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2.
Circ Res ; 117(1): 41-51, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-25977309

RESUMEN

RATIONALE: Post-ischemic contractile dysfunction is a contributor to morbidity and mortality after the surgical correction of congenital heart defects in neonatal patients. Pre-existing hypertrophy in the newborn heart can exacerbate these ischemic injuries, which may partly be due to a decreased energy supply to the heart resulting from low fatty acid ß-oxidation rates. OBJECTIVE: We determined whether stimulating fatty acid ß-oxidation with GW7647, a peroxisome proliferator-activated receptor-α (PPARα) activator, would improve cardiac energy production and post-ischemic functional recovery in neonatal rabbit hearts subjected to volume overload-induced cardiac hypertrophy. METHODS AND RESULTS: Volume-overload cardiac hypertrophy was produced in 7-day-old rabbits via an aorto-caval shunt, after which, the rabbits were treated with or without GW7647 (3 mg/kg per day) for 14 days. Biventricular working hearts were subjected to 35 minutes of aerobic perfusion, 25 minutes of global no-flow ischemia, and 30 minutes of aerobic reperfusion. GW7647 treatment did not prevent the development of cardiac hypertrophy, but did prevent the decline in left ventricular ejection fraction in vivo. GW7647 treatment increased cardiac fatty acid ß-oxidation rates before and after ischemia, which resulted in a significant increase in overall ATP production and an improved in vitro post-ischemic functional recovery. A decrease in post-ischemic proton production and endoplasmic reticulum stress, as well as an activation of sarcoplasmic reticulum calcium ATPase isoform 2 and citrate synthase, was evident in GW7647-treated hearts. CONCLUSIONS: Stimulating fatty acid ß-oxidation in neonatal hearts may present a novel cardioprotective intervention to limit post-ischemic contractile dysfunction.


Asunto(s)
Butiratos/uso terapéutico , Cardiomegalia/fisiopatología , Contracción Miocárdica/fisiología , Isquemia Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , PPAR alfa/agonistas , Compuestos de Fenilurea/uso terapéutico , ATP Citrato (pro-S)-Liasa/metabolismo , Adenosina Trifosfato/biosíntesis , Animales , Animales Recién Nacidos , Butiratos/farmacología , ATPasas Transportadoras de Calcio/metabolismo , Cardiomegalia/prevención & control , Ciclo del Ácido Cítrico/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Ácidos Grasos/metabolismo , Femenino , Glucólisis , Corazón/efectos de los fármacos , Inflamación , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Contracción Miocárdica/efectos de los fármacos , PPAR alfa/fisiología , Compuestos de Fenilurea/farmacología , Conejos , Retículo Sarcoplasmático/enzimología , Volumen Sistólico/efectos de los fármacos
3.
Cardiovasc Drugs Ther ; 30(4): 379-391, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27497930

RESUMEN

Despite continuous advances in myocardial revascularization procedures and intracoronary devices, patients with ischemic heart disease (IHD) still experience worse prognosis and poor quality of life (QoL). Indeed, chronic stable angina (CSA) is a common disease with a large burden on healthcare costs. Traditionally, CSA is interpreted as episodes of reversible myocardial ischemia related to the presence of stable coronary artery plaque causing myocardial demand/supply mismatch when myocardial oxygen consumption increases. Accordingly, revascularization procedures are performed with the aim to remove the flow limiting stenosis, whereas traditional medical therapy (hemodynamic agents) aims at reducing myocardial oxygen demands. However, although effective, none of these treatment strategies or their combination is either able to confer symptomatic relief in all patients, nor to reduce mortality. Failure to significantly improve QoL and prognosis may be attributed at least in part to this "restrictive" understanding of IHD. Despite for many years myocardial metabolic derangement has been overlooked, recently it has gained increased attention with the development of new pharmacological agents (metabolic modulators) able to influence myocardial substrate selection and utilization thus improving cardiac efficiency. Shifting cardiac metabolism from free fatty acids (FA) towards glucose is a promising approach for the treatment of patients with stable angina, independently of the underling disease (macrovascular and/or microvascular disease). In this sense cardiac metabolic modulators open the way to a "revolutionary" understanding of ischemic heart disease and its common clinical manifestations, where myocardial ischemia is no longer considered as the mere oxygen and metabolites demand/supply unbalance, but as an energetic disorder. Keeping in mind such an alternative approach to the disease, development of new pharmacological agents directed toward multiple metabolic targets is mandatory.


Asunto(s)
Angina Estable/tratamiento farmacológico , Fármacos Cardiovasculares/uso terapéutico , Miocardio/metabolismo , Angina Estable/metabolismo , Animales , Fármacos Cardiovasculares/farmacología , Humanos
4.
Circ Res ; 112(1): 57-65, 2013 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-22982985

RESUMEN

RATIONALE: Muscle carnitine palmitoyltransferase I is predominant in the heart, but the liver isoform (liver carnitine palmitoyltransferase I [L-CPT1]) is elevated in hearts with low long chain fatty acid oxidation, such as fetal and hypertrophied hearts. OBJECTIVE: This work examined the effect of acute L-CPT1 expression on the regulation of palmitate oxidation and energy metabolism in intact functioning rat hearts for comparison with findings in hypertrophied hearts. METHODS AND RESULTS: L-CPT1 was expressed in vivo in rat hearts by coronary perfusion of Adv.cmv.L-CPT1 (L-CPT1, n=15) vs. phosphate-buffered saline (PBS) infusion (PBS, n=7) or empty virus (empty, n=5). L-CPT1 was elevated 5-fold at 72 hours after Adv.cmv.L-CPT1 infusion (P<0.05), but muscle carnitine palmitoyltransferase I was unaffected. Despite similar tricarboxylic acid cycle rates, palmitate oxidation rates were reduced with L-CPT1 (1.12 ± 0.29 µmol/min per gram of dry weight, mean±SE) vs. PBS (1.6 ± 0.34). Acetyl CoA production from palmitate was reduced with L-CPT1 (69 ± 0.02%; P<0.05; PBS=79 ± 0.01%; empty=81 ± 0.02%), similar to what occurs in hypertrophied hearts, and with no difference in malonyl CoA content. Glucose oxidation was elevated with L-CPT1 (by 60%). Surprisingly, L-CPT1 hearts contained elevated atrial natriuretic peptide, indicating induction of hypertrophic signaling. CONCLUSIONS: The results link L-CPT1 expression to reduced palmitate oxidation in a nondiseased adult heart, recapitulating the phenotype of reduced long chain fatty acid oxidation in cardiac hypertrophy. The implications are that L-CPT1 expression induces metabolic remodeling hypertrophic signaling and that regulatory factors beyond malonyl CoA in the heart regulate long chain fatty acid oxidation via L-CPT1.


Asunto(s)
Cardiomegalia/enzimología , Carnitina O-Palmitoiltransferasa/metabolismo , Metabolismo Energético , Hígado/enzimología , Miocardio/enzimología , Ácido Palmítico/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Carboxiliasas/metabolismo , Cardiomegalia/genética , Carnitina O-Palmitoiltransferasa/genética , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica , Técnicas de Transferencia de Gen , Genotipo , Espectroscopía de Resonancia Magnética , Masculino , Malonil Coenzima A/metabolismo , Oxidación-Reducción , Fenotipo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Regulación hacia Arriba
5.
Clin Res Cardiol ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39046472

RESUMEN

BACKGROUND: To assess the interaction between heart failure (HF) severity and optimal reduction of secondary mitral regurgitation (SMR) on mortality in patients undergoing transcatheter edge-to-edge repair (M-TEER). METHODS AND RESULTS: Among 1656 patients included in the Italian Society of Interventional Cardiology (GIse) registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO) 984 had SMR and complete data on advanced HF. Advanced HF was defined as NYHA class III or IV, left ventricular ejection fraction ≤ 30%, and > 1 HF hospitalization during the last 12 months. Optimal M-TEER was defined as residual SMR ≤ 1 + at discharge. One hundred sixteen patients (11.8%) had advanced HF. Achievement of an optimal SMR reduction was similar in patients with and without advanced HF (65% and 60% respectively). Advanced HF was an independent predictor of 2-year all-cause death (adjusted HR 1.52, 95% CI 1.09-2.10). Optimal M-TEER, as compared to a no-optimal M-TEER, was associated with a reduced risk of death both in patients with advanced (HR 0.55, 95% CI 0.32-0.97; p = 0.039) and no-advanced HF (HR 0.59, 95% CI 0.46-0.78; p < 0.001; p = 0.778 for interaction). CONCLUSIONS: Advanced HF is associated with poor outcome in patients undergoing M-TEER. However, an optimal SMR reduction reduces the risk of 2-year mortality regardless of HF severity.

6.
Am J Physiol Heart Circ Physiol ; 302(9): H1784-94, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22408020

RESUMEN

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower (P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% (P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.


Asunto(s)
Animales Recién Nacidos/metabolismo , Ácidos Grasos/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Derecha/metabolismo , Isquemia Miocárdica/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Metabolismo Energético/fisiología , Femenino , Glucólisis/fisiología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Derecha/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Modelos Animales , Isquemia Miocárdica/fisiopatología , Miocardio/metabolismo , Oxidación-Reducción , PPAR alfa/metabolismo , Conejos
7.
Vascul Pharmacol ; 147: 107123, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36202288

RESUMEN

Non-vitamin K antagonist oral anticoagulants (NOACs) have revolutionized treatment of atrial fibrillation. Although benefits of anticoagulation therapy are clear, a minority of patients still experience treatment inefficacy or harm. All NOACs have varying degree of renal clearance, which may significantly affect plasma concentrations. Pivotal clinical trials have explored the effects of dose reduction in patients with chronic renal disease. None of these have, however, specifically addressed the need for a dose up-titration in patients with renal hyperfiltration, in whom lower drug plasma levels are to be expected. A signal for lower efficacy in this patient subset has recently emerged. We systematically assessed the peer-reviewed scientific literature on this topic, including a recently reported randomized pharmacokinetic study in renal hyperfiltrators also reporting on ischemic and bleeding events. We conclude that the reduction in NOAC plasma levels in AF patients with renal hyperfiltration is limited in extent and, does not translate into a clinically meaningful reduction in efficacy for NOACs as compared to vitamin K antagonists (VKAs) in such patients. At the current state of knowledge, NOAC current dosing should not be altered in patients with high-normal renal function.


Asunto(s)
Anticoagulantes , Fibrilación Atrial , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Administración Oral , Fibrinolíticos/uso terapéutico , Riñón/fisiología
8.
Am J Cardiovasc Drugs ; 10 Suppl 1: 27-32, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21391731

RESUMEN

Percutaneous coronary intervention (PCI) has not been shown to reduce mortality in patients with stable coronary artery disease (CAD). The long-term clinical success of PCI is defined as the persistent relief of signs and symptoms of myocardial ischemia for more than 6 months after the index procedure. Data from large trials investigating the use of PCI in patients with stable CAD show that angina is still experienced in a large number of patients one year after the procedure and that this proportion increases over time. These data are, however, largely from post-hoc analyses of studies powered to measure other end points. We conducted the first prospective study investigating the incidence of persistent angina and inducible ischemia in patients with stable CAD undergoing PCI rated as 'successful' by the interventional cardiologist, and present an interim analysis of data from 220 patients. The mean age of our patients was 65 years; they were mostly male, mildly obese, hypertensive and dyslipidemic. Most patients had single-vessel disease affecting the left anterior descending artery and received a drug-eluting stent, and all patients had a positive stress test before PCI. At the follow-up visit, which was performed within 4 weeks of the index procedure, 52% of patients still had a positive stress test. Before PCI, 66% of patients reported experiencing angina on exertion. At the follow-up visit, one-third of those patients were still experiencing angina. Patients experiencing persistent angina (21% of the study population) graded their symptoms as improved (66%), unchanged (33%) or worsened (1%) after the procedure. We hypothesize that coronary microvascular dysfunction is a possible cause of persistent angina in this highly select group of patients. Risk factors for microvascular dysfunction include dyslipidemia, smoking and diabetes. It is currently difficult to dissect the relative contributions of coronary artery stenosis and microvascular dysfunction in precipitating myocardial ischemia. A better understanding of these mechanisms could reduce the number of unnecessary PCI procedures. Moreover, treatment options in patients who continue to experience angina despite 'optimal' medical therapy and 'successful' PCI are urgently required.


Asunto(s)
Angina de Pecho/etiología , Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria/terapia , Anciano , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
9.
Int J Cardiol ; 314: 32-35, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32348810

RESUMEN

Although current guidelines on the management of stable coronary artery disease acknowledge that multiple mechanisms may precipitate myocardial ischemia, recommended diagnostic, prognostic and therapeutic algorithms are still focused on obstructive epicardial atherosclerotic lesions, and little progress has been made in identifying management strategies for non-atherosclerotic causes of myocardial ischemia. The purpose of this consensus paper is three-fold: 1) to marshal scientific evidence that obstructive atherosclerosis can co-exist with other mechanisms of ischemic heart disease (IHD); 2) to explore how the awareness of multiple precipitating mechanisms could impact on pre-test probability, provocative test results and treatment strategies; and 3) to stimulate a more comprehensive approach to chronic myocardial ischemic syndromes, consistent with the new understanding of this condition.


Asunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Isquemia Miocárdica , Humanos , Isquemia Miocárdica/diagnóstico , Pronóstico , Síndrome
10.
Thromb Haemost ; 101(6): 1138-46, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19492159

RESUMEN

Levels of circulating endothelial progenitor cells (EPCs) and CXCR4-positive cells are decreased in patients with coronary artery disease (CAD); however, their ability to change in response to acute vascular injury remains to be elucidated. Progenitor and CXCR4-positive cells were analysed by flow cytometry from the peripheral blood of 23 healthy controls and 23 patients with CAD, of which 13 patients underwent angiogram and 10 patients received percutaneous coronary intervention (PCI) with stent implantation. Baseline levels of progenitor and CXCR4-positive cells were substantially reduced in CAD patients compared to controls, although they were still capable of increasing in response to vascular injury. Levels of progenitor and CXCR4-positive cells were increased to a greater extent in the PCI group compared to angiogram patients. At presentation, levels of putative endothelial progenitor and CXCR4-positive cells were found to be negatively correlated with disease severity. A one-year follow-up revealed that out of the cell populations examined, only levels of CXCR4-positive cells were positively correlated with angina frequency in the PCI group, but not in patients receiving angiogram. Baseline levels of progenitor cells are differentially increased depending upon the severity of vascular injury incurred, regardless of a significant deficit in baseline levels in CAD patients. Levels of putative EPCs and CXCR4-positive cells were negatively correlated with disease severity at presentation, however, only CXCR4-positive cells were associated with patient condition in a one-year follow-up.


Asunto(s)
Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Células Endoteliales/metabolismo , Receptores CXCR4/metabolismo , Células Madre/metabolismo , Anciano , Angioplastia Coronaria con Balón , Antígenos CD/metabolismo , Antígenos de Diferenciación/metabolismo , Implantación de Prótesis Vascular , Separación Celular , Enfermedad de la Arteria Coronaria/terapia , Células Endoteliales/patología , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Células Madre/patología , Stents
11.
Minerva Cardioangiol ; 67(4): 330-339, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29642694

RESUMEN

Stress echocardiography (SE) is an established diagnostic technique. For 40 years, the cornerstone of the technique has been the detection of regional wall motion abnormalities (RWMA), due to the underlying physiologically-relevant epicardial coronary artery stenosis. In the last decade, three new parameters (more objective than RWMA) have shown the potential to integrate and complement RWMA: 1) B-lines, also known as ultrasound lung comets, as a marker of extravascular lung water, measured using lung ultrasound with the 4-site simplified scan symmetrically of the antero-lateral thorax on the third intercostal space, from mid-axillary to anterior axillary and mid-clavicular line; 2) left ventricular contractile reserve (LVCR), assessed as the peak stress/rest ratio of left ventricular force, also known as elastance (systolic arterial pressure by cuff sphygmomanometer/end-systolic volume from 2D echocardiography); 3) coronary flow velocity reserve (CFVR) on left anterior descending coronary artery, calculated as peak stress/rest ratio of diastolic peak flow velocity assessed using pulsed-wave Doppler. The 4 parameters (RWMA, B-lines, LVCR and CFVR) now converge conceptually, logistically, and methodologically in the Integrated Quadruple (IQ)-SE. IQ-SE optimizes the versatility of SE to include in a one-stop shop the core "ABCD" (asynergy+B-lines+contractile reserve+Doppler flowmetry) protocol. It allows a synoptic assessment of parameters mirroring the epicardial artery stenosis (RWMA), interstitial lung water (B-lines), myocardial function (LVCR) and small coronary vessels (CFVR). Each variable has a clear clinical correlate, different and complementary to all others: RWMA identify an ischemic vs. non-ischemic heart; B-lines a wet vs. dry lung; LVCR a strong vs. weak heart; CFVR a warm vs. cold heart. IQ-SE is highly feasible, with minimal increase in the imaging and analysis time, and obvious diagnostic and prognostic impact also beyond coronary artery disease - especially in heart failure. Large scale effectiveness studies with IQ-SE are now under way with the Stress Echo 2020 Study, and will provide the necessary evidence base prior to large scale acceptance of the technique.


Asunto(s)
Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Ecocardiografía de Estrés/métodos , Enfermedad de la Arteria Coronaria/fisiopatología , Estenosis Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Ecocardiografía/métodos , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/fisiopatología
12.
Anticancer Res ; 39(10): 5741-5745, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31570476

RESUMEN

BACKGROUND/AIM: Cardiovascular risk factors (CVRFs) predict cardiotoxicity in cancer patients but their role in late cardiac toxicity is less clear. PATIENTS AND METHODS: This was a retrospective analysis of patients treated with anthracyclines (A) and/or trastuzumab (T) and a correlation with early (≤5 years) or late (>5 years) cardiac toxicity, and baseline CVRFs and CVRFs at toxicity time. RESULTS: A total of 610 patients were included, 422 with (Group A) and 188 without (Group B) baseline CVRFs. In group A toxicity incidence was 4.7% with all events during treatment or immediately after [mean onset time 0.7 years (range=0.2-1.6)]. Events rate was 3.2% in group B with all events after five years [mean time onset 6.9 years (range=5.2-7.5)]. All group B patients who developed late cardiac toxicity presented with CVRFs at the time of toxicity not reported before. CONCLUSION: CVRFs could predict late cardiac toxicity and their control should be part of the survivorship program.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/etiología , Cardiopatías/inducido químicamente , Adulto , Anciano , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos
13.
J Am Soc Echocardiogr ; 31(6): 692-701, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29625884

RESUMEN

BACKGROUND: Coronary flow velocity reserve (CFVR) and left ventricular contractile reserve (LVCR) have demonstrated prognostic importance in patients with diabetes. The aim of this study was to investigate the prognostic contribution of combined evaluation of CFVR and LVCR in patients with diabetes with nonischemic stress echocardiography. METHODS: Three hundred seventy-five patients with diabetes (mean age, 68 ± 9 years) with nonischemic dipyridamole stress echocardiography underwent assessment of CFVR of the left anterior descending coronary artery (prospectively) and LVCR with left ventricular force (retrospectively) in a multicenter study. RESULTS: On receiver operating characteristic analysis, LVCR ≤ 1.1 was the best prognostic predictor and was considered an abnormal value. CFVR was abnormal (≤2) in 139 patients (37%), LVCR in 156 (42%), neither in 157 (42%), and both in 77 (21%). During a median follow-up period of 16 months, 86 major adverse cardiac events occurred: 16 deaths, 13 myocardial infarctions, and 57 revascularizations. Multivariate prognostic indicators were CFVR ≤ 2 (P < .0001), age (P = .03), and LVCR ≤ 1.1 (P = .04). The 3-year rate of major adverse cardiac events was 63% in patients with both abnormal CFVR and LVCR, 42% in those with abnormal CFVR only, 19% in those with abnormal LVCR only, and 10% in patients with both normal CFVR and LVCR. The 3-year hard event rate was 3% in patients with both normal CFVR and LVCR, fivefold higher in patients with abnormal CFVR or LVCR only, and ninefold higher in patients with both abnormal CFVR and LVCR. CONCLUSIONS: Patients with diabetes with nonischemic dipyridamole stress echocardiography may still have significant risk in presence of abnormal CFVR and/or LVCR, which assess the underlying, largely unrelated, microvascular and myocardial components of coronary circulation.


Asunto(s)
Enfermedad de la Arteria Coronaria/fisiopatología , Diabetes Mellitus/fisiopatología , Ecocardiografía de Estrés/métodos , Reserva del Flujo Fraccional Miocárdico/fisiología , Ventrículos Cardíacos/fisiopatología , Contracción Miocárdica/fisiología , Función Ventricular Izquierda/fisiología , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/etiología , Circulación Coronaria/fisiología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Vasodilatadores/farmacología
14.
Eur Cardiol ; 13(2): 104-111, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30697354

RESUMEN

Treatment goals for people with chronic angina should focus on the relief of symptoms and improving mortality rates so the patient can feel better and live longer. The traditional haemodynamic approach to ischaemic heart disease was based on the assumption that increasing oxygen supply and decreasing oxygen demand would improve symptoms. However, data from clinical trials, show that about one third of people continue to have angina despite a successful percutaneous coronary intervention and medical therapy. Moreover, several trials on chronic stable angina therapy and revascularisation have failed to show benefits in terms of primary outcome (survival, cardiovascular death, all-cause mortality), symptom relief or echocardiographic parameters. Failure to significantly improve quality of life and prognosis may be attributed in part to a limited understanding of ischaemic heart disease, by neglecting the fact that ischaemia is a metabolic disorder. Shifting cardiac metabolism from free fatty acids towards glucose is a promising approach for the treatment of patients with stable angina, independent of the underlying disease (macrovascular and/or microvascular disease). Cardiac metabolic modulators open the way to a greater understanding of ischaemic heart disease and its common clinical manifestations as an energetic disorder rather than an imbalance between the demand and supply of oxygen and metabolites.

15.
JCI Insight ; 3(10)2018 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-29769443

RESUMEN

A dramatic increase in cardiac fatty acid oxidation occurs following birth. However, cardiac hypertrophy secondary to congenital heart diseases (CHDs) delays this process, thereby decreasing cardiac energetic capacity and function. Cardiac lysine acetylation is involved in modulating fatty acid oxidation. We thus investigated what effect cardiac hypertrophy has on protein acetylation during maturation. Eighty-four right ventricular biopsies were collected from CHD patients and stratified according to age and the absence (n = 44) or presence of hypertrophy (n = 40). A maturational increase in protein acetylation was evident in nonhypertrophied hearts but not in hypertrophied hearts. The fatty acid ß-oxidation enzymes, long-chain acyl CoA dehydrogenase (LCAD) and ß-hydroxyacyl CoA dehydrogenase (ßHAD), were hyperacetylated and their activities positively correlated with their acetylation after birth in nonhypertrophied hearts but not hypertrophied hearts. In line with this, decreased cardiac fatty acid oxidation and reduced acetylation of LCAD and ßHAD occurred in newborn rabbits subjected to cardiac hypertrophy due to an aortocaval shunt. Silencing the mRNA of general control of amino acid synthesis 5-like protein 1 reduced acetylation of LCAD and ßHAD as well as fatty acid oxidation rates in cardiomyocytes. Thus, hypertrophy in CHDs prevents the postnatal increase in myocardial acetylation, resulting in a delayed maturation of cardiac fatty acid oxidation.


Asunto(s)
Cardiomegalia/metabolismo , Metabolismo Energético , Miocardio/metabolismo , Acetilación , Adulto , Anciano , Animales , Ácidos Grasos/metabolismo , Femenino , Glucólisis , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Proteínas Musculares/metabolismo , Oxidación-Reducción , Conejos
16.
Eur Cardiol ; 11(2): 85-89, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30310453

RESUMEN

Following revascularisation the majority of patients obtain symptom relief and improved quality of life. However, myocardial ischaemia may recur or persist in a significant patient subset. Symptom recurrence is usually attributed to inaccurate evaluation of epicardial stenosis, incomplete revascularisation or stent failure and disease progression. However, technological advances with modern imaging and/or physiological evaluation of epicardial plaques have not solved this issue. Conversely, recent clinical studies have shown that abnormal coronary vasomotion and increased myocardial resistance are frequent determinants of post-percutaneous coronary intervention (PCI) myocardial ischaemia. Strategies to enhance prediction of post-PCI angina include proper selection of patients undergoing revascularisation, construction of clinical prediction models, and further invasive evaluation at the time of coronary angiography in those with high likelihood.

17.
Can J Cardiol ; 32(8): 986.e23-9, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27038505

RESUMEN

BACKGROUND: Noninvasive stress tests play a determinant role in the initial management of patients with chronic angina. Nonetheless, their use in the same patient population is considered inappropriate within 2 years after percutaneous coronary intervention (PCI). Indeed, early abnormal results correlate less well with angiographic control and are attributed to a number of confounding factors. We prospectively assessed prevalence and impact on the quality of life of abnormal stress test results in a highly selected patient population. METHODS: Patients with no cardiac comorbidities who underwent successful and complete PCI with stenting for typical angina and had an abnormal exercise stress test (EST) under guideline-directed medical treatment were administered the Seattle Angina Questionnaire (SAQ). Clinical evaluation, EST, and the SAQ were repeated at 1, 6, and 12 months after the index PCI. RESULTS: One hundred ninety-eight patients qualified and were included in the study (mean age, 64 years; 79% men). Although the majority had normal EST results or an increased threshold to angina, at 1 month after the index PCI, 29% of patients still had an abnormal result. At 6 and 12 months, 31% and 29% of patients had abnormal results, respectively. Quality-of-life assessment by the SAQ showed consistent results, with persistent angina in one third of patients. Control angiography documented a critical lesion, attributable to in-stent coronary restenosis, in only 8% of patients. CONCLUSIONS: When stress testing is systematically performed after PCI, the prevalence of abnormal results is high and is associated with impaired quality of life. Prognostic significance along with the underlying pathophysiological mechanisms of such findings should be investigated.


Asunto(s)
Angina Estable/psicología , Prueba de Esfuerzo , Intervención Coronaria Percutánea , Calidad de Vida , Angina Estable/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y Cuestionarios
18.
PLoS One ; 10(3): e0120257, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25768019

RESUMEN

Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation. We report here the first direct evidence that human bone marrow mesenchymal stem cell (BMMSC) energy metabolism is highly glycolytic with low rates of mitochondrial oxidative metabolism. The contribution of glycolysis to ATP production is greater than 97% in undifferentiated BMMSCs, while glucose and fatty acid oxidation combined only contribute 3% of ATP production. We also assessed the effect of physiological levels of fatty acids on human BMMSC survival and energy metabolism. We found that the saturated fatty acid palmitate induces BMMSC apoptosis and decreases proliferation, an effect prevented by the unsaturated fatty acid oleate. Interestingly, chronic exposure of human BMMSCs to physiological levels of palmitate (for 24 hr) reduces palmitate oxidation rates. This decrease in palmitate oxidation is prevented by chronic exposure of the BMMSCs to oleate. These results suggest that reducing saturated fatty acid oxidation can decrease human BMMSC proliferation and cause cell death. These results also suggest that saturated fatty acids may be involved in the long-term impairment of BMMSC survival in vivo.


Asunto(s)
Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Células Madre Mesenquimatosas/fisiología , Análisis de Varianza , Western Blotting , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Técnica del Anticuerpo Fluorescente , Glucólisis/fisiología , Humanos , Mitocondrias/fisiología , Oxidación-Reducción/efectos de los fármacos , Palmitatos/farmacología , Sales de Tetrazolio , Tiazoles
19.
Pharmacol Ther ; 144(3): 283-302, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25004087

RESUMEN

In recent decades coronary microvascular dysfunction has been increasingly identified as a relevant contributor to several cardiovascular conditions. Indeed, coronary microvascular abnormalities have been recognized in patients suffering acute myocardial infarction, chronic stable angina and cardiomyopathies, and also in patients with hypertension, obesity and diabetes. In this review, we will examine pathophysiological information needed to understand pharmacological approaches to coronary microvascular dysfunction in these different clinical contexts. Well-established drugs and new pharmacological agents, including those for which only preclinical data are available, will be covered in detail.


Asunto(s)
Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Microcirculación/efectos de los fármacos , Animales , Ensayos Clínicos como Asunto , Enfermedad Coronaria/etiología , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/fisiopatología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatología , Evaluación Preclínica de Medicamentos , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/fisiopatología , Especies Reactivas de Oxígeno/metabolismo
20.
Curr Pharm Des ; 19(13): 2366-74, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23173585

RESUMEN

For decades coronary macrovascular atherosclerosis has been considered the principal manifestation of coronary heart disease, with most of our effort dedicated to identifying and removal of coronary stenosis. However, growing body of literature indicates that coronary microcirculation also contributes substantially to the pathophysiology of cardiovascular disease. An understanding of mechanisms regulating microvascular function is of critical importance in understanding its role in disease, especially because these regulatory mechanisms vary substantially across species, vascular bed and due to comorbidities. Indeed, the most obvious consequence of coronary stenosis is that it may limit blood supply to the dependent myocardium to the point of causing ischaemia during exercise or even at rest. However, this flow limiting effect is not only due to the passive hydraulic effect of a narrowed conduit, but also to active responses in the coronary microcirculation triggered by the presence of an epicardial stenosis. To understand this problem it is important to review the inter-related mechanisms that regulate flow to the left ventricular wall and modulate transmural distribution of flow. These regulatory mechanisms operate hierarchically and are heterogeneously distributed along the coronary vascular tree. It is also important to discuss the effect of myocardial performance in modulating both blood flow demands and coronary resistance. Some of the interactions between coronary stenosis and microcirculation are transient, like those documented in acute coronary syndromes or during percutaneous interventions. However, microcirculatory remodeling may be triggered by a chronic coronary stenosis, leading to a sustained impairment of blood supply even after successful removal of the epicardial stenosis. A deeper understanding of these phenomena may explain paradoxical findings in patients undergoing coronary revascularization, particularly when functional tests are used in their assessment. These aspects are discussed in detail in this review.


Asunto(s)
Estenosis Coronaria/fisiopatología , Microvasos/fisiopatología , Animales , Vasos Coronarios/fisiopatología , Humanos , Flujo Sanguíneo Regional , Estrés Fisiológico
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