ABSTRACT
AIMS: Pulmonary vein isolation (PVI) is a well-established strategy for the treatment of paroxysmal atrial fibrillation (PAF). Despite randomized controlled trials and real-world data showing the promise of pulsed-field ablation (PFA) for this treatment, long-term efficacy and safety data demonstrating single-procedure outcomes off antiarrhythmic drugs remain limited. The aim of the FARA-Freedom Study was to evaluate the long-term efficacy and safety of PFA using the pentaspline catheter for PAF. METHODS AND RESULTS: FARA-Freedom, a prospective, non-randomized, multicentre study, enrolled patients with PAF undergoing de novo PVI with PFA, who were followed for 12 months with weekly transtelephonic monitoring and a 72-h Holter ECG at 6 and 12 months. The primary safety endpoint was a composite of device- or procedure-related serious adverse events out to 7 days post-ablation and PV stenosis or atrioesophageal (AE) fistula out to 12 months. Treatment success is a composite of acute PVI and chronic success, which includes freedom from any documented atrial tachyarrhythmia longer than 30â s, use of antiarrhythmic drugs or cardioversion after a 3-month blanking period, or use of amiodarone or repeat ablation at any time. The study enrolled 179 PAF patients (62 ± 10â years, 39% female) at 13 centres. At the index procedure, all PVs were successfully isolated with the pentaspline PFA catheter. Procedure and left atrial dwell times, with a 20-min waiting period, were 71.9 ± 17.6 and 41.0 ± 13.3â min, respectively. Fluoroscopy time was 11.5 ± 7.4â min. Notably, monitoring compliance was high, with 88.4 and 90.3% with weekly events and 72-h Holter monitors, respectively. Freedom from the composite primary effectiveness endpoint was 66.6%, and 41 patients had atrial tachyarrhythmia recurrence, mostly recurrent atrial fibrillation (31 patients). The composite safety endpoint occurred in two patients (1.1%), one tamponade and one transient ischaemic attack. There was no coronary spasm, PV stenosis, or AE fistula. There were four cases of transient phrenic nerve palsy, but all resolved during the index procedure. CONCLUSION: In this prospective, non-randomized, multicentre study, PVI using a pentaspline PFA catheter was effective in treating PAF patients despite rigourous endpoint definitions and high monitoring compliance and demonstrated favourable safety. REGISTRATION: Clinical Trials.gov Identifier: NCT05072964 (sponsor: Boston Scientific Corporation).
Subject(s)
Atrial Fibrillation , Catheter Ablation , Fistula , Pulmonary Veins , Female , Humans , Male , Anti-Arrhythmia Agents , Atrial Fibrillation/surgery , Catheter Ablation/methods , Constriction, Pathologic/surgery , Fistula/surgery , Prospective Studies , Pulmonary Veins/surgery , Recurrence , Tachycardia/surgery , Treatment Outcome , Middle Aged , AgedABSTRACT
BACKGROUND: ß1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. ß3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. METHODS AND RESULTS: Mice with cardiac myocyte-specific expression of human ß3-AR (ß3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). ß3-TG and WT had similar morphometric and hemodynamic parameters at baseline. ß3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in ß3-TG mice, which also had less re-expression of fetal genes and transforming growth factor ß1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of ß3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, ß3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS: Cardiac-specific overexpression of ß3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac ß3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.
Subject(s)
Heart Ventricles/pathology , Myocytes, Cardiac/metabolism , Neurotransmitter Agents/pharmacology , Nitric Oxide Synthase/physiology , Receptors, Adrenergic, beta-3/metabolism , Ventricular Remodeling/drug effects , Angiotensin II/adverse effects , Angiotensin II/pharmacology , Animals , Cells, Cultured , Cyclic GMP/physiology , Cyclic GMP-Dependent Protein Kinases/physiology , Disease Models, Animal , Heart Ventricles/physiopathology , Humans , Hypertrophy/chemically induced , Hypertrophy/pathology , Hypertrophy/physiopathology , In Vitro Techniques , Isoproterenol/adverse effects , Isoproterenol/pharmacology , Male , Mice , Mice, Transgenic , Myocytes, Cardiac/pathology , Myocytes, Cardiac/physiology , Neurotransmitter Agents/adverse effects , Receptors, Adrenergic, beta-3/genetics , Signal Transduction/physiology , Ventricular Remodeling/physiologyABSTRACT
BACKGROUND: In treating atrial fibrillation, pulsed-field ablation (PFA) has comparable efficacy to conventional thermal ablation, but with important safety advantages: no esophageal injury or pulmonary vein stenosis, and rare phrenic nerve injury. However, when PFA is delivered in proximity to coronary arteries using a pentaspline catheter, which generates a broad electrical field, severe vasospasm can be provoked. OBJECTIVES: The authors sought to study the vasospastic potential of a focal PFA catheter with a narrower electrical field and develop a preventive strategy with nitroglycerin. METHODS: During atrial fibrillation ablation, a focal PFA catheter was used for cavotricuspid isthmus ablation. Angiography of the right coronary artery (some with fractional flow reserve measurement) was performed before, during, and after PFA. Beyond no nitroglycerin (n = 5), and a few testing strategies (n = 8), 2 primary nitroglycerin administration strategies were studied: 1) multiple boluses (3-2 mg every 2 min) into the right atrium (n = 10), and 2) a bolus (3 mg) into the right atrium with continuous peripheral intravenous infusion (1 mg/min; n = 10). RESULTS: Without nitroglycerin, cavotricuspid isthmus ablation provoked moderate-severe vasospasm in 4 of 5 (80%) patients (fractional flow reserve 0.71 ± 0.08). With repetitive nitroglycerin boluses, severe spasm did not occur, and mild-moderate vasospasm occurred in only 2 of 10 (20%). Using the bolus + infusion strategy, severe and mild-moderate spasm occurred in 1 and 3 of 10 patients (aggregate 40%). No patient had ST-segment changes. CONCLUSIONS: Ablation of the cavotricuspid isthmus using a focal PFA catheter routinely provokes right coronary vasospasm. Pretreatment with high doses of parenteral nitroglycerin prevents severe spasm.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Coronary Vasospasm , Nitroglycerin , Humans , Atrial Fibrillation/surgery , Nitroglycerin/administration & dosage , Nitroglycerin/therapeutic use , Coronary Vasospasm/prevention & control , Male , Middle Aged , Female , Catheter Ablation/methods , Catheter Ablation/adverse effects , Aged , Vasodilator Agents/therapeutic use , Vasodilator Agents/administration & dosage , Coronary Angiography , Coronary Vessels/drug effects , Coronary Vessels/surgery , Coronary Vessels/physiopathologyABSTRACT
BACKGROUND: Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential. METHODS: Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student's t-test or one-way ANOVA followed by a Fisher's LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher's LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant. RESULTS: Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob. CONCLUSION: Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Caloric Restriction/methods , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/therapy , Ischemic Preconditioning, Myocardial/methods , Animals , Diabetes Mellitus, Experimental/enzymology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Time FactorsABSTRACT
AIMS: Insulin resistance, dyslipidemia and hypertension are independent mediators of endothelial dysfunction. It is incompletely defined whether dyslipidemia and hypertension in addition to diabetes mellitus type II (DMII), as seen in the metabolic syndrome (MS), worsen diabetes-induced endothelial dysfunction. Furthermore, it is unclear whether treatment influences endothelial dysfunction similarly in MS and DMII. Therefore, we studied vascular reactivity and the effect of in vivo treatment with angiotensin-converting enzyme inhibition (ACE-I) or hypocaloric diet in LDL receptor- and leptin-deficient (ob/ob), double knockout mice (DKO), featuring MS and in ob/ob mice with DMII. METHODS AND RESULTS: Vascular reactivity was studied in isolated aortic ring segments. Maximum vasorelaxant response to acetylcholine (Ach) was more depressed in DKO than in ob/ob mice, whereas response to bradykinin (BK) was equally attenuated in both genotypes (52 ± 3 and 23 ± 9% reversal of preconstriction induced by 10(-7) M phenylephrine in DKO vs. 76 ± 3 and 23 ± 8% reversal of preconstriction in ob/ob mice, respectively). ACE-I and hypocaloric diet improved ACh-induced vasorelaxation significantly (89 ± 2 and 59 ± 2% reversal of preconstriction in DKO vs. 80 ± 3 and 84 ± 4% in ob/ob mice, respectively), but not the response to BK. CONCLUSION: These results indicate a differential impact of DMII and MS on endothelial function. ACE-I and hypocaloric diet improved ACh-, but not BK-induced vasorelaxation in these mouse models of DMII and MS.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Caloric Restriction , Captopril/pharmacology , Diabetes Mellitus, Type 2/therapy , Dyslipidemias/therapy , Endothelium, Vascular/drug effects , Hypertension/therapy , Nitric Oxide/metabolism , Weight Loss , Animals , Biomarkers/blood , Blood Glucose/metabolism , Combined Modality Therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Dyslipidemias/blood , Dyslipidemias/genetics , Dyslipidemias/physiopathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Hypertension/blood , Hypertension/genetics , Hypertension/physiopathology , Leptin/deficiency , Leptin/genetics , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Receptors, LDL/deficiency , Receptors, LDL/genetics , Time Factors , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling. METHODS: This study was performed in LDL-receptor (LDLR-/-) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR-/-, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during ß-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp. RESULTS: In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and ß-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to ß-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+. CONCLUSIONS: Cardiomyocyte contractility and ß-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to ß-adrenergic stimulation in MS.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Metabolic Syndrome/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Weight Loss/physiology , Animals , Calcium Signaling/drug effects , Calcium Signaling/physiology , Cells, Cultured , Female , Male , Metabolic Syndrome/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Myocytes, Cardiac/pathology , Weight Loss/drug effectsABSTRACT
BACKGROUND: The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome. METHODS: C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student's t-test or factorial ANOVA followed by a Fisher's LSD post hoc test. RESULTS: Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR. CONCLUSION: ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Caloric Restriction , Diabetes Mellitus, Type 2/complications , Myocardial Infarction/etiology , Myocardial Reperfusion Injury/etiology , Animals , Biomarkers/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Disease Models, Animal , Leptin/deficiency , Leptin/genetics , Metabolic Syndrome/blood , Metabolic Syndrome/complications , Metabolic Syndrome/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Myocardial Contraction , Myocardial Infarction/blood , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/blood , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Myocardium/pathology , Receptors, LDL/deficiency , Receptors, LDL/genetics , Time Factors , Ventricular Function, Left , Ventricular PressureABSTRACT
BACKGROUND: Conventional contact-based electroanatomic mapping is poorly suited for rapid or dynamic ventricular arrhythmias. Whole-chamber charge density (CD) mapping could efficiently characterize complex ventricular tachyarrhythmias and yield insights into their underlying mechanisms. OBJECTIVE: The purpose of this study was to evaluate the feasibility and accuracy of noncontact whole-chamber left ventricular (LV) CD mapping and to characterize CD activation patterns during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF). METHODS: Ischemic scar as defined by CD amplitude thresholds was compared to late gadolinium enhancement criteria on magnetic resonance imaging using an iterative closest point algorithm. Electrograms recorded at sites of tissue contact were compared to the nearest noncontact CD-derived electrograms to calculate signal morphology cross-correlations and time differences. Regions of consistently slow conduction were examined relative to areas of scar and to localized irregular activation (LIA) during VF. RESULTS: Areas under receiver operating characteristic curves (AUCs) of CD-defined dense and total LV scar were 0.92 ± 0.03 and 0.87 ± 0.06, with accuracies of 0.86 ± 0.03 and 0.80 ± 0.05, respectively. Morphology cross-correlation between 8677 contact and corresponding noncontact electrograms was 0.93 ± 0.10, with a mean time difference of 2.5 ± 5.6 ms. Areas of consistently slow conduction tended to occur at scar borders and exhibited spatial agreement with LIA during VF (AUC 0.90 ± 0.02). CONCLUSION: Noncontact LV CD mapping can accurately delineate ischemic scar. CD-derived ventricular electrograms correlate strongly with conventional contact-based electrograms. Regions with consistently slow conduction are often at scar borders and tend to harbor LIA during VF.
Subject(s)
Heart Ventricles , Tachycardia, Ventricular , Animals , Arrhythmias, Cardiac/pathology , Cicatrix , Contrast Media , Gadolinium , SheepABSTRACT
We investigated glucose tolerance and left ventricular contractile performance in 4 frequently used mouse strains (Swiss, C57BL/6J, DBA2, and BalbC) at 24 weeks. Glucose tolerance was tested by measuring blood glucose levels in time after intraperitoneal glucose injection (2 mg/g body weight). Left ventricular contractility was assessed by pressure-conductance analysis. Peak glucose levels and glucose area under the curve were higher (all P < .05) in C57BL/6J (418 ± 65 mg/dL and 813 ± 100 mg·h/dL) versus Swiss (237 ± 66 mg/dL and 470 ± 126 mg·h/dL), DBA2 (113 ± 20 mg/dL and 304 ± 49 mg·h/dL, P < .01), and BalbC mice (174 ± 55 mg/dL and 416 ± 70 mg·h/dL). Cardiac output was higher (all P < .05) in Swiss (14038 ± 4530 µL/min) versus C57BL/6J (10405 ± 2683 µL/min), DBA2 (10438 ± 3251 µL/min), and BalbC mice (8466 ± 3013 µL/min). Load-independent left ventricular contractility assessed as recruitable stroke work (PRSW) was comparable in all strains. In conclusion, glucose tolerance and load-dependent left ventricular performance parameters were different between 4 mice background strains, but PRSW was comparable.
Subject(s)
Stroke Volume/physiology , Ventricular Pressure/physiology , Animals , Glucose Tolerance Test , Heart Rate/drug effects , Injections, Intraperitoneal , Isoproterenol/administration & dosage , Isoproterenol/pharmacology , Mice , Mice, Inbred Strains , Stroke Volume/drug effects , Ventricular Pressure/drug effectsABSTRACT
PURPOSE: This study aimed to investigate the spatial relationship between low-voltage areas (LVAs) in bipolar voltage mapping (BVM) and localized complex conduction (LCC)-cores in a global, non-contact, charge-density-based imaging, and mapping system (AcM). METHODS: Patients with history of index PVI for PsAF and scheduled for a repeat ablation procedure for recurrence of the same arrhythmia were enrolled between August 2018 and February 2020. All patients underwent both substrate mappings of the left atrium (LA) with the CARTO 3D map-ping system and with AcM. RESULTS: Ten patients where included in our analysis. All presented with persistency of PVI in all veins at the moment of repeat procedure. There was no linear relationship in BVM maps between SR and CSd (correlation coefficient 0.31 ± 0.15), SR and CSp (0.36 ± 0.12) and CSd and CSp (0.43 ± 0.10). The % overlap of localized irregular activation (LIA), localized rotational activation (LRA) and Focal (F) regions with LVA was lower at 0.2 mV compared to 0.5 mV (4.97 ± 7.39%, 3.27 ± 5.25%, 1.09 ± 1.92% and 12.59 ± 11.81%, 7.8 ± 9.20%, 4.62 ± 5.27%). Sensitivity and specificity are not significantly different when comparing composite maps with different LVA cut-offs. AURC was 0.46, 0.48, and 0.39 for LIA, LRA, and Focal, respectively. CONCLUSION: Due to wave front direction dependency, LVAs mapped with BVM in sinus rhythm and during coronary sinus pacing only partially overlap in patients with PsAF. LCC-cores mapped during PsAF partially co-localize with LVAs.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Atrial Fibrillation/diagnostic imaging , Atrial Fibrillation/surgery , Electrophysiologic Techniques, Cardiac , Heart Atria/diagnostic imaging , Heart Atria/surgery , Heart Rate , HumansABSTRACT
AIMS: Type II diabetes, often associated with abdominal obesity, frequently leads to heart failure. Clinical and epidemiological evidence suggests that supplemental dyslipidaemia and hypertension, as clustered in the metabolic syndrome, aggravate the cardiovascular outcome. The differential impact of type II diabetes and the metabolic syndrome on left ventricular function, however, remains incompletely defined. METHODS AND RESULTS: We studied left ventricular function in vivo using pressure-volume analysis in obese diabetic mice with leptin deficiency (ob/ob) and obese diabetic dyslipidemic mice with combined leptin and low-density lipoprotein-receptor deficiency (DKO). ob/ob and DKO mice developed a diabetic cardiomyopathy, characterized by impaired contractility and relaxation, from the age of 24 weeks onwards. This was-at least partially-explained by increased apoptosis and disturbed Ca(2+) reuptake in the sarcoplasmic reticulum (SR) in both mouse models. DKO, but not ob/ob, developed increased end-diastolic ventricular stiffness, paralleled by increased left ventricular myocardial fibrosis. Cardiac output was preserved in ob/ob mice by favourable loading conditions, whereas it decreased in DKO mice. CONCLUSIONS: Type II diabetes in mice leads to impaired contractility and relaxation due to disturbed Ca(2+) reuptake in the SR, but only when dyslipidaemia and hypertension are superimposed does vascular-ventricular stiffening increase and left ventricular myocardial fibrosis develop.
Subject(s)
Diabetes Mellitus, Type 2/complications , Dyslipidemias/physiopathology , Myocardial Contraction , Ventricular Function, Left , Animals , Blood Pressure , Dyslipidemias/complications , Female , Leptin/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardium/pathology , Receptors, LDL/physiology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/physiologyABSTRACT
AIMS: The metabolic syndrome (MS) leads to myocardial fibrosis (MF) and diastolic dysfunction. Statins have proven beneficial effects in MS, but their impact on cardiac remodelling is uncertain. We examined the effects and mechanisms of chronic statin treatment on cardiac remodelling, e.g. fibrosis and diastolic properties. METHODS AND RESULTS: We used a mouse model deficient in leptin and the LDL-receptor (DKO) that reproduces this MS phenotype. DKO mice (12 weeks) were treated with rosuvastatin (R) for 6 months vs. placebo. Morphometric and echocardiographic measurements showed that R reduced cardiac mass and increased left-ventricular end-diastolic diameter despite unchanged cardiomyocyte dimensions. Similarly, R had no effect on the hypertrophic response to neurohormones in isolated cardiomyocytes. Conversely, R reversed the age-dependent development of MF as well as mRNA expression of TGF-ß1 and several pro-fibrotic markers (procollagen type I, its carboxy-terminal proteinase, Lysyl oxidase). R similarly inhibited the pro-fibrotic effects of TGF-ß1 on procollagen type I, alpha Smooth Muscle Actin expression and migratory properties of cardiac fibroblasts in vitro. In parallel, R increased the activation of AMP-activated protein kinase (AMPK), a known inhibitor of fibrosis, in vivo and in vitro, and the anti-fibrotic effects of R were abrogated in fibroblasts transfected with AMPKα1/α2 siRNA. The reversal of MF by R in DKO mice was accompanied with improved diastolic properties assessed by P-V loop analysis (slope of EDPVR, dP/dt min and cardiac output). CONCLUSION: In this model of MS, statin treatment reverses myocardial remodelling and improves ventricular relaxation through AMPK-mediated anti-fibrotic effects.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Fluorobenzenes/pharmacology , Heart Diseases/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Metabolic Syndrome/drug therapy , Myocardium/enzymology , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Ventricular Function, Left/drug effects , AMP-Activated Protein Kinases/genetics , Actins/metabolism , Animals , Cells, Cultured , Collagen Type I/metabolism , Diastole , Disease Models, Animal , Enzyme Activation , Fibroblasts/drug effects , Fibroblasts/enzymology , Fibroblasts/pathology , Fibrosis , Heart Diseases/enzymology , Heart Diseases/genetics , Heart Diseases/pathology , Heart Diseases/physiopathology , Leptin/deficiency , Leptin/genetics , Metabolic Syndrome/enzymology , Metabolic Syndrome/genetics , Metabolic Syndrome/pathology , Metabolic Syndrome/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardium/pathology , Procollagen/metabolism , Rats , Receptors, LDL/deficiency , Receptors, LDL/genetics , Recovery of Function , Rosuvastatin Calcium , Signal Transduction/drug effects , Time Factors , Transfection , Transforming Growth Factor beta1/metabolism , Ventricular Remodeling/drug effectsABSTRACT
AIMS: Weight reduction programmes in morbidly obese, diabetic, and hyperlipidaemic subjects usually improve cardiac load and subsequently reverse hypertrophy. However, their effect on contractile dysfunction and impaired cardiac functional reserve is unknown. METHODS AND RESULTS: The effect of food-restriction-induced weight loss on in vivo cardiac contractility before and during beta-adrenergic stimulation was assessed using left ventricular pressure-volume analysis in a mouse model featuring obesity and Type II diabetes (ob/ob), obesity, Type II diabetes, atherogenic dyslipidaemia, and hypertension (LDLR-/-;ob/ob), or wild-type. In addition, sarcoendoplasmic reticulum (SR) Ca(2+) reuptake, interstitial collagen accumulation, and aortic atherosclerosis were measured. Food-restriction resulted in a 54% lower weight. Weight loss largely normalized pre- and afterload in both ob/ob and LDLR-/-;ob/ob mice. Contractility and relaxation improved after weight loss, partly explained by improved SR Ca(2+) reuptake. Ventricular-vascular stiffening, interstitial collagen accumulation, and aortic atherosclerosis were less in food-restricted than in free-fed LDLR-/-;ob/ob mice. In contrast, cardiac reserve was similarly impaired in free-fed and food-restricted ob/ob and LDLR-/-;ob/ob mice. CONCLUSION: Food-restriction in obese diabetic mice leads to improved cardiac performance by diminishing cardiac load and by ameliorating the intrinsic contractile properties of the cardiac muscle. However, cardiac reserve under dobutamine stimulation did not increase.