RESUMEN
In Western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density, and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a trend towards normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced phosphoinositide 3-kinase phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size, and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.
Asunto(s)
Estenosis de la Válvula Aórtica/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Animales Recién Nacidos , Estenosis de la Válvula Aórtica/complicaciones , Factor Natriurético Atrial/genética , Peso al Nacer , Capilares/patología , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Fibrosis , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Tamaño de la Camada , Ratones , Ratones Endogámicos C57BL , Miocardio/patología , Cadenas Pesadas de Miosina/genética , Péptido Natriurético Encefálico/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Embarazo , Complicaciones Cardiovasculares del Embarazo/etiología , Complicaciones Cardiovasculares del Embarazo/genética , Complicaciones Cardiovasculares del Embarazo/patología , Índice de Embarazo , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT1/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Factores de Tiempo , Transcriptoma , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/patologíaRESUMEN
AIMS: Increasing evidence supports a role for the angiotensin II-AT1-receptor axis in aneurysm development. Here, we studied whether counteracting this axis via stimulation of AT2 receptors is beneficial. Such stimulation occurs naturally during AT1-receptor blockade with losartan, but not during renin inhibition with aliskiren. METHODS AND RESULTS: Aneurysmal homozygous fibulin-4 mice, displaying a four-fold reduced fibulin-4 expression, were treated with placebo, losartan, aliskiren, or the ß-blocker propranolol from day 35 to 100. Their phenotype includes cystic media degeneration, aortic regurgitation, left ventricular dilation, reduced ejection fraction, and fractional shortening. Although losartan and aliskiren reduced hemodynamic stress and increased renin similarly, only losartan increased survival. Propranolol had no effect. No drug rescued elastic fiber fragmentation in established aneurysms, although losartan did reduce aneurysm size. Losartan also increased ejection fraction, decreased LV diameter, and reduced cardiac pSmad2 signaling. None of these effects were seen with aliskiren or propranolol. Longitudinal micro-CT measurements, a novel method in which each mouse serves as its own control, revealed that losartan reduced LV growth more than aneurysm growth, presumably because the heart profits both from the local (cardiac) effects of losartan and its effects on aortic root remodeling. CONCLUSION: Losartan, but not aliskiren or propranolol, improved survival in fibulin-4 mice. This most likely relates to its capacity to improve structure and function of both aorta and heart. The absence of this effect during aliskiren treatment, despite a similar degree of blood pressure reduction and renin-angiotensin system blockade, suggests that it might be because of AT2-receptor stimulation.
Asunto(s)
Aneurisma/fisiopatología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/metabolismo , Proteínas de la Matriz Extracelular , Insuficiencia Cardíaca/fisiopatología , Receptor de Angiotensina Tipo 1/metabolismo , Renina/metabolismo , Animales , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Ratones , Ratones Transgénicos , Renina/antagonistas & inhibidoresRESUMEN
OBJECTIVES: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations. BACKGROUND: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. METHODS: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies. RESULTS: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005). CONCLUSIONS: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.
Asunto(s)
Aneurisma/genética , Enfermedades Cardiovasculares/genética , Variación Estructural del Genoma/genética , Osteoartritis/genética , Fenotipo , Proteína smad3/genética , Adolescente , Adulto , Anciano , Aneurisma/diagnóstico por imagen , Aneurisma/mortalidad , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/genética , Disección Aórtica/mortalidad , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/mortalidad , Aortografía , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/genética , Trastornos Cerebrovasculares/mortalidad , Aberraciones Cromosómicas , Estudios de Cohortes , Femenino , Genes Dominantes/genética , Humanos , Interpretación de Imagen Asistida por Computador , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/genética , Osteoartritis/diagnóstico por imagen , Osteoartritis/mortalidad , Fragmentos de Péptidos/genética , Embarazo , Análisis de Supervivencia , Síndrome , Rigidez Vascular/genética , Adulto JovenRESUMEN
Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT(1)) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R)) and 4-fold (homozygous Fibulin-4(R/R)) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-ß signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-ß. Tissue levels of Ang II, a regulator of TGF-ß signaling, were increased. Prenatal treatment with the AT(1) receptor antagonist losartan, which blunts TGF-ß signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R) mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1) receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.
Asunto(s)
Aorta Torácica/fisiopatología , Aneurisma de la Aorta/fisiopatología , Proteínas de la Matriz Extracelular/deficiencia , Vasoconstricción/fisiología , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/prevención & control , Proteínas de la Matriz Extracelular/genética , Femenino , Humanos , Inmunohistoquímica , Técnicas In Vitro , Losartán/farmacología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenilefrina/farmacología , Embarazo , Receptor de Angiotensina Tipo 1/fisiología , Proteína Smad2/genética , Proteína Smad2/metabolismo , Transcriptoma , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/genética , Vasoconstrictores/farmacologíaRESUMEN
Thoracic aortic aneurysms (TAAs) are a potential life-threatening disease with limited pharmacological treatment options. Current treatment options are aimed at lowering aortic hemodynamic stress, predominantly with ß-adrenoceptor blockers. Increasing evidence supports a role for the renin-angiotensin system (RAS) in aneurysm development. RAS blockade would not only lower blood pressure, but might also target the molecular pathways involved in aneurysm formation, in particular the transforming growth factor-ß and extracellular signal-regulated kinase 1/2 pathways. Indeed, the angiotensin II type 1 (AT1) receptor blocker losartan was effective in lowering aortic root growth in mice and patients with Marfan's syndrome. RAS inhibition (currently possible at 3 levels, i.e. renin, ACE and the AT1 receptor) is always accompanied by a rise in renin due to interference with the negative feedback loop between renin and angiotensin II. Only during AT1 receptor blockade will this result in stimulation of the non-blocked angiotensin II type 2 (AT2) receptor. This review summarizes the clinical aspects of TAAs, provides an overview of the current mouse models for TAAs, and focuses on the RAS as a new target for TAA treatment, discussing in particular the possibility that AT2 receptor stimulation might be crucial in this regard. If true, this would imply that AT1 receptor blockers (and not ACE inhibitors or renin inhibitors) should be the preferred treatment option for TAAs.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Aneurisma de la Aorta Torácica/tratamiento farmacológico , Aneurisma de la Aorta Torácica/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Ensayos Clínicos como Asunto , HumanosRESUMEN
BACKGROUND: The blood pressure-lowering effect of the renin inhibitor aliskiren equals that of angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II type 1 (AT1) receptor blockers. Whether aliskiren offers end-organ protection remains to be investigated. Here, we compared the cardiac effects of aliskiren, the AT1 receptor blocker irbesartan and the ACE inhibitor captopril in spontaneously hypertensive rats (SHR) at equi-hypotensive doses. METHODS AND RESULTS: SHR were treated for 1-3 weeks with vehicle, aliskiren, captopril or irbesartan (100, 3 and 15 mg/kg per day, respectively) using an osmotic minipump, and compared to vehicle-treated Wistar-Kyoto (WKY) controls. All drugs lowered (but not normalized) mean arterial pressure in SHR equi-effectively, as monitored by radiotelemetry, without altering heart rate. All drugs also reduced the increased cardiomyocyte area in SHR, and tended to normalize the elevated brain natriuretic peptide plasma levels. In the Langendorff set-up, all drugs normalized the diminished endothelium-dependent vasodilator response to bradykinin in SHR. Moreover, aliskiren and irbesartan, but not captopril, decreased the enhanced coronary Ang II response in SHR. Aliskiren reduced plasma renin activity and the plasma and tissue angiotensin levels at 1 week of treatment; yet, after 3 weeks of aliskiren treatment only the cardiac angiotensin levels remained suppressed, whereas no tissue angiotensin reductions were seen with captopril or irbesartan. CONCLUSION: For a given decrease in blood pressure, aliskiren improves coronary endothelial function and decreases cardiac hypertrophy in SHR to at least the same degree as ACE inhibition and AT1 receptor blockade. In addition, aliskiren diminishes the enhanced Ang II response in the coronary circulation of SHR and offers superior long-term cardiac angiotensin suppression.
Asunto(s)
Amidas/farmacología , Presión Sanguínea/efectos de los fármacos , Fumaratos/farmacología , Corazón/efectos de los fármacos , Hipertensión/fisiopatología , Renina/antagonistas & inhibidores , Amidas/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Angiotensinas/sangre , Animales , Compuestos de Bifenilo/farmacología , Presión Sanguínea/fisiología , Captopril/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fumaratos/uso terapéutico , Corazón/fisiopatología , Ventrículos Cardíacos/patología , Hipertensión/sangre , Hipertensión/tratamiento farmacológico , Hipertrofia/tratamiento farmacológico , Irbesartán , Masculino , Péptido Natriurético Encefálico/sangre , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Renina/sangre , Tetrazoles/farmacologíaRESUMEN
Even after successful repair, hypertension is one of the main determinants of cardiovascular morbidity and mortality in patients with aortic coarctation (CoA). We compared the effect of candesartan (angiotensin II receptor blockade) and metoprolol (beta-adrenergic receptor blockade) on blood pressure, large artery stiffness, and neurohormonal status in hypertensive patients after repair of CoA. In the present open-label, crossover study, hypertensive patients after CoA repair were first randomly assigned to treatment with candesartan 8 mg or metoprolol 100 mg once per day. After 8 weeks of treatment with one of the drugs, the other treatment was given for 8 weeks. The treatment effects were assessed with 24-hour ambulatory blood pressure monitoring, measurement of large artery stiffness, and neurohormonal plasma levels at baseline and after 8 weeks of either treatment. Sixteen patients (mean age 37 +/- 12 years, 26 +/- 15 years after repair, 63% men) completed the study. The 24-hour mean arterial pressure at baseline was 97.7 +/- 6.2 mm Hg. Metoprolol (mean dose 163 +/- 50 mg/day) decreased the mean arterial pressure (7.0 +/- 4.2 and 4.1 +/- 3.6 mm Hg, respectively) more than did candesartan (mean dose 13 +/- 4 mg/day; p = 0.018, 95% confidence interval 0.6 to 5.5). Large artery stiffness did not change with either treatment. With metoprolol, plasma B-type natriuretic peptide increased and plasma renin decreased. With candesartan, the plasma renin and noradrenaline levels increased and aldosterone levels decreased. In conclusion, in adult hypertensive patients after CoA repair, metoprolol had more of an antihypertensive effect than did candesartan. Moreover, the neurohormonal outcome did not support a significant role for the renin-angiotensin system in the causative mechanism of hypertension after CoA.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Coartación Aórtica/cirugía , Bencimidazoles/uso terapéutico , Hipertensión/tratamiento farmacológico , Metoprolol/uso terapéutico , Tetrazoles/uso terapéutico , Adulto , Coartación Aórtica/sangre , Coartación Aórtica/fisiopatología , Compuestos de Bifenilo , Estudios de Cohortes , Estudios Cruzados , Femenino , Humanos , Hipertensión/sangre , Hipertensión/etiología , Masculino , Persona de Mediana Edad , Hormonas Peptídicas/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
Because angiotensin (Ang) metabolites mediate functions independent of Ang II, we investigated their effects on coronary flow in spontaneously hypertensive rats (SHRs). Results were compared with those in the iliac artery and abdominal aorta and the coronary circulation of the Wistar rat. Ang II, III, and IV decreased coronary flow in SHRs and Wistar rats, with Ang III and IV being approximately 10 and approximately 1000 times less potent than Ang II. Ang-(1-7) decreased coronary flow at concentrations >1 micromol/L in SHRs. The Ang II type 1 receptor antagonist irbesartan blocked the effects of Ang II, III, and IV, whereas the Ang II type 2 receptor antagonist PD123319 blocked the effects of Ang-(1-7). The maximal Ang II- and III-induced decreases in coronary flow in SHRs were twice as large as those in Wistar rats. PD123319 enhanced the constrictor effects of Ang II and III in Wistar rats so that, in the presence of this drug, their effects were comparable to those in SHRs. In contrast, PD123319 did not alter the Ang II- and III-induced responses in SHRs and blocked the constrictor effect of Ang II in iliac arteries. Ang II type 2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of Ang metabolites in these vessels were identical in Wistar rats and SHRs. In conclusion, coronary constriction induced by Ang II, Ang III, and Ang-(1-7) is enhanced in SHRs as compared with Wistar rats. This is attributable to the absence of counterregulatory Ang II type 2 receptor-mediated relaxation and/or a change of the Ang II type 2 receptor phenotype from relaxant to constrictor.