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Introduction: Heart failure (HF) is among the leading causes of morbidity and mortality worldwide. Several conditions trigger left ventricular chronic pressure or volume overload, hypertrophy, systolic and diastolic dysfunction, leading to cardiac remodeling and a rapid progression toward HF. Therapeutic interventions elicit reverse remodeling (RR), a highly variable myocardial response that ranges from none to total ventricular structural/functional recovery. However, HF patients present several comorbidities and medications that mask a comprehensive molecular knowledge of RR and hinder the identification of potential biomarkers of its progression or prognosis. Therefore, instead of using this heterogeneous population or even animal models to understand myocardial remodeling, we propose studying pregnancy-induced cardiovascular remodeling and postpartum-induced RR., Objectives: To assess cardiovascular functional and structural adaptations during pregnancy and in postpartum, characterizing the associated molecular changes; as well as to explore the impact of hypertension, obesity and diabetes on these processes., Methods: We will perform echocardiography and assess endothelial function and arterial stiffness (EndoPAT® and pulse wave velocity, respectively) and assess potential markers of remodeling and RR using plasma and urine samples from pregnant women. To translate to a HF context, we will determine the impact of risk factors (hypertension, obesity and diabetes) by studying subgroups of pregnant women with these comorbidities., Results: Not applicable., Conclusion: We are convinced that understanding the impact of these comorbidities in such a homogeneous population, such as pregnant women, provides a valuable model to unveil the most relevant pathologic and often masked signaling pathways underlying cardiac remodeling and incomplete RR in a heterogeneous population, such as HF patients. Moreover, we expect to identify potential novel biomarkers of RR progression/prognosis more easily., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls., Methods and Results: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels., Conclusions: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.

Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant β, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF., (Copyright © 2015 the American Physiological Society.)

Background: We evaluated the impact of hypertension on the left ventricular mass regression in aortic stenosis after aortic valve replacement., Methods: We prospectively studied 135 patients with severe aortic stenosis at baseline and 1 year after surgery. In 32 patients we analyzed myocardial gene expression of collagen types I and III, connective tissue growth factor, transforming growth factor-β1, metalloproteinase-2 and its tissue inhibitor and compared its levels vs controls., Results: Seventy-six patients (56.3%) had a history of hypertension. Hypertensive patients were older, had higher Euroscore-II and NYHA class, with no differences in stenosis severity. At 1 year follow-up there was a median decrease of mass index of 14.2% (P25-75: -4.3%-30.4%; p<0.001). Mass regression was significantly higher in patients without hypertension, with a median decrease of 25.9% (P25-75: 12.0%-38.7%) vs 5.4% (P25-75: -12.5%-20.1%; p=0.001), despite similar increase in effective orifice area and no differences in valvuloarterial impedance. After 1 year, higher baseline left ventricular mass index (p=0.005) and the absence of hypertension (p=0.002) or diabetes (p=0.041) were the only independent predictors of mass regression higher than the median. Comparing with controls, aortic stenosis patients had an increased expression of collagen types I and III, but only hypertensive patients had higher relative expression of collagen type I vs III. In hypertensive patients TIMP2 expression was up-regulated and correlated with higher baseline left ventricular mass index (r=0.61; p=0.020)., Conclusions: In aortic stenosis, hypertension impairs mass regression one year after valve replacement, independently of total afterload. Differences in the expression of extracellular matrix remodeling genes might contribute to this finding., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure-volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 ± 0.4 μm, SHAM 18.2 ± 0.3 μm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m(2), SHAM 18.6 ± 1.4 kN/m(2)), Ca(2+) sensitivity (BA 5.56 ± 0.02, SHAM 5.50 ± 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment (K (tr); BA 14.9 ± 1.1 s(-1), SHAM 25.2 ± 1.5 s(-1)). At the extracellular matrix level, fibrosis (BA 10.8 ± 0.9%, SHAM 5.3 ± 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired (τ; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 μm, 13.9 ± 1.8%, DB 20.6 ± 0.4 μm, 13.8 ± 0.8%, respectively), myofilament Ca(2+)sensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm(2), DB 5.1 ± 0.4 score/mm(2), SHAM 2.1 ± 0.3 score/mm(2)), and apoptosis, while decreasing K (tr) (DM 13.5 ± 1.9 s(-1), DB 15.2 ± 1.4 s(-1)), Akt phosphorylation and MMP-9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end-diastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolic-pressure-volume relation: DM 0.59 ± 0.18, DB 0.83 ± 0.17, SHAM 0.41 ± 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 ± 0.21 g/kg, SHAM 3.80 ± 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals.

Background: Structural and functional changes involved in cardiac injury induced by diabetes mellitus, pressure-overload, or both conditions were evaluated., Methods: Pressure-overload was established by suprarenal aortic banding in rats. Six weeks later, diabetes was induced by streptozotocin (STZ, 65 mg/kg, intraperitoneally), resulting in four groups: SHAM, banded (BA), diabetic (DM), and diabetic-banded (DM-BA). On the 12th week, left ventricular (LV) structure and function were evaluated. LV function was assessed in vivo with pressure-volume catheters and in vitro by papillary muscles' performance at baseline and in response to isoprenaline (ISO, 10(-8) to 10(-5) M)., Results: Compared to SHAM, we observed a significant increase of type-B natriuretic peptide (BA = 370 +/- 110%; DM-BA = 580 +/- 210%), LV mass (BA = 36.8 +/- 3.6%; DM-BA = 32.1 +/- 3.1%), cardiomyocyte diameter (BA = 19.5 +/- 2.3%; DM = 14.3 +/- 1.9%; DM-BA = 11.4 +/- 2.0%), fibrosis (BA = 85 +/- 14%; DM = 145 +/- 28%; DM-BA = 155 +/- 14%), advanced glycation end-product (AGE) deposition (DM = 141 +/- 29%; DM-BA = 166 +/- 46%), contraction (tAT: DM = 13.7 +/- 2.4%; DM-BA = 26.3 +/- 7.1%); a delayed relaxation (tHR: DM = 13.8 +/- 2.6%; DM-BA = 25.5 +/- 9.2%) and a decrease of collagen type-I/type-III ratio (DM = -66.1 +/- 4.6%; DM-BA = -51.9 +/- 5.5). In SHAM animals, ISO (10(-5) M) increased 86.5 +/- 26.2% active tension, 105.3 +/- 20.2% dT/dt(max), and 166.8 +/- 29.9% dT/dt(min). Similar effects were observed in BA and DM animals, whereas in DM-BA these inotropic and lusitropic responses were blunted. Moreover, at a similar resting muscle length, ISO decreased passive tension by 12 +/- 3% in SHAM and 11 +/- 3% in BA, indicating an increase in myocardial distensibility, an effect that was absent in both diabetic groups., Conclusion: Long-standing pressure-overload increased LV mass, while diabetes promoted AGE and collagen deposition, which might explain the abolition of ISO-induced increased myocardial distensibility. Association of pressure-overload and diabetes completely blunted the inotropic and lusitropic responses to ISO, with no additional structural damages than in pressure-overload or diabetes alone.

OBJECTIVES: Persistent left ventricular (LV) hypertrophy after surgery is frequent, but its clinical relevance is controversial. We evaluated if residual LV hypertrophy (LVH) is associated with clinical outcomes after aortic valve replacement (AVR) for severe aortic stenosis (AS). METHODS: We analysed clinical and echocardiographic parameters before and after AVR, in a prospective cohort of 132 patients with severe AS. The mean follow-up was 6.0 ± 1.5 years. Clinical endpoints were all-cause death and combination of as in all-cause death and non-fatal cardiovascular hospitalization. At AVR, myocardial biopsies for collagen volume fraction (CVF) evaluation were done in 56 random patients. RESULTS: Residual LVH was present in 44% of patients after AVR. Patients with residual LVH were older, more frequently women and had hypertension (HT). Preoperatively, they had higher LV mass indices (LVMI), higher E/e0 and left atrial volume indices, as well as lower peak systolic annular velocity. Female gender, HT, LVMI and E/e0 were independent predictors of persistent LVH. CVF at the time of surgery was higher in those with residual LVH (20.0 ± 14.6 vs 13.2 ± 11.5%, P = 0.027). The risk of all-cause death and non-fatal cardiovascular hospitalization was higher in patients with residual LVH [OR 2.89 (95% CI 1.12-7.44); P = 0.035], but there were no differences in all-cause mortality. Residual LVH was associated with a worse outcome in women but not in men. CONCLUSIONS: Residual LVH after AVR is common and is associated with worse prognosis, particularly in women. In addition, HT, higher baseline LVM and worse diastolic dysfunction can help to identify patients at risk for incomplete normalization of LVM. [ABSTRACT FROM AUTHOR]