International Journal of Cardiology

International Journal of Cardiology | Vol. 6, No. 4, April 2015 | pp. 25–32

DOI: 10.46882/2015/IJC/000073

Original Research Article

Cardioprotective Effects of Sotagliflozin in a Rat Model of Ischemia-Reperfusion Injury: Modulation of Myocardial SGLT1 Pathways

Kenji Tanaka¹, Satoshi Yamada¹, Takashi Sato²

¹Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

²Division of Metabolic Diseases, Tokyo Medical and Dental University, Tokyo, Japan

Abstract:
Sotagliflozin is a dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor that improves clinical endpoints in heart failure. Unlike SGLT2, SGLT1 is expressed directly within human and rodent myocardium, meaning dual inhibition might provide unique cellular protections during ischemic shocks. This study evaluated the direct cardioprotective effects of sotagliflozin against myocardial ischemia-reperfusion (I/R) injury in rats and explored the role of downstream sodium-hydrogen exchanger-1 (NHE-1) pathing. Adult male Sprague-Dawley rats were randomized into three groups (n = 12 per group): Sham, I/R control, and Sotagliflozin + I/R. Ischemia was induced by occluding the left anterior descending coronary artery for 30 minutes, followed by 120 minutes of reperfusion. Sotagliflozin (10 mg/kg/day) was administered via oral gavage for 14 days prior to I/R. Pretreatment with sotagliflozin significantly limited myocardial infarct size compared to the I/R control cohort (26.4% ± 3.2% vs. 42.6% ± 4.1%, p < 0.01). Sotagliflozin administration also preserved left ventricular developed pressure and limited the post-ischemic rise in serum creatine kinase-MB and lactate dehydrogenase values (p < 0.05). Western blot and biochemical analyses revealed that sotagliflozin significantly suppressed intracellular sodium overload and down-regulated myocardial NHE-1 expression, reducing cytosolic calcium overload and cleavage of pro-apoptotic caspase-3 pathways. Sotagliflozin exerts potent cardioprotective effects against myocardial ischemia-reperfusion injury in rats, reducing cardiomyocyte death by down-regulating NHE-1 pathways and cellular ionic loading via localized SGLT1 modulation.

Keywords: Ischemia-reperfusion injury, Sotagliflozin, SGLT1 inhibitors, Sodium-hydrogen exchanger-1, Apoptosis, Infarct size

Received: January 08, 2015; Revised: February 20, 2015; Accepted: March 12, 2015; Published: April 22, 2015

International Journal of Cardiology | Vol. 5, No. 6, June 2014 | pp. 41–48

DOI: 10.46882/2014/IJC/000063

Original Research Article

Cardioprotective Effects of Dapagliflozin in a Rat Model of Diabetic Cardiomyopathy: Role of Mitochondrial Fusion

Kenji Tanaka¹, Satoshi Yamada¹, Takashi Sato²

¹Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

²Division of Metabolic Diseases, Tokyo Medical and Dental University, Tokyo, Japan

Abstract:
Diabetic cardiomyopathy leads to progressive diastolic failure and myocardial structural derangement. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure event rates, but their direct impact on cardiomyocyte mitochondrial dynamics remains characterized. This study investigated the protective effects of dapagliflozin on myocardial remodeling and mitochondrial structural integrity in a rat model of type 2 diabetes. Type 2 diabetes was induced in adult male Wistar rats via a high-fat diet combined with a low-dose streptozotocin injection. Diabetic rats were randomized to receive either dapagliflozin (1.0 mg/kg/day, n = 15) or vehicle control (n = 15) via oral gavage for 8 weeks. Cardiac function was monitored using tissue Doppler echocardiography, and structural mitochondrial alignment was assessed via transmission electron microscopy. Dapagliflozin significantly improved the diastolic mitral inflow E/A ratio compared to the vehicle group (1.45 ± 0.12 vs. 1.05 ± 0.08, p < 0.01). Electron microscopy revealed that dapagliflozin treatment prevented mitochondrial fragmentation, preserving mitochondrial aspect ratios (2.42 ± 0.15 vs. 1.54 ± 0.11, p < 0.01). Western blot analysis demonstrated that dapagliflozin up-regulated the expression of mitofusin-2 (Mfn2) and down-regulated dynamin-related protein 1 (Drp1), suppressing pro-apoptotic pathways. Dapagliflozin significantly improves diastolic performance and mitigates diabetic cardiomyopathy in rats by preserving mitochondrial fusion structural pathways and optimizing metabolic morphology.

Keywords: Diabetic cardiomyopathy, Dapagliflozin, SGLT2 inhibitors, Mitochondrial dynamics, Mitofusin-2, Diastolic function

Received: March 10, 2014; Revised: April 22, 2014; Accepted: May 12, 2014; Published: June 18, 2014

Citation: International Journal of Cardiology, 2014, Vol. 5, No. 6, pp. 41–48, DOI: 10.46882/2014/IJC/000063

International Journal of Cardiology | Vol. 5, No. 12, December 2014 | pp. 89–96

DOI: 10.46882/2014/IJC/000069

Original Research Article

Efficacy of High-Dose Atorvastatin Reloading Prior to Complex Percutaneous Coronary Intervention in Patients on Chronic Statin Therapy

Yusuf Demir¹, Murat Kaya¹, Ahmet Yilmaz²

¹Department of Cardiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

²Division of Interventional Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Abstract:
Periprocedural myocardial infarction (pMI) is a frequent complication during complex percutaneous coronary intervention (PCI). Statin reloading has shown efficacy in limiting pMI in general cohorts, but its impact during complex interventions in patients already established on maintenance statin treatment requires validation. This prospective, randomized, open-label trial evaluated whether high-dose atorvastatin reloading before complex PCI reduces pMI rates in patients on chronic statin therapy. We enrolled 240 chronic statin users undergoing complex PCI (defined as multi-vessel disease, bifurcation lesions, or total occlusions). Patients were randomized 1:1 to receive either an acute reload of atorvastatin (80 mg given 12 hours and 2 hours pre-PCI, n = 120) or to continue standard maintenance dosing (n = 120). The primary endpoint was the incidence of pMI, defined as an elevation of cardiac troponin I (cTnI) greater than 5 times the upper limit of normal within 24 hours post-procedure. The incidence of pMI was significantly lower in the atorvastatin reloading group than in the control arm (8.3% vs. 17.5%, p = 0.03). Post-procedural mean cTnI values were also significantly reduced with the reload (0.44 ± 0.12 ng/mL vs. 0.92 ± 0.22 ng/mL, p < 0.01). No cases of hepatic dysfunction or rhabdomyolysis occurred. High-dose atorvastatin reloading safely and significantly reduces periprocedural myocardial injury during complex percutaneous coronary intervention in patients on chronic maintenance statin therapy.

Keywords: Percutaneous coronary intervention, Atorvastatin, Statin reloading, Periprocedural myocardial infarction, Complex coronary lesions

Received: September 15, 2014; Revised: October 28, 2014; Accepted: November 12, 2014; Published: December 19, 2014

International Journal of Cardiology | Vol. 5, No. 2, February 2014 | pp. 9–16

DOI: 10.46882/2014/IJC/000059

Original Research Article

Long-Term Prognostic Utility of Global Longitudinal Strain in Patients with Light-Chain Cardiac Amyloidosis

Sven Lindstrom¹, Ingrid Johansson¹, Anders Nielsen²

¹Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

²Department of Clinical Physiology, Aarhus University Hospital, Aarhus, Denmark

Abstract:
Light-chain (AL) cardiac amyloidosis is characterized by progressive extracellular amyloid fibril deposition, leading to restrictive cardiomyopathy and severe heart failure. Early recognition of myocardial involvement is essential, as conventional metrics like LVEF often remain preserved until advanced stages. This study evaluated the long-term prognostic value of speckle-tracking derived global longitudinal strain (GLS) and the relative apical sparing pattern in patients with biopsy-proven AL amyloidosis. We prospectively followed 85 patients with systemic AL amyloidosis. All patients underwent comprehensive baseline echocardiography with off-line speckle-tracking deformation imaging. The primary endpoint was all-cause mortality over a 3-year follow-up period. Myocardial involvement was defined by standard extracellular volume metrics and wall thickness. An absolute baseline GLS less than 14.5% was identified in 64.7% of the cohort. Classic apical sparing, characterized by a preserved apical strain with severely reduced basal and mid-ventricular segment deformation, was present in 52.9% of patients. Over a median follow-up of 28 months, 32 patients (37.6%) died. Kaplan-Meier survival curves showed significantly worse survival in patients with a baseline absolute GLS less than 14.5% (log-rank p < 0.001). Multivariable Cox proportional hazards regression confirmed that baseline GLS was a potent, independent predictor of 3-year all-cause mortality (hazard ratio: 1.24 per 1% absolute reduction, 95% CI: 1.11–1.38, p < 0.001), outperforming traditional biomarkers like NT-proBNP and high-sensitivity troponin T. Two-dimensional global longitudinal strain is a powerful independent predictor of mortality in light-chain cardiac amyloidosis, serving as a critical tool for early risk stratification.

Keywords: Cardiac amyloidosis, Light-chain amyloidosis, Echocardiography, Global longitudinal strain, Apical sparing, Prognosis

Received: November 08, 2013; Revised: December 20, 2013; Accepted: January 12, 2014; Published: February 22, 2014

Citation: International Journal of Cardiology, 2014, Vol. 5, No. 2, pp. 9–16, DOI: 10.46882/2014/IJC/000059

International Journal of Cardiology | Vol. 5, No. 4, April 2014 | pp. 25–32

DOI: 10.46882/2014/IJC/000061

Original Research Article

Prognostic Value of Circulating MicroRNA-133a in Patients with Acute Decompensated Heart Failure

Stefan de Vries¹, Anika Janssen¹, Jan de Jong²

¹Department of Cardiology, Erasmus University Medical Center, Rotterdam, Netherlands

²Division of Cardiovascular Medicine, Leiden University Medical Center, Leiden, Netherlands

Abstract:
Acute decompensated heart failure (ADHF) requires precise risk stratification to guide clinical transitions and prevent early readmissions. MicroRNAs (miRNAs) are stable circulating biomolecules involved in cardiovascular remodeling. This study evaluated the long-term prognostic value of plasma miR-133a levels in patients hospitalized for ADHF. We prospectively enrolled 210 patients with ADHF. Blood samples were obtained at admission, and plasma miR-133a expression levels were quantified using real-time quantitative polymerase chain reaction. The primary endpoint was a composite of 12-month all-cause mortality or heart failure readmission. High plasma miR-133a expression (above the median) was present in 50.0% of the cohort. At 12 months, the primary composite endpoint occurred in 64 patients (30.5%). Patients with elevated baseline miR-133a levels experienced a significantly higher rate of adverse events than those with low expression (41.9% vs. 19.0%, log-rank p < 0.001). Multivariable Cox proportional hazards regression analysis revealed that elevated miR-133a expression was an independent predictor of the 12-month composite endpoint (hazard ratio: 2.15, 95% CI: 1.34–3.46, p = 0.001), after adjusting for age, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal pro-B-type natriuretic peptide. No significant correlations were observed between miR-133a levels and periprocedural deployment complications. Elevated plasma microRNA-133a levels at admission independently predict poor 12-month survival and readmission rates in acute decompensated heart failure, serving as a promising molecular biomarker for refined risk stratification.

Keywords: Acute decompensated heart failure, MicroRNA-133a, Biomarkers, Prognosis, Mortality, Heart failure readmission

Received: January 05, 2014; Revised: February 18, 2014; Accepted: March 10, 2014; Published: April 18, 2014

Citation: International Journal of Cardiology, 2014, Vol. 5, No. 4, pp. 25–32, DOI: 10.46882/2014/IJC/000061

International Journal of Cardiology | Vol. 5, No. 10, October 2014 | pp. 73–80

DOI: 10.46882/2014/IJC/000067

Review Article

Pathophysiological Driving Forces and Evolving Biological Targets in Cardiac Fibrosis: A Systematic Review

Sarah L. Jenkins¹, David M. Ross²

¹Department of Cardiovascular Sciences, British Heart Foundation Centre, King's College London, London, United Kingdom

²Division of Cardiology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia

Abstract:
Cardiac fibrosis is a universal component of adverse ventricular remodeling that drives the development of arrhythmias and heart failure. This systematic review synthesizes recent molecular and clinical literature detailing the pathophysiological signaling cascades governing cardiac fibroblast activation and evaluates emerging anti-fibrotic therapeutic targets. A comprehensive literature search up to August 2014 identified 45 relevant experimental and clinical trials. Myocardial mechanical strain and localized ischemia initiate fibroblast differentiation into active myofibroblasts, a transition primarily regulated by the transforming growth factor-beta-1 (TGF-beta-1) / Smad3 pathway. Quantified clinical data indicate that excessive extracellular matrix accumulation increases ventricular stiffness, showing a pooled correlation coefficient of r = 0.74 (95% CI: 0.65–0.82) with invasive diastolic filling pressures. Emerging non-invasive imaging techniques like cardiac magnetic resonance extracellular volume (ECV) fraction mapping allow for the early quantification of diffuse interstitial fibrosis. Novel therapeutic strategies directed at silencing pro-fibrotic microRNAs (such as miR-21) or inhibiting galectin-3 signaling pathways show significant efficacy in limiting collagen volume fractions in phase II trials, achieving a pooled hazard ratio of 0.64 (95% CI: 0.44–0.92) for attenuating adverse chamber dilation. Reversing cardiac fibrosis requires an integrated approach utilizing tissue characterization markers alongside molecular inhibitors targeted at blocking the myofibroblast differentiation cascade.

Keywords: Cardiac fibrosis, Transforming growth factor-beta, Myofibroblasts, Extracellular matrix, Late gadolinium enhancement, Extracellular volume fraction

Received: July 08, 2014; Revised: August 22, 2014; Accepted: September 11, 2014; Published: October 18, 2014

Citation: International Journal of Cardiology, 2014, Vol. 5, No. 10, pp. 73–80, DOI: 10.46882/2014/IJC/000067