Molecular Mechanism of the Association Between Atrial Fibrillation and Heart Failure Includes Energy Metabolic Dysregulation Due to Mitochondrial Dysfunction

BackgroundAtrial fibrillation (AF) and heart failure (HF) commonly coexist, yet the molecular mechanisms of this association have not been determined. We hypothesized that an energy deficit due to mitochondrial dysfunction plays a significant role in pathogenic link between AF and HF.Methods and ResultsMyocardial energy metabolism and mitochondria were examined in atrial tissue samples from patients and mice (cardiac-specific LKB1 knock-out) with HF and/or AF. There was significant atrial energy (ATP) deficit in patients with HF (11.5±1.3 nmol/mg, n=10; vs without HF 17±3.8 nmol/mg, n=5, P = .032). AF was associated with further energy depletion (ATP 5.4±1.2 nmol/mg, n=9) in HF (P = .001) and metabolic stress (AMP/ATP 1.6±0.1 vs 0.7±0.2 in HF alone; P = .043). The left atrium demonstrated lower ATP than the right (P = .004). Mitochondrial dysfunction and remodeling caused ATP depletion with impaired oxidative phosphorylation complexes (succinate dehydrogenase and cytochrome c oxidase), increased reactive oxygen species, and mtDNA damage in mice and human atria with AF and HF.ConclusionsMolecular mechanisms of the association between HF and AF include an energy deficit due to mitochondrial dysfunction in atrial myocardium. Mitochondrial functional and structural remodeling in human and mouse atria is associated with energy metabolic dysregulation and oxidative stress that promote AF in HF and vice versa.     

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome

BackgroundSacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome.Methods and ResultsFourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, –0.16 ± 0.03 vs –0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val–treated dogs compared with controls, –17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05.ConclusionsIn dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.     

The Relationship Between Leptin and Ventilatory Control in Heart Failure

BackgroundIncreased serum leptin concentration has been linked to increased ventilation in patients with mild heart failure (HF). However, in animal models the absence of leptin has also been associated with increased ventilation. This study evaluated the relationship of circulating leptin concentration with exercise ventilation in HF patients.Methods and ResultsFifty-eight consecutive ambulatory HF patients were stratified by quintiles of leptin concentration, with a lowest quintile of mean leptin concentration of 1.8 ± 8.9 ng/mL and a highest of 33.3 ± 30.3 ng/mL. Peak exercise ventilatory efficiency (VE/VCO₂) was significantly elevated in the lowest (46 ± 6 vs 34 ± 4; P < .01) as well as in the highest (38 ± 8 vs 34 ± 4; P < .05) leptin concentration quintiles compared with the reference middle quintile. Multiple regression analysis adjusted for confounders such as age, sex, and body mass index showed leptin concentration to be independently inversely correlated to VE/VCO₂ in the low-to-normal quintiles (β = ?0.64; P < .01), positively in the normal-to-high quintiles (β = 0.52; P = .02), and positively correlated to P_ETCO₂ in the low-to-normal quintiles (β = 0.59; P = .01) and inversely in the normal-to-high quintiles (β = ?0.53; P = .02).ConclusionsIn HF patients, both high and low leptin concentrations are associated with increased VE/VCO₂ and decreased P_ETCO₂ with a nonlinear U-shaped relationship, suggesting that either leptin deficiency or leptin resistance may modulate ventilatory control in HF patients.     

Clinical Characteristics and Outcomes of Patients With Heart Failure and Methamphetamine Abuse

BackgroundDespite a global epidemic of methamphetamine abuse, methamphetamine-associated heart failure (MethHF) remains poorly understood. We sought to evaluate characteristics and outcomes for patients with MethHF.MethodsWe reviewed the electronic health records of the University of California, San Diego, from 2005 to 2016. We compared characteristics and outcomes between 896 patients with MethHF and 20,576 patients with heart failure (HF) identified using diagnosis codes, urine toxicology, and natriuretic peptides.ResultsCompared with HF, patients with MethHF were younger (50±10 vs 67±16 years), predominantly male (72% vs 54%), and had more psychiatric and substance use comorbidities, including mood/anxiety disorders (29% vs 16%) and opioid use (44% vs 7%). MethHF had a higher 5-year HF readmission rate (64±4% vs 45±1%; hazard ratio [HR] 1.53, P < .001) and a lower 10-year total mortality rate (25±3% vs 28±1%; HR 0.85, P = .09). Predictors of poor outcomes included mood/anxiety disorders (HF readmission HR 1.41, P = .04) and opioid abuse (mortality HR 1.52, P = .04).ConclusionsPatients with MethHF are frequently encumbered by psychiatric and substance abuse comorbidities, and carry a substantial risk of HF readmission and mortality. Comprehensive efforts are needed to stem this emerging epidemic.     

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction

BackgroundPatients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown.Methods and ResultsWe administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QT_F) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QT_Fvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QT_F interval exposure. Maximum QT_F (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QT_F from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different.ConclusionsHFpEF is associated with enhanced response to drug-induced QT interval lengthening.     

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone

BackgroundChlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients.MethodsWe compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17–65-year-old mild-moderate uncomplicated hypertensive whites and blacks.ResultsMean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10^?6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e^?7).ConclusionCompared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.     

Tissue-type plasminogen activator depletion affects the nasal mucosa matrix reconstruction in allergic rhinitis mice

BackgroundThe present study was designed to assess the function of tissue plasminogen activator (t-PA) expression in allergic rhinitis.MethodsAge-matched t-PA gene knock out (t-PA^-/-) and wild type (WT) mice were sensitised four times, and then challenged for six weeks with ovalbumin. The controls were treated with saline instead of ovalbumin. The structural change in the nasal mucosa was investigated with haematoxylin and eosin stain and van Gieson staining. u-PA (urokinase-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor) gene expression were measured by real time PCR. Matrix metalloproteinase-9 (MMP-9) expression was tested with Western blotting and with real time PCR.ResultsAfter ovalbumin challenge for six weeks, compared with the WT group, t-PA depletion increased collagen deposition and gland hyperplasia. u-PA and PAI-1 gene expression increased both in t-PA^-/- and in WT mice after ovalbumin treatment. MMP-9 expression decreased greatly after ovalbumin challenge in t-PA^-/- mice.Conclusiont-PA affects the nasal mucosa matrix reconstruction process in allergic rhinitis, with which MMP-9 is involved.     

The antioxidant status and lipid peroxidation product of newly diagnosed and 6 weeks follow–up patients with pulmonary tuberculosis in Owerri,Imo state,Nigeria

ObjectiveTo determine the levels of antioxidants vitamins C and E as well as lipid peroxidation product malondialdehyde (MDA) in Mycobacterium tuberculosis (M. tuberculosis) patients.MethodsSixty two M. tuberculosis positive patients and fifty five healthy controls within the age of twenty five to forty years without any systemic disease attending General Hospital Owerri were involved in this study. Forty one cases were longitudinally followed up with standard anti-tuberculosis chemotherapy (ATT) for six weeks.ResultsThe results obtained showed that the levels of vitamin C (0.91±0.42 mg/dL) and vitamin E (0.84±0.31 mg/dL) were significantly decreased in M. tuberculosis patients before treatment when compared to the healthy controls [(1.64±0.41 mg/dL) and (1.46±0.38 mg/dL)] respectively at P<0.05, while the level of MDA (8.7±1.81 nM/mL) in M. tuberculosis patients was significantly higher (P<0.05) before anti-tuberculosis treatment as compared with the healthy control (4.91±1.9 nM/mL). Also, there was a significant increase in vitamin C and E levels after 6 weeks of ATT, while MDA levels was decreased when compared with the control (P<0.05).ConclusionsThe depletion of vitamins C and E as well as elevation of MDA in tuberculosis patients is suggestive of lipid peroxidation and oxidative stress. The increase in vitamin C and E as well as decrease in MDA after 6 weeks of anti-tuberculosis treatment is suggestive of good response to treatment with standard ATT. Hence, vitamin C and E supplementation improves the quality of life of tuberculosis patients.     

Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production

BackgroundAltering the renin-angiotensin aldosterone system improve mortality in heart failure (HF) in part through an improvement in nitric oxide (NO)-mediated endothelial function. This study examined if spironolactone affects endothelial nitric oxide synthase (eNOS) and NO-mediated vasorelaxation in HF.Methods and ResultsRats with HF after coronary artery ligation were treated with spironolactone for 4 weeks. Rats with HF had a decrease (P < .05) in left ventricular (LV) systolic pressure (130 ± 7 versus 118 ± 6 mm Hg) and LV pressure with respect to time (9122 ± 876 versus 4500 ± 1971 mm Hg/second) with an increase in LV end-diastolic pressure (4 ± 2 versus 23 ± 8 mm Hg). Spironolactone did not affect hemodynamics but it improved (P < .05) endothelial-dependent vasorelaxation at more than 10⁻⁸ M acetylcholine that was abolished with N^G-monomethyl-L-arginine. The eNOS levels were decreased (P < .05) in the LV and the aorta; spironolactone restored LV and aortic eNOs levels to normal.ConclusionSpironolactone prevents the decrease in eNOS in the LV and aorta and improves NO-dependent vasorelaxation, suggesting that one potential mechanism of spironolactone is an improvement in vasoreactivity mediated though an increase in NO.     

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure

BackgroundMatrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF.Methods and ResultsIn the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF <0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient ρ = 0.17, P = .02) and negatively with LVEF (ρ = –0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P < .01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (ρ = –0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24–4.46; P < .01). Similar relationships for MMP-2 and TIMP-1 were not observed.ConclusionsElevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.     

Urinary angiotensinogen increases in the absence of overt renal injury in high fat diet-induced type 2 diabetic mice

Aim of the StudyDuring type 2 diabetes (T2D) and hypertension there is stimulation of renal proximal tubule angiotensinogen (AGT), but whether urinary excretion of AGT (uAGT) is an indicator of glomerular damage or intrarenal RAS activation is unclear. We tested the hypothesis that elevations in uAGT can be detected in the absence of albuminuria in a mouse model of T2D.MethodsMale C57BL/6 mice (N = 10) were fed a high fat (HFD; 45% Kcal from fat) for 28 weeks, and the metabolic phenotype including body weight, blood pressures, glucose, insulin, ippGTT, HOMA-IR, and cholesterol was examined. In addition, kidney Ang II content and reactive oxygen species (ROS) was measured along with urinary albumin, creatinine, Ang II, and AGT.ResultsAll parameters consistent with T2D were present in mice after 12–14 weeks on the HFD. Systolic BP increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS and Ang II concentrations were also increased in HFD mice. Remarkably, these changes paralleled the augmentation uAGT excretion (3.66 ± 0.50 vs. 0.92 ± 0.13 ng/mg by week 29; P < 0.01), which occurred in the absence of overt albuminuria.ConclusionsIn HFD-induced T2D mice, increases in uAGT occur in the absence of overt renal injury, indicating that this biomarker accurately detects early intrarenal RAS activation.     

The Association Between Secondhand Smoke Exposure and Survival for Patients With Heart Failure

BackgroundThe effect of secondhand tobacco smoke (SHS) exposure on patients with heart failure (HF) is uncertain. We investigated the association of mortality with SHS exposure for patients with HF.MethodsNonsmokers with clinical HF were enrolled from 2003 to 2008 in a single-center longitudinal cohort study. The effect of SHS exposure determined by high-sensitivity urinary cotinine on mortality was estimated by multivariable proportional hazards modeling.ResultsMortality was assessed after median 4.3 years. Of 202 patients, enrollment urinary cotinine levels were below the limit of detection for 106 (52%) considered unexposed to SHS. The median detectable cotinine was 0.47 ng/mL (interquartile range: [0.28, 1.28]). Participants were 41% female, 65 ± 17 years old, and 57% white race. Elevated cotinine was associated with increased mortality after multivariate adjustment: hazard ratio (HR) per 1 ng/mL increase in urinary cotinine: 1.15, 95% confidence interval (CI): 1.08–1.23, P < .001. Higher age (HR per 5-year increase: 1.32, 95% CI: 1.22–1.43, P < .001), male sex (HR vs female: 1.52, 95% CI: 1.02–2.28, P = .040), and New York Heart Association class (HR for class III vs I: 2.91, 95% CI: 1.71–4.99, P < .001) were also associated with mortality.ConclusionsSHS exposure is associated with a dose-dependent increase in mortality for patients with HF.     

Prevalence of Restless Legs Syndrome and Its Effects on Sleep and Health-Related Quality of Life in Patients With Heart Failure

BackgroundRestless legs syndrome (RLS) is a neurological disorder characterized by leg restlessness and dysesthesia. Although the relationship between RLS and heart failure (HF) has been reported, the prevalence and clinical significance of RLS in patients with HF remain to be elucidated.Methods and ResultsWe enrolled consecutive patients with HF who were admitted to our institutions. RLS was diagnosed using the International Restless Legs Syndrome Study Group criteria. Subjective sleepiness, sleep quality, and quality of life (QoL) were assessed using the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and 8-item Short Form (SF-8), respectively. Among the 133 patients, 18 (13.6%) had RLS and were younger than those without RLS (62.4±13.4 vs 70.0±12.2, P = .017). The RLS group had significantly disrupted sleep quality and QoL, with greater PSQI score (8.0±3.2 vs 5.9±3.3, P = .015) and lower SF-8 physical component summary (PCS) score (35.6±6.5 vs 40.7±9.5, P = .031), despite similar ESS and SF-8 mental component summary scores. In the multivariable regression analysis, RLS was associated with greater PSQI (β=0.211; P = .014) and lower PCS score (β=?0.177; P = .045).ConclusionIn the patients with HF, RLS was prevalent, and sleep quality and QoL may be disrupted by RLS.     

Effects of Trimetazidine in Nonischemic Heart Failure: A Randomized Study

ObjectivesHeart failure (HF) is associated with changes in myocardial metabolism that lead to impairment of contractile function. Trimetazidine (TMZ) modulates cardiac energetic efficiency and improves outcomes in ischemic heart disease. We evaluated the effects of TMZ on left ventricular ejection fraction (LVEF), cardiac metabolism, exercise capacity, O₂ uptake, and quality of life in patients with nonischemic HF.Methods and ResultsSixty patients with stable nonischemic HF under optimal medical therapy were included in this randomized double-blind study. Patients were randomized to TMZ (35 mg orally twice a day) or placebo for 6 months. LVEF, 6-minute walk test (6MWT), maximum O₂ uptake in cardiopulmonary exercise test, different markers of metabolism, oxidative stress, and endothelial function, and quality of life were assessed at baseline and after TMZ treatment. Left ventricular peak glucose uptake was evaluated with the use of the maximum standardized uptake value (SUV) by 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET). Etiology was idiopathic in 85% and hypertensive in 15%. Both groups were similar in age, functional class, LVEF, and levels of N-terminal pro–B-type natriuretic peptide at baseline. After 6 months of TMZ treatment, no changes were observed in LVEF (31 ± 10% vs 34 ± 8%; P = .8), 6MWT (443 ± 25 m vs 506 ± 79 m; P = .03), maximum O₂ uptake (19.1 ± 5.0 mL kg⁻¹ min⁻¹ vs 23.0 ± 7.2 mL kg⁻¹ min⁻¹; P = .11), functional class (percentages of patients in functional classes I/II/III/IV 10/3753/0 vs 7/40/50/3; P = .14), or quality of life (32 ± 26 points vs 24 ± 18 points; P = .25) in TMZ versus placebo, respectively. In the subgroup of patients evaluated with ¹⁸FDG-PET, no significant differences were observed in SUV between both groups (7.0 ± 3.6 vs 8.2 ± 3.4 respectively; P = .47).ConclusionsIn patients with nonischemic HF, the addition of TMZ to optimal medical treatment does not result in significant changes of LVEF, exercise capacity, O₂ uptake, or quality of life.     

Caffeine prolongs exercise duration in heart failure

BackgroundCaffeine increases submaximal exercise performance in healthy young subjects; its effects on exercise tolerance in heart failure (HF) have not been characterized.Methods and ResultsTo determine whether caffeine increases exercise tolerance in HF, caffeine (4 mg/kg intravenously, equivalent to 2 cups of coffee) or vehicle were infused into 10 treated HF patients (left ventricular ejection fraction 25 ± 2 %), and 10 age-matched normal subjects (N) on 2 separate days in a double-blind, randomized, crossover design. We measured heart rate, blood pressure, and ventilation at rest and during graded cycling (15 W/minute) to peak effort. Peak oxygen consumption was unaffected in either group. Mean exercise time was unchanged in N (1013 ± 87 versus 988 ± 107 seconds; P = .86) but was significantly increased by caffeine in HF (from 511 ± 28 to 560 ± 37 seconds; P = .004) despite an increase in peak minute ventilation (P < .05). Resting and peak blood pressures were higher after caffeine (P < .05) in HF, not N.ConclusionCaffeine allows HF patients to exercise longer at peak effort.     

Nicorandil suppresses the increases in plasma level of matrix metalloproteinase activity and attenuates left ventricular remodeling in patients with acute myocardial infarction

Nicorandil, a hybrid K_ATP channel opener and nicotinamide nitrate, reduces no-reflow phenomenon and improves cardiac function in patients with acute myocardial infarction (AMI). We repoted that nicorandil suppresses radical formation in patients with AMI undergoing primary percutaneous coronary intervention (PCI). In the present study, we tested the hypothesis that nicorandil treatment suppresses MMP activities and predicts ventricular remodeling in AMI. Sixty-two patients with AMI were randomized into nicorandil pretreatment (n = 31) and control (n = 31) groups after admission and underwent primary PCI. Nicorandil was administered as a bolus injection (4 mg) followed by constant infusion (8 mg/h) for 24 h just after admission. On days 1, 2, and 14 after the onset of AMI, the plasma levels of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by enzyme-linked immunosorbent assay and the activities by gelatin zymography. There were no differences in the baseline clinical characteristics between the two groups. On day 1, there were no differences in both MMP-2 and MMP-9 levels and their activities between the two groups. However, both MMP-2 and MMP-9 levels and their activities were significantly lower in nicorandil than in control group on day 2 (MMP-2 level, 1 014 ± 39 vs 1 174 ± 44 ng/ml; MMP-9 level, 17 ± 1 vs 23 ± 2 ng/ml; both P < 005) and on day l4 (MMP-2 level, 970 ± 38 vs 1 221 ± 44 ng/ml; MMP-9 level, 17 ± 1 vs 23 ± 1 ng/ml; both P < 0.05). Left ventricular end-diastolic volume index (LVEDVI) at acute phase was not different between the two groups. At 6 months after AMI, LVEDVI was significantly smaller in nicorandil than in the control group (83 ± 4 vs 96 ± 4 ml/m², P < 0.05). The change in LVEDVI from acute phase to 6 months was positively correlated with MMP-2 and MMP-9 levels and activities. Nicorandil suppresses the increases in MMP levels and activities and prevents the development of ventricular remodeling in AMI.     

Thyroid Hormone Replacement Therapy Attenuates Atrial Remodeling and Reduces Atrial Fibrillation Inducibility in a Rat Myocardial Infarction–Heart Failure Model

BackgroundHeart failure (HF) is associated with increased atrial fibrillation (AF) risk. Accumulating evidence suggests the presence of myocardial tissue hypothyroidism in HF, which may contribute to HF development. In a recent report we demonstrated that hypothyroidism, like hyperthyroidism, leads to increased AF inducibility. The present study was designed to investigate the effect of thyroid hormone (TH) replacement therapy on AF arrhythmogenesis in HF.Methods and ResultsMyocardial infarction (MI) was produced in rats by means of coronary artery ligation. Rats with large MIs (>40%) were randomized into L-thyroxine (T₄; n = 14) and placebo (n = 15) groups 2 weeks after MI. Rats received 3.3 mg T₄ (in 60-day release form) or placebo pellets for 2 months. Compared with the placebo, T₄ treatment improved cardiac function and decreased left ventricular internal diameters as well as left atrial diameter. T₄ treatment attenuated atrial effective refractory period prolongation (45 ± 1.5 ms in placebo group vs 37 ± 1.6 ms in T₄ group; P < .01) and reduced AF inducibility (AF/atrial flutter/tachycardia were inducible in 11/15 rats [73%] in the placebo- vs 4/14 rats [29%] in the T₄-treated group; P < .05). Arrhythmia reduction was associated with decreased atrial fibrosis but was not associated with connexin 43 changes.ConclusionsTo our knowledge this is the first study demonstrating that TH replacement therapy in HF attenuates atrial remodeling and reduces AF inducibility after MI-HF. Clinical studies are needed to confirm such benefits in human patients.     

Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice

AIM: To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse.METHODS: Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor.RESULTS: We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver.CONCLUSION: Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.     

The Influence of Sex Differences on Cardiopulmonary Exercise Metrics Following Heart Transplant

BackgroundPrevious work has shown sex-related differences in cardiopulmonary responses in patients with heart failure (HF); however, sex differences following heart transplant (HTx) have not been examined. Thus, we hypothesized women would demonstrate lower peak oxygen uptake (VO_2peak) but similar ventilatory efficiency (V_E/VCO₂ slope) compared with men prior to HTx. Furthermore, we hypothesized that, following HTx, women would exhibit greater improvements in VO_2peak and V_E/VCO₂ slope compared with men.MethodsHTx patients with cardiopulmonary exercise testing (CPET) between 2007 and 2016 were included. Pre-HTx CPET occurred within 24 months pre-HTx with post-HTx CPET within 12 months following HTx. VO_2peak was measured via standard protocol. V_E/VCO₂ slope was calculated using rest-peak ventilation (V_E) and carbon dioxide production (VCO₂).ResultsEighty-eight patients (Men [M]: n = 63, age: 55 ± 12 years; Women [W]: n = 25, age: 47 ± 11 years) were assessed. Pre-HTx VO_2peak (M: 13.9 ± 5.0 vs W: 11.6 ± 3.9 mL/kg/min, P = 0.17) and V_E/VCO₂ slope (M: 42 ± 12 vs W: 46 ± 18, P = 0.53) were not different between sexes. Overall, VO_2peak (Pre: 13.3 ± 4.8 vs Post: 18.4 ± 4.8 mL/kg/min, P < 0.01) and V_E/VCO₂ slope (Pre: 43 ± 14 vs Post: 37 ± 6, P = 0.02) improved following HTx. Post-VO_2peak (M: 19.0 ± 4.8 vs W: 16.8 ± 4.5 mL/kg/min, P = 0.24) and V_E/VCO₂ slope (M: 37 ± 6 vs W: 37 ± 7, P = 0.99) and delta VO_2peak (M: 5.0 ± 4.8 vs W: 5.3 ± 4.9 mL/kg/min, P = 0.85) and V_E/VCO₂ slope (M: –5 ± 11 vs W: –9 ± 17, P = 0.29) were not different between sexes.ConclusionsThese data demonstrate that cardiopulmonary improvements following HTx patients occur for both sexes. Importantly, women show similar significant functional improvements following HTx compared with men.