Stretch-induced compliance mechanism in pregnancy-induced cardiac hypertrophy and the impact of cardiovascular risk factors.

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.

Clinical and Pathophysiologic Insights of Free triiodothyronine/Free thyroxine Ratio in Patients with Heart Failure with Preserved Ejection Fraction: Data from the NETDiamond Cohort.

BACKGROUND: Thyroid dysfunction is common in patients with heart failure (HF). Impaired conversion of free T4 (FT4) into free T3 (FT3) is thought to occur in these patients, decreasing the availability of FT3 and contributing to HF progression. In HF with preserved ejection fraction (HFpEF), it is not known whether changes in conversion of thyroid hormones (THs) are associated with clinical status and outcomes. OBJECTIVES: The objective of this study was to evaluate the association of FT3/FT4 ratio and TH with clinical, analytical, and echocardiographic parameters, as well as their prognostic impact in individuals with stable HFpEF. METHODS: We evaluated 74 HFpEF participants of the NETDiamond cohort without known thyroid disease. We performed regression modeling to study the associations of TH and FT3/FT4 ratio with clinical, anthropometric, analytical, and echocardiographic parameters, and survival analysis to evaluate associations with the composite of diuretic intensification, urgent HF visit, HF hospitalization, or cardiovascular death over a median follow-up of 2.8 years. RESULTS: The mean age was 73.7 years and 62% were men. The mean FT3/FT4 ratio was 2.63 (standard deviation: 0.43). Subjects with lower FT3/FT4 ratio were more likely to be obese and have atrial fibrillation. Lower FT3/FT4 ratio was associated with higher body fat (ß = -5.60 kg per FT3/FT4 unit, p = 0.034), higher pulmonary arterial systolic pressure (PASP) (ß = -10.26 mm Hg per FT3/FT4 unit, p = 0.002), and lower left ventricular ejection fraction (LVEF) (ß = 3.60% per FT3/FT4 unit, p = 0.008). Lower FT3/FT4 ratio was associated with higher risk for the composite HF outcome (HR = 2.50, 95% CI: 1.04-5.88, per 1-unit decrease in FT3/FT4, p = 0.041). CONCLUSIONS: In patients with HFpEF, lower FT3/FT4 ratio was associated with higher body fat, higher PASP, and lower LVEF. Lower FT3/FT4 predicted a higher risk of diuretic intensification, urgent HF visits, HF hospitalization, or cardiovascular death. These findings suggest that decreased FT4 to FT3 conversion might be a mechanism associated with HFpEF progression.

The impact of time-of-day reperfusion on remote ischemic conditioning in ST-elevation myocardial infarction: a RIC-STEMI substudy.

Daytime variation affects the tolerance of cardiomyocytes to ischemia-reperfusion injury (IRI). This study aims to evaluate the impact of time-of-day reperfusion on clinical outcomes of remote ischemic conditioning (RIC) as an adjuvant to primary percutaneous coronary intervention(PPCI) in ST-elevation myocardial infarction(STEMI) patients. A post-hoc analysis of a prospective, single-center parallel 1:1 randomized trial (RIC-STEMI) was performed. This analysis included 448 STEMI patients previously randomized to either PPCI alone (PPCI group) (n = 217) or RIC as an adjuvant to PPCI (RIC + PPCI group) (n = 231). Moreover, the sample was divided according to the time of PPCI: night-morning (22 h-11h59min) (n = 216) or afternoon (12 h-21h59min) (n = 232) groups. The primary follow-up endpoint was a composite of cardiac death and hospitalization due to heart failure. There were no significant differences in the clinical characteristics and the follow-up outcomes between groups. The afternoon period (HR = 0.474; 95% CI 0.230-0.977; p = 0.043) and RIC (HR = 0.423; 95% CI 0.195-0.917; p = 0.029) were independent predictors of the primary follow-up endpoint. An univariate analysis showed a lower frequency of primary follow-up endpoint, just in the afternoon period (10.3%vs0.9%; p = 0.002), in the RIC + PPCI group. A multivariate analysis revealed that RIC was an independent predictor of the primary follow-up endpoint in the afternoon group (HR = 0.098; 95% CI 0.012-0.785; p = 0.029), but not in the night-morning group. In addition, the afternoon period was not an independent predictor of the primary follow-up endpoint when the multivariate analysis was performed in the PPCI group. In conclusion, this study showed an important cardioprotective effect of RIC, namely in the afternoon period, suggesting that the afternoon period enhances the cardioprotection induced by RIC.

Human umbilical cord tissue-derived mesenchymal stromal cells as adjuvant therapy for myocardial infarction: a review of current evidence focusing on pre-clinical large animal models and early human trials.

Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic "of-the-shelf" cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.

Histological and haemodynamic characterization of right ventricle in sedentary and trained rats with heart failure with preserved ejection fraction.

NEW FINDINGS: What is the central question of this study? Right ventricle (RV) dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF), nearly doubling the risk of death: what are the RV functional and structural changes in HFpEF and how does aerobic exercise impact them? What is the main finding and its importance? The HFpEF ZSF1 rat model presents RV structural and functional changes mimicking the human condition. Aerobic exercise prevented the decline in V̇O2max , lowered surrogate markers of RV overload (e.g., higher mean and maximum systolic pressure) and improved diastolic dysfunction (e.g., end-diastolic pressure and relaxation time constant). This emphasizes the importance of using exercise to manage HFpEF. ABSTRACT: Right ventricle (RV) dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF) and is a marker of poor prognosis. We assessed the obese ZSF1 rat model of HFpEF to ascertain if these animals also develop RV dysfunction and evaluated whether aerobic exercise could prevent this. Obese ZSF1 rats were randomly allocated to an aerobic exercise training group (n = 7; treadmill running, 5 days/week, 60 min/day, 15 m/min for 5 weeks) or to a sedentary group (n = 7). We used lean ZSF1 rats (n = 7) as the control group. After 5 weeks, rats were submitted to an exercise tolerance test and invasive haemodynamic evaluation, killed and samples from the RV collected for histological analysis. Obese sedentary ZSF1 rats showed lower V̇O2max , RV pressure overload (e.g., higher mean and maximum systolic pressure) and diastolic dysfunction (e.g., higher minimum and end-diastolic pressure and relaxation time constant), paralleled by RV cardiomyocyte hypertrophy. Except for cardiomyocyte hypertrophy, aerobic exercise prevented these functional changes. Our data support that this model of HFpEF shows functional and structural changes in the RV that resemble the human HFpEF phenotype, reinforcing its utility to understand this pathophysiology and to adress novel therapeutic targets to manage HFpEF. In addition, we showed that aerobic exercise is cardioprotective for the RV. A deeper knowledge of the mechanisms underlying the benefits of aerobic exercise could also lead to the identification of therapeutic targets to be further explored.

A directed network analysis of the cardiome identifies molecular pathways contributing to the development of HFpEF.

AIMS: The metabolic syndrome and associated comorbidities, like diabetes, hypertension and obesity, have been implicated in the development of heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms underlying the development of HFpEF remain to be elucidated. We developed a cardiome-directed network analysis and applied this to high throughput cardiac RNA-sequencing data from a well-established rat model of HFpEF, the obese and hypertensive ZSF1 rat. With this novel system biology approach, we explored the mechanisms underlying HFpEF. METHODS AND RESULTS: Unlike ZSF1-Lean, ZSF1-Obese and ZSF1-Obese rats fed with a high-fat diet (HFD) developed diastolic dysfunction and reduced exercise capacity. The number of differentially expressed genes amounted to 1591 and 1961 for the ZSF1-Obese vs. Lean and ZSF1-Obese+HFD vs. Lean comparison, respectively. For the cardiome-directed network analysis (CDNA) eleven biological processes related to cardiac disease were selected and used as input for the STRING protein-protein interaction database. The resulting STRING network comprised 3.460 genes and 186.653 edges. Subsequently differentially expressed genes were projected onto this network. The connectivity between the core processes within the network was assessed and important bottleneck and hub genes were identified based on their network topology. Classical gene enrichment analysis highlighted many processes related to mitochondrial oxidative metabolism. The CDNA indicated high interconnectivity between five core processes: endothelial function, inflammation, apoptosis/autophagy, sarcomere/cytoskeleton and extracellular matrix. The transcription factors Myc and Peroxisome Proliferator-Activated Receptor-α (Ppara) were identified as important bottlenecks in the overall network topology, with Ppara acting as important link between cardiac metabolism, inflammation and endothelial function. CONCLUSIONS: This study presents a novel systems biology approach, directly applicable to other cardiac disease-related transcriptome data sets. The CDNA approach enabled the identification of critical processes and genes, including Myc and Ppara, that are putatively involved in the development of HFpEF.

Early And Midterm Outcomes Following Aortic Valve Replacement With Mechanical Versus Bioprosthetic Valves In Patients Aged 50 To 70 Years.

OBJECTIVES: To compare 7-year survival and freedom from reoperation, as well as early clinical and hemodynamic outcomes, after surgical aortic valve replacement (SAVR) with mechanical or bioprosthetic valves in patients aged 50-70 years. METHODS: single-center retrospective cohort study including adults aged 50-70 years who underwent SAVR in 2012 with a mechanical or bioprosthetic valve. Median follow-up was 7 years. Univariable analyses were performed using Kaplan-Meier curves and Log-Rank tests for survival and freedom from reoperation analyses. Multivariable time-to-event analyses were conducted using Cox Regression. RESULTS: Of a total of 193 patients, 76 (39.4%) received mechanical valves and 117 (60.6%) received bioprosthetic valves. A trend for better survival was found for mechanical prostheses when adjusting for EuroSCORE II (HR: 0.35; 95%CI: 0.12-1.02, p=0.054), but using a backward stepwise Cox regression prosthesis type was not retained by the model as an independent predictor of survival. Moreover, mechanical prostheses showed trends for higher freedom from reoperation (100% vs. 95.5%, Log-Rank, p=0.076), higher median EuroSCORE II (2.52% vs. 1.95%, p=0.06) and early mortality (7.9% vs. 2.6%, p=0.086). However, after adjusting for EuroSCORE II, there was no significant difference in early mortality (OR: 2.3, 95%CI: 0.5-10.5, p=0.272). Regarding hemodynamic performance at follow-up echocardiogram, there were no differences other than left ventricular mass regression, which was not as pronounced in the mechanical group (-12% vs. -21%, p=0.002). CONCLUSION: Mechanical and bioprosthetic aortic valves prostheses showed similar mid-term survival in the 50-70 age group. Further prospective and larger studies are needed to provide evidence-based recommendations on this topic.

Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI).

To test whether remote ischaemic conditioning (RIC) as adjuvant to standard of care (SOC) would prevent progression towards heart failure (HF) after ST-elevation myocardial infarction (STEMI). Single-centre parallel 1:1 randomized trial (computerized block-randomization, concealed allocation) to assess superiority of RIC (3 cycles of intermittent 5 min lower limb ischaemia) over SOC in consecutive STEMI patients (NCT02313961, clinical trials.gov). From 258 patients randomized to RIC or SOC, 9 and 4% were excluded because of unconfirmed diagnosis and previously unrecognized exclusion criteria, respectively. Combined primary outcome of cardiac mortality and hospitalization for HF was reduced in RIC compared with SOC (n = 231 and 217, respectively; HR = 0.35, 95% CI 0.15-0.78) as well as each outcome in isolation. No difference was found in serum troponin I levels between groups. Median and maximum follow-up time were 2.1 and 3.7 years, respectively. In-hospital HF (RR = 0.68, 95% CI 0.47-0.98), need for diuretics (RR = 0.68, 95% CI 0.48-0.97) and inotropes and/or intra-aortic balloon pump (RR = 0.17, 95% CI 0.04-0.76) were decreased in RIC. On planned 12 months follow-up echocardiography (n = 193 and 173 in RIC and SOC, respectively) ejection fraction (EF) recovery was enhanced in patients presenting with impaired left ventricular (LV) function (10% absolute difference in median EF compared with SOC; P < 0.001). In addition to previously reported improved myocardial salvage index and reduced infarct size RIC was shown beneficial in a combined hard clinical endpoint of cardiac mortality and hospitalization for HF. Improved EF recovery was also documented in patients with impaired LV function.

Improvement in left intraventricular pressure gradients after aortic valve replacement in aortic stenosis patients.

NEW FINDINGS: What is the central question of this study? Normal diastolic and systolic intraventricular pressure gradients are decreased when left ventricular filling and/or emptying are compromised. We hypothesized that in patients with severe aortic valve stenosis, a condition that interferes with ventricular filling and emptying, those gradients would be disturbed. What is the main finding and its importance? We showed the existence of intraventricular pressure gradients throughout the cardiac cycle in the human left ventricle. Moreover, we demonstrated, for the first time, that diastolic and systolic gradients, which are markers of normal ventricular filling and emptying, respectively, improved in patients with severe aortic valve stenosis immediately after valve replacement. The present study was conducted to characterize left intraventicular pressure gradients, which are markers of normal cardiac function, in patients with severe aortic stenosis, a condition that interferes with ventricular filling and emptying. In 10 patients (four male; mean age 71.3 ± 4.8 years old) undergoing aortic valve replacement, two high-fidelity pressure catheters were inserted inside the cavity of the left ventricle through an apical puncture and positioned in the apex and outflow tract below the aortic valve. Pressures were continuously acquired and gradients calculated as apical minus outflow tract pressure, before and immediately after aortic valve replacement. During early filling, we recorded a negative intraventricular gradient along the basal portion of the left ventricle in the apical direction (-0.82 ± 0.45 mmHg), which increased to -3.97 ± 0.42 mmHg after aortic valve replacement. In late filling, intraventricular flow was now directed towards the outflow tract, with a positive pressure gradient both before (+1.23 ± 0.37 mmHg) and after surgery (+2.12 ± 0.58 mmHg). During systole, before surgery we observed a positive pressure gradient between the apex and outflow tract during both rapid (+1.60 ± 0.21 mmHg) and slow ejection phases (+1.68 ± 0.12 mmHg), whereas after aortic valve replacement the positive gradient (+1.54 ± 0.15 mmHg) during rapid ejection was inverted (-3.92 ± 0.34 mmHg) during the slow ejection phase. We demonstrated that in patients with severe aortic stenosis both diastolic and systolic intraventricular pressure gradients are significantly attenuated but can be restored immediately after aortic valve replacement. The assessment and measurement of intraventricular pressure gradients and their modulation in pathophysiological conditions may provide novel insights into cardiac physiology.

Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure.

Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SVi) in experimental HFpEF. Eighteen-week-old Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n = 8 each group) or closed-chest hemodynamic evaluation (CC, n = 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. End-diastolic stiffness (ßi) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum (P < 0.001), higher STF gain between end-diastolic volume and EDP, and impaired STF gain between EDP and SVi compared with both hypertensive ZSF1 Ln and normotensive WKY controls (P < 0.001). Likewise ßi was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis ßi and not Eesi correlated with impaired STF gain from EDP to SVi (P < 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher ßi prediction (P < 0.001). Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF.

Right ventricular end-diastolic stiffness heralds right ventricular failure in monocrotaline-induced pulmonary hypertension.

Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI). All underwent RV pressure-volume (PV) evaluation 24-34 days after MCT, under halogenate anesthesia and constant positive-pressure ventilation. End-diastolic stiffness (ßi), end-systolic elastance (Eesi), arterial elastance for indexed volumes (Eai), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Eai was the strongest determinant of CI, alongside ßi but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher ßi, along with low end-diastolic pressure (EDP) and stroke volume index (SVi) STF gain, denoting impaired preload reserve. On multivariate analysis ßi and not Eesi correlated with EDP-SVi STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SVi STF gain showed an area under curve of 0.84 for ßi prediction (P = 0.002). Afterload, impaired VVC and RV stiffness are major players in RV failure. RV stiffness can be assessed by STF gain analysis of respiratory fluctuations between EDP and SVi, which may constitute a prognostic tool in PH.

Echocardiography and invasive hemodynamics during stress testing for diagnosis of heart failure with preserved ejection fraction: an experimental study.

Inclusion of exercise testing in diagnostic guidelines for heart failure with preserved ejection fraction (HFpEF) has been advocated, but the target population, technical challenges, and underlying pathophysiological complexity raise difficulties to implementation. Hemodynamic stress tests may be feasible alternatives. Our aim was to test Trendelenburg positioning, phenylephrine, and dobutamine in the ZSF1 obese rat model to find echocardiographic surrogates for end-diastolic pressure (EDP) elevation and HFpEF. Seventeen-week-old Wistar-Kyoto, ZSF1 lean, and obese rats (n = 7 each) randomly and sequentially underwent (crossover) Trendelenburg (30°), 5 µg·Kg(-1)·min(-1) dobutamine, and 7.5 µg·Kg(-1)·min(-1) phenylephrine with simultaneous left ventricular (LV) pressure-volume loop and echocardiography evaluation under halogenate anesthesia. Effort testing with maximum O2 consumption (V̇o 2 max) determination was performed 1 wk later. Obese ZSF1 showed lower effort tolerance and V̇o 2 max along with higher resting EDP. Both Trendelenburg and phenylephrine increased EDP, whereas dobutamine decreased it. Significant correlations were found between EDP and 1) peak early filling Doppler velocity of transmitral flow (E) to corresponding myocardial tissue Doppler velocity (E') ratio, 2) E to E-wave deceleration time (E/DT) ratio, and 3) left atrial area (LAA). Diagnostic efficiency of E/DT*LAA by receiver-operating characteristic curve analysis for elevation of EDP above a cut-off of 13 mmHg during hemodynamic stress was high (area under curve, AUC = 0.95) but not higher than that of E/E' (AUC = 0.77, P = 0.15). Results in ZSF1 obese rats suggest that noninvasive echocardiography after hemodynamic stress induced by phenylephrine or Trendelenburg can enhance diagnosis of stable HFpEF and constitute an alternative to effort testing.

Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction.

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 ß, 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.

Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways.

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI. Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure-volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats. Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading. Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.

Exercise training impacts skeletal muscle remodelling induced by metabolic syndrome in ZSF1 rats through metabolism regulation.

Metabolic syndrome (MetS), characterized by a set of conditions that include obesity, hypertension, and dyslipidemia, is associated with increased cardiovascular risk. Exercise training (EX) has been reported to improve MetS management, although the underlying metabolic adaptations that drive its benefits remain poorly understood. This work aims to characterize the molecular changes induced by EX in skeletal muscle in MetS, focusing on gastrocnemius metabolic remodelling. 1H NMR metabolomics and molecular assays were employed to assess the metabolic profile of skeletal muscle tissue from lean male ZSF1 rats (CTL), obese sedentary male ZSF1 rats (MetS-SED), and obese male ZF1 rats submitted to 4 weeks of treadmill EX (5 days/week, 60 min/day, 15 m/min) (MetS-EX). EX did not counteract the significant increase of body weight and circulating lipid profile, but had an anti-inflammatory effect and improved exercise capacity. The decreased gastrocnemius mass observed in MetS was paralleled with glycogen degradation into small glucose oligosaccharides, with the release of glucose-1-phosphate, and an increase in glucose-6-phosphate and glucose levels. Moreover, sedentary MetS animals' muscle exhibited lower AMPK expression levels and higher amino acids' metabolism such as glutamine and glutamate, compared to lean animals. In contrast, the EX group showed changes suggesting an increase in fatty acid oxidation and oxidative phosphorylation. Additionally, EX mitigated MetS-induced fiber atrophy and fibrosis in the gastrocnemius muscle. EX had a positive effect on gastrocnemius metabolism by enhancing oxidative metabolism and, consequently, reducing susceptibility to fatigue. These findings reinforce the importance of prescribing EX programs to patients with MetS.

Human-umbilical cord matrix mesenchymal cells improved left ventricular contractility independently of infarct size in swine myocardial infarction with reperfusion.

Background: Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine. Methods: In a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing. Results: As compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = -2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC. Conclusion: Intracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease.

In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP(iso)) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP(iso) (r = -0.96), and directly related to changes in the time constant of relaxation τ (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP(iso) (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterload-induced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P < 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading.

Prospective randomised comparison of Marsh and Schnider pharmacokinetic models for propofol during induction of anaesthesia in elective cardiac surgery.

CONTEXT: Haemodynamic stability during induction is a cornerstone of cardiac anaesthesia. The evaluation of pharmacokinetic models for propofol during induction is lacking. OBJECTIVE: To compare haemodynamics during cardiac anaesthesia induction with two pharmacokinetic models. DESIGN: Randomised controlled trial. SETTING: Department of Cardiothoracic Surgery, São João Hospital; July to December 2010. PATIENTS: Ninety consecutive elective adult cardiac surgical patients. INTERVENTION: Random assignment to effect-site target-controlled infusion by Marsh (n = 45) or Schnider (n = 45) pharmacokinetic models with an equilibration constant of 1.2 min(-1) adapted to Marsh's model. Invasive blood pressure measurements, propofol dose, and bispectral index (BIS) were recorded. After an initial target concentration of 1.5 µg ml(-1), concentrations were upward-titrated in 0.5 µg ml(-1) increments until the BIS was <50. RESULTS: No differences were observed between Marsh and Schnider models in required propofol dose (0.99 ± 0.26 vs. 0.93 ± 0.31 mg kg(-1), P = 0.322), decrease in mean blood pressure (25 ± 13 vs. 22 ± 14%, P = 0.192) or the need for vasopressors (20 vs. 24%, P = 0.800), but the use of the Marsh model resulted in a lower predicted effect-site concentration (2.3 ± 0.4 vs. 2.7 ± 0.6 µg ml(-1), P = 0.006) and shorter time to induction (296 ± 59 vs. 338 ± 87 s, P = 0.024). There was a greater decrease in mean blood pressure in older patients (>60 years; 29 ± 10 vs. 22 ± 11%, P = 0.004) irrespective of model, but obese (BMI ≥30 kg m(-2)) and nonobese patients did not differ. MAIN OUTCOME MEASURES: Decrease in mean blood pressure. CONCLUSION: In effect-site targeting with a 1.2 min(-1) equilibration constant, Marsh's model is comparable to Schnider's during induction of anaesthesia.

Multiple versus single arterial grafting in the elderly: a meta-analysis of randomized controlled trials and propensity score studies.

INTRODUCTION: The benefit of adding a second arterial conduit is still controversial, mainly in specific subgroups. We conducted a meta-analysis of randomized controlled trials (RCTs) and propensity score (PS) studies comparing survival and early results in elderly patients who underwent coronary artery bypass grafting (CABG) with multiple (MAG) versus single arterial grafting (SAG). EVIDENCE ACQUISITION: MEDLINE, Web of Science and Cochrane Library were used to find relevant literature (1960-April 2020). Survival at a ≥1-year follow-up and early outcomes were evaluated. Outcomes were collected from matched samples or PS adjusted analysis: hazard ratio (HR) along with their variance, frequencies or odds ratios. Random effect models were used to compute combined statistical measures and 95% confidence intervals (CI) through generic inverse variance method (time-to-event) or Mantel-Haenszel method (binary events). EVIDENCE SYNTHESIS: Eleven PS cohorts and 1 RCT comprising >18,800 patients older than 70 (>6200 MAG and >12,500 SAG) were included in this meta-analysis. MAG was associated with lower long-term mortality (pooled HR: 0.81, 95% CI: 0.72-0.91, P<0.01, I2=64%) in the absence of higher risk of early mortality (pooled OR: 0.74, 95% CI: 0.44 to 1.25, P=0.27, I2=0%). In a meta-regression, MAG survival advantage was more pronounced in studies with a higher MAG usage rate (ß=-0.0052, P=0.021). CONCLUSIONS: Current evidence suggests that advanced age should not limit MAG's use considering its benefits in long-term survival. Of note, an individualized patient selection for this approach is warranted.