM in HF (cardiogenic DM) is common and has been attributed to an increase in the resistance to insulin, especially in the skeletal muscle, liver, and adipose tissue as well as in diminished insulin secretory response to hyperglycemia by pancreatic β-cells. Cardiogenic DM further deteriorates cardiac dysfunction and adversely affects outcome in HF. Novel lifesaving medications employed in HF management such as sacubitril/valsartan and sodium glucose cotransporter 2 inhibitors (SGLT-2i) have a favorable metabolic profile and lower the incidence of cardiogenic diabetes. Whether mitigation of cardiogenic DM should be a treatment target in HF deserves further investigation.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis

BackgroundCardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD.MethodsMEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model.ResultsOut of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70–0.96), embolic stroke (RR 0.32, 95% CI 0.12–0.85), AF/AFL (RR 0.82, 95% CI 0.71–0.95), and VT (RR 0.73, 95% CI 0.53–0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58–1.17) and cardiac arrest (RR 0.83, 95% CI 0.61–1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used.ConclusionsSGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias.

Elevated GDF-15 levels may indicate malnutrition in chronic compensated heart failure with or without diabetes mellitus

Abstract Background/Introduction Malnutrition is common in chronic heart failure (HF) and is associated with adverse outcomes. Elevated NT-proBNP may indicate increased cardiac stress, whereas growth differentiation factor 15 (GDF-15) is increased in response to tissue injury, inflammation and in diabetes mellitus (DM). GDF-15 also negatively regulates appetite, body weight and skeletal muscle homeostasis. Purpose We aim to assess the nutritional status of HF patients with or without DM, and determine if GDF-15 is associated with malnutrition. Methods We did a cross-sectional analysis on chronic HF patients in a prospective cohort study, forecAsting Heart Failure decompensation (AHF). Chronic compensated HF was defined as a state following hospital discharge for &amp;gt;30 days, or where there had not been hospitalisation for 30 days preceding phenotyping. Patients with a history of HF decompensation were included. Geriatric Nutritional Risk Index (GNRI), including body mass index (BMI) and serum albumin, was used to assess and categorise nutritional status. Patients were classified as being “malnourished” or “well-nourished” based on GNRI scores of &amp;lt;92 and ≥92, respectively. NT-proBNP and GDF-15 levels were measured and echocardiography was done. The study was approved by institutional review board and complied with Declaration of Helsinki. Results Among 73 patients (mean age 66 y, 58.9% male), 32.7% exhibited malnutrition as determined by GNRI. There was no difference in age, sex ratio and NYHA functional class between the malnourished and the well-nourished. BMI (22.1 vs 25.6, P&amp;lt;0.001) and levels of GDF-15 (7216.0 vs 2469.0, P&amp;lt;0.001) and NT-proBNP (7158.0 vs 1321.0, P=0.01) were different between the malnourished and well-nourished. Both GDF-15 and NT-proBNP were inversely correlated with GNRI (GDF-15, r=−0.39, P&amp;lt;0.001; NT-proBNP, r=−0.46, P&amp;lt;0.0001). As expected, DM HF patients had significantly higher levels of GDF-15 than non-DM HF patients. In subgroup analysis of DM HF patients, GDF-15 and NT-proBNP levels were higher in the malnourished than well-nourished (median log-[GDF-15], 9.15 vs 8.10, P&amp;lt;0.01; median log-[NT-proBNP], 9.44 vs 7.00, P&amp;lt;0.01). Whereas in non-DM HF, NT-proBNP levels were not different between the malnourished and well-nourished. Age- and sex-adjusted logistic regression model determined that per log increment in GDF-15 level there was a 5.8-fold increased risk of malnutrition (OR 5.81 [2.43–17.62], P&amp;lt;0.001), and for every log increment in NT-proBNP level there was a 1.8-fold increase in the risk of malnutrition (OR 1.82 [1.23–2.88], P&amp;lt;0.01). Conclusion(s) Malnutrition is common in chronic compensated HF patients with a history of hospitalisation, and is associated with elevated NT-proBNP and GDF-15 levels. Elevated GDF-15 levels independently predicted poor nutritional status, and with NT-proBNP may indicate a particularly high-risk HF subgroup Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): 1) Health and Medical Research Fund, Food and Health Bureau, 2) Direct Grant, Faculty of Medicine, CUHK

Analisis Faktor Risiko Pasien Gagal Jantung dengan Reduced Ejection Fraction di RSUD Dr. H. Abdul Moeloek Provinsi Lampung

ABSTRACT&#x0D; Introduction: The number one cause of death for non-communicable diseasesis cardiovascular disease. Congestive heart failure (CHF) is one of the health problems in the cardiovascular systems with increasing incidence every year.&#x0D; Methods: This study used a retrospective analytic study design using secondary data from patients medical recordsto observethe characteristics of heart failure patients in RSUD Dr. H. Abdul Moeloek Hospital Lampung fromJanuary to June 2018. Data was then processed by using IBM SPSS Statistics v.24.0.&#x0D; Results : The results of statistical analysis with chi square on risk factors of patients with HFERF showed that age had p-value of 0.85; gender had 0.611and other risk factors such as hypertension, diabetes mellitus (DM), coronary heart disease (CHD) and smoking had p-valuesof 0.113; 0.044; 0.057 and 0.083 respectively. Statistically, the risk factor whichcorrelated to the incidence of HFERF was diabetes mellitus.&#x0D; Discussion : Patients with DM havegreater risk factor to heart failure. In the Framingham study, it showed that DM independently increases the risk of heart failure bytwo times in men and five times in women. The increased incidence of heart failure in DM also persists despite of other factors like age, hypertension, hypercholesterolemiaand CHD.&#x0D; Conclusions : DM risk factors significantly related to the high incidence of HFrEF. Gender, age, hypertension, CHD and smoking did not significantly related to the incidence of HFrEF at RSUD Dr. H. Abdul Moeloek. Thisshowedthathe risk factors observed were notsignificantlydifferent from HFrEFandothertypesofheartfailure.&#x0D; Keywords: ejection fraction, heart failure, risk factor

Reducing the risk of heart failure in diabetes mellitus: review of new therapeutics

Diabetes mellitus (DM) and heart failure (HF) are closely related: patients with diabetes have an increased risk of developing HF and those with HF are at higher risk of developing diabetes. When the two diseases are considered individually, HF has a much poorer prognosis than diabetes mellitus; therefore, treatment of HF is a priority in these group of patients. There are many drugs now available to achieve glycemic control in individuals with DM. However, as we enter an era of personalization in the management of DM, the next challenge will be the identification of therapeutic strategies that will not only achieve and maintain glycemic control, but that will also reverse existing complications. Given the high prevalence of HF in DM, there is a strong imperative to advance this field, with the view of identifying robust strategies that will not only improve long-term outcomes in subjects with DM and HF but also limit the likelihood of developing HF in the first place. Newer therapies like sodium- glucose transport protein- 2 inhibitors (SGLT-2 I) and sacubitril or valsartan have shown potential benefit for reducing the risk of heart failure in diabetic population. This review will summarize the new therapeutics to reduce the risk of HF in patients with DM.

Mitochondrial Mechanisms in Diabetic Cardiomyopathy.

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca2+ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

Mechanisms underlying heart failure in type 2 diabetes mellitus

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

Type 2 Diabetes Mellitus and Heart Failure: Innovative Possibilities for Management of Prognosis

Type 2 diabetes mellitus (T2DM) has gone beyond the professional interests of one specialty. T2DM, cardiovascular (CV) diseasesand chronic kidney disease, considered from the standpoint of a single cardio-reno-metabolic continuum, place a heavy economicburden on society. At the same time, the improvement of diagnostic methods and medical technologies led to distinct decreasein the frequency and mortality from a number of complications of T2DM, including myocardial infarction and stroke, but other statestook their place. Thus, heart failure (HF) has taken the position of one of the most frequent complications with average prevalenceof 24-40 % and significant predominance of HF with preserved ejection fraction (HFpEF). According to this paradigm, HFpEF is nota disease of diastolic dysfunction, but a systemic disease, the central element of which is impaired renal function. All this togetherhas a potential value for choosing the optimal therapy. In recent years the results of specially designed studies assessing the CV-safetyof antidiabetic drugs from the groups of dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like preptide-1 (GLP-1) receptor agonists and sodium - glucose co-transporter-2 (SGLT2) inhibitors have become known. These drugs, except for SGLT2 inhibitors, by their mechanism of action affecting insulin resistance and hyperglycemia, demonstrated neutral or negative result on the frequency of hospitalizations due to HF. The EMPA-REG OUTCOME study with SGLT2, which has a special insulin-independent mechanism of action, demonstrated not only the efficacy and CV-safety of the drug in the form of a decrease in CV mortality by 38 %, but also a decrease in hospitalizations for HF by 35 %. Further studies with SGLT2 inhibitors confirmed positive effect on HF, indicating a class effect of the drugs. The recently completed study DECLARE-TIMI 58 proved the advantages of using dapagliflozin for the primary and secondary prevention of HF. This review highlights the prevalence of HF in diabetes mellitus, a new concept of the pathophysiology of HF, the main groups of sugar-lowering drugs and their effect on CV outcomes, in particular on HF.

Coronary Microvascular Smooth Muscle Cells Contribute to Heart Failure in Diabetes Mellitus by Increasing Methylglyoxal Flux

Prognosis for patients with type 1 diabetes mellitus (T1DM) who have heart failure is poor because of an incomplete understanding of molecular cues that trigger it and a lack of specific pharmacologic agents/strategies to slow/reverse its development. Supra-physiologic levels of the α-oxoaldehyde methylglyoxal (MG) have emerged as a possible cue. However, its source remains poorly characterized. Here we investigated MG levels and expression of its degrading and synthesizing enzymes glyoxalase-I (Glo-I) and vascular adhesion protein-1 (VAP-1) in ventricular tissues from rats with chronic streptozotocin-induced T1DM. We also used a gene transfer approach to prevent Glo-I downregulation in ventricular tissues to determine if it would be cardio-protective. When compared to controls, hearts of rats with chronic T1DM (10 -12 weeks) had 5-fold higher MG in ventricular tissues, 2.2-fold lower level of Glo-I in ventricular tissues and 2.5-fold higher in coronary microvascular smooth muscle cells (cSMCs). Preventing Glo-I levels downregulation in myocytes and cSMCs of rats by injecting them with an adeno-associated virus contain Glo-I driven by the endothelin promoter one week after the onset of T1DM, attenuated ventricular MG increase, with no effect in blood MG. Increasing Glo-I also blunted VAP-1 upregulation in cSMCs, attenuated microvascular leakage, inflammation, and fibrosis. These data support the notion that an increase in MG arising in part from increased expression of VAP-1 is contributing to HF development in T1DM rats and lowering ventricular MG levels T1DM rats is cardio-protective. Disclosure K. Bidasee: None.

Modeling heart failure risk in diabetes and kidney disease: limitations and potential applications of transverse aortic constriction in high-fat-fed mice.

There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson's trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.

Ipragliflozin Prevents the Worsening of Ischemic Heart Failure in Diabetic Rats Independent of its Diuretic Effect

IntroductionAlthough diabetes mellitus (DM) increases cardiovascular events, no clinical trials had ever shown the benefit of glucose‐lowering therapy on heart failure (HF). Recently, sodium‐glucose cotransporter 2 (SGLT2) inhibitor has shown to lower cardiovascular events and hospitalization for HF in DM (EMPA‐REG OUTCOME). To clarify the beneficial mechanisms of SGLT2‐inhibitor for HF, we investigated the impact of SGLT2‐inhibitor, ipragliflozin, on hemodynamics and cardiac function in a rat model of HF with DM.MethodsWe allocated Sprague‐Dawley rats into streptozotocin (60 mg/kg)‐induced DM or non‐DM groups. We created myocardial infarction (MI) in both groups and administered ipragliflozin (3 mg/kg/day) or vehicle from two weeks after MI. Four weeks after the initiation of treatment, we compared hemodynamic parameters among 4 groups (DM‐MI+ipragliflozin, n=9; DM‐MI+vehicle, n=6; MI+ipragliflozin, n=7; MI+vehicle, n=7).ResultsDaily urine volume nearly quadrupled in DM rats in comparison with non‐DM rats. In DM rats, ipragliflozin significantly lowered blood glucose (309±36 vs. 478±107 mg/dL, p&lt;0.01), prevented the worsening of left ventricular (LV) ejection fraction (−1.4±4.8 vs. −8.8±5.1%, p&lt;0.05), increased max LVdP/dt (6193±667 vs. 5015±456 mmHg/sec, p&lt;0.01) and tended to decrease LV end‐diastolic pressure (24.8±5.3 vs. 30.5±5.7 mmHg, p=0.069). However, ipragliflozin did not affect urine volume. In non‐DM rats, the beneficial effects of ipragliflozin on HF were limited.ConclusionsIpragliflozin attenuated the worsening of HF in DM rats, while its beneficial effects were obscured in non‐DM rats. These results indicate that ipragliflozin has direct cardioprotective effects on HF in DM independent of its diuretic effects.

ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure — A network meta-analysis

BackgroundAngiotensin receptor blockers (ARBs) are a valuable option to reduce cardiovascular (CV) mortality and morbidity in cardiac patients in whom ACE-inhibitors (ACE-Is) cannot be used. However, clinical outcome data from direct comparisons between ACE-Is and ARBs are scarce, and some data have recently suggested superiority of ACE-Is over ARBs. MethodsWe performed a Bayesian network-meta-analysis, with data from both direct and indirect comparisons, from 27 randomized controlled trials (RCTs), including a total population of 125,330 patients, to assess the effects of ACE-Is and ARBs on the composite endpoint of CV death, myocardial infarction (MI) and stroke, and on all-cause death, new-onset heart failure (HF) and new-onset diabetes mellitus (DM) in high CV risk patients without HF. ResultsUsing placebo as a common comparator, we found no significant differences between ACE-Is and ARBs in preventing the composite endpoint of CV death, MI and stroke (RR: 0.92; 95% CI 0.78–1.08). When components of the composite outcome were analysed separately, ACEi and ARBs were associated with a similar risk of CV death (RR: 0.92; 95% CI 0.73–1.10), MI (RR: 0.91; 95% CI 0.78–1.07) and stroke (RR: 0.97; 95% CI 0.79–1.19), as well as a similar incident risk of all-cause death (RR: 0.94; 95% CI 0.85–1.05), new-onset HF (RR: 0.92; 95% CI 0.77–1.15) and new-onset DM (RR: 99; 95% CI 0.81–1.21). ConclusionsWith the limitations of indirect comparisons, we found that in patients at high CV risk without HF, ARBs were similar to ACE-Is in preventing the composite endpoint of CV death, MI and stroke. Compared with ARBs, we found no evidence of statistical superiority for ACE-Is, as a class, in preventing incident risk of all-cause death, CV death, MI, stroke, new-onset DM and new-onset HF.

A pilot test of an integrated self-care intervention for persons with heart failure and concomitant diabetes

Studies show 30% to 47% of people with heart failure (HF) have concomitant diabetes mellitus (DM). Self-care for persons with both of these chronic conditions is conflicting, complex, and often inadequate. This pilot study tested an integrated self-care program for its effects on HF and DM knowledge, self-care efficacy, self-care behaviors, and quality of life (QOL). Hospitalized HF-DM participants (N = 71) were randomized to usual care or intervention using a 1:2 allocation and followed at 30 and 90 days after intervention. Intervention was an integrated education and counseling program focused on HF-DM self-care. Variables included demographic and clinical data, knowledge about HF and DM, HF- and DM-specific self-efficacy, standard HF and DM QOL scales, and HF and DM self-care behaviors. Analysis included descriptive statistics, multilevel longitudinal models for group and time effects, post hoc testing, and effect size calculations. Sidak adjustments were used to control for type 1 error inflation. The integrated HF-DM self-care intervention conferred effects on improved HF knowledge (30 days, p = .05), HF self-care maintenance (30 and 90 days, p < .001), HF self-care management (90 days, p = .05), DM self-efficacy (30 days, p = .03; 90 days, p = .004), general diet (30 days, p = .05), HF physical QOL (p = .04), and emotional QOL scores (p = .05) at 90 days within the intervention group. The participants in the usual care group also reported increased total and physical QOL. Greater percentages of participants in the intervention group improved self reported exercise between 0 and 30 days (p = .005 and moderate effect size ES = .47) and foot care between 0 and 90 days (p = .03, small ES = .36). No group differences or improvements in DM-specific QOL were observed. An integrated HF-DM self-care intervention was effective in improving essential components of self-care and had sustained (90 day) effects on selected self-care behaviors. Future studies testing HF-DM integrated self-care interventions in larger samples with longer follow-up and on other outcomes such as hospitalization and clinical markers are warranted.

Abstract 306: Mitochondrial Aldehyde Dehydrogenase, A Therapeutic Target In Post-myocardial Infarction Heart Failure In Diabetes

Development of heart failure (HF) and pathological remodeling occurs after myocardial infarction (MI). However, in diabetic patients the prognosis is far worse. Hyperglycemia leads to accumulation of reactive aldehydes like 4-hydroxy-2 nonenal (4-HNE) in the heart. 4-HNE impairs cellular function and causes organ damage by forming adducts with critical proteins. In this study, we hypothesized that 1) 4-HNE-induced impairment of mitochondrial aldehyde dehydrogenase (ALDH) i.e. ALDH2 contributed to myocardial ischemia-induced HF in diabetes mellitus (DM) and 2) pharmacological activation of ALDH2 by Alda-1 prevent post-MI cardiac damage in DM. To test these hypotheses, first 8-week old C57BLC/6J male mice were injected with streptozotocin (STZ) (150 mg/Kg). After 8 weeks of STZ, mice were infused with isoproterenol (Iso) (45 mg/Kg) for 2 weeks by mini pumps to induce chronic myocardial ischemia and HF. Cardiac dysfunction was assessed in conscious mice by echocardiography periodically until sacrifice (16 weeks after STZ). We had normal control (Con), DM control (DM), DM + Iso and non-diabetic Iso control (Iso) with n 6 in each group. Fractional shortening (FS) was reduced in DM + Iso group (47 ± 1.2%) compared to Con (53 ± 0.9 %) and DM (55 ± 1.6 %) P&lt;0.01, but not with Iso (49 ± 1.4%). Decrease in myocardial ALDH2 activity and increase in 4-HNE adduct formation in ALDH2 and mitochondrial damage were observed in DM + Iso at various degrees compared to Con, DM and Iso. Increased cardiac fibrosis was also recorded in DM + Iso (4 ± 0.4%) relative to Con (1 ± 0.2%; P&lt;0.001), DM (2 ± 0.1%; P&lt;0.05) and Iso (2.4 ± 0.3%; P&lt;0.01). In the treatment protocol, DM + Iso group were treated with Alda-1 (10mg/kg/day) from weeks 12 to 16. Alda-1 ameliorated cardiac damage in DM as evident from enhanced FS (55 ± 3.5%; P&lt;0.01) and reduced fibrosis. Besides improving ALDH activity Alda-1 also attenuated 4-HNE adduct formation on ALDH2 and mitochondrial damage. Myocardial levels of ALDH2 activity was lower in diabetic patients with cardiomyopathy (50% reduction; P&lt;0.007). Finally, we conclude that activation of ALDH2 ameliorates HF in diabetic mice and which has a potential to be developed as a therapeutic strategy for HF in diabetic patients.

STRUCTURAL REMODELLING IN THE LEFT VENTRICLE OF STREPTOZOTOCIN ‐INDUCED TYPE 1 DIABETIC RAT

Heart failure in diabetes mellitus is a major cause of premature morbidity and mortality but the underlying mechanisms are elusive and treatment remains empirical. This study investigated the role of chronic hyperglycemia (HG) in the development of hypertrophy and fibrosis in the left ventricle (LV) of streptozotocin (STZ)‐induced type 1 diabetic (T1DM) rats compared to age‐matched Wistar controls. T1DM rats and their hearts weighed significantly (p&lt;0.05) less than age‐matched controls along with a reduction in the heart weight/body weight ratio. Plasma glucose levels were 5–6 folds higher in T1DM animals. Visual analysis of the stained LV sections revealed general disorganization of myocardial architecture characterized by thinner fibers, disarray of myofibers and scarcity of myofibrils in the T1DM group compared to control. The width and diameter of myocytes from the T1DM group were significantly less compared to age‐matched controls. In addition, the LV of T1DM rats were infiltrated with increased ECM deposition in both interstitial and perivascular regions and area of interstitial fibrosis was significantly greater in T1DM hearts compared to controls. LV of T1DM rats exhibited signs of end stage apoptosis, manifesting as condensation of nuclei and cell shrinkage. The results show that chronic HG can produce marked alterations in myocardial architecture characterized by fibrosis proliferation, apoptotic cell death and atrophy of myocytes. Supported in part by University of Central Lancanshire and NIH HL085061.