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.

Transcatheter Tricuspid Valve Replacement: Illustrative Case Reports and Review of State-of-Art.

Tricuspid regurgitation (TR) is one of the most common heart valve diseases, associated a with poor prognosis since significant TR is associated with an increased mortality risk compared to no TR or mild regurgitation. Surgery is the standard treatment for TR, although it is associated with high morbidity, mortality, and prolonged hospitalization, particularly in tricuspid reoperation after left-sided surgery. Thus, several innovative percutaneous transcatheter approaches for repair and replacement of the tricuspid valve have gathered significant momentum and have undergone extensive clinical development in recent years, with favorable clinical outcomes in terms of mortality and rehospitalization during the first year of follow-up. We present three clinical cases of transcatheter tricuspid valve replacement in an orthotopic position with two different innovative systems along with a review of the state-of-the-art of this emergent topic.

A new era in patent foramen ovale closure - a percutaneous suture-based 'deviceless' technique (NobleStitch®): Experience of a Portuguese center.

INTRODUCTION: In patients with cryptogenic stroke, one of the most frequently found abnormalities is patent foramen ovale (PFO). Percutaneous 'deviceless' systems based on surgical suture-mediated PFO closure have recently been introduced and show a favorable efficacy and safety profile with clear advantages. OBJECTIVES: To present procedural details of the technique and baseline characteristics of patients who underwent the procedure in our center. METHODS: A single-center prospective observational registry was established between February 2020 and February 2021, to assess the safety, efficacy and possible advantages of a novel percutaneous PFO closure system (NobleStitch® EL). Patient and PFO characteristics as well as technical features were collected for analysis. RESULTS: Twenty-three patients were considered suitable for this technique after transesophageal echocardiography. Their mean age was 51 years and 69.5% were women. Most patients (91.3%) had a history of cryptogenic stroke. PFO closure with the NobleStitch® system was successfully performed in all patients. All procedures were performed under local anesthesia and fluoroscopic monitoring. The mean duration of the procedure was 52 min and median contrast dose used was 187 ml. Median radiation dose absorbed per patient was 61.5 Gy cm2. All patients were discharged asymptomatic 24 hours after the procedure with no peri- or postprocedural complications recorded. CONCLUSION: Suture-mediated PFO closure represents a valid and safe alternative to traditional umbrella-like devices, and is feasible in the majority of PFO anatomies. Follow-up information, results of larger series and clinical trials may possibly validate this technique as the first choice for PFO closure.

Coronary artery fistulas: A 12-year single-center experience.

INTRODUCTION AND OBJECTIVES: Coronary artery fistulas (CAFs) are rare abnormalities, often detected incidentally during invasive coronary angiography (ICA). While most are clinically silent, they can cause significant morbidity. We aimed to investigate the clinical, angiographic and management features of CAFs in a population undergoing ICA. METHODS: We retrospectively reviewed the data of all ICAs conducted in our department between May 2008 and January 2020 and selected those with CAFs. Clinical, angiographic, therapeutic and follow-up data were obtained from medical records. RESULTS: A total of 55 patients with CAFs (35 male, median age 64 years) were identified among 32 174 ICAs. The majority (n=37) had a single fistula. CAFs arose most frequently from the left anterior descending artery (LAD), followed by the right coronary and left circumflex coronary arteries. The most frequent drainage site was the pulmonary artery. Fourteen patients had fistulas originating from both left and right coronary systems. Seven had concomitant congenital cardiovascular disorders. The majority (n=40) were incidental findings. Chest pain was the most common symptom attributable to CAFs and heart murmur the most frequent sign. Conservative management was the main approach (n=40). Eight patients underwent transcatheter closure and seven underwent surgical ligation (six of those during surgery for another heart condition), with no periprocedural mortality. CONCLUSIONS: In our series, the prevalence of CAFs was 0.2%. The majority originated from the LAD and the pulmonary artery was the main drainage site. In patients undergoing intervention, both percutaneous and surgical techniques were safe and effective.

Does the type of seizure influence heart rate variability changes?

OBJECTIVE: Heart rate variability (HRV), an index of the autonomic cardiac activity, is decreased in patients with epilepsy, and a low HRV is associated with a higher risk of sudden death. Generalized tonic-clonic seizures are one of the most consistent risk factors for SUDEP, but the influence (and relative risk) of each type of seizure on cardiac function is still unknown. Our objective was to assess the impact of the type of seizure (focal to bilateral tonic-clonic seizure - FBTCS - versus non-FBTCS) on periictal HRV, in a group of patients with refractory epilepsy and both types of seizures. METHODS: We performed a 48-hour Holter recording on 121 patients consecutively admitted to our Epilepsy Monitoring Unit. We only included patients with both FBTCS and non-FBTCS on the Holter recording and selected the first seizure of each type to analyze. To evaluate HRV parameters (AVNN, SDNN, RMSSD, pNN20, LF, HF, and LF/HF), we chose 5-min epochs pre- and postictally. RESULTS: We included 14 patients, with a median age of 36 (min-max, 16-55) years and 64% were female. Thirty-six percent had cardiovascular risk factors, but no previously known cardiac disease. In the preictal period, there were no statistically significant differences in HRV parameters, between FBTCS and non-FBTCS. In the postictal period, AVNN, RMSSD, pNN20, LF, and HF were significantly lower, and LF/HF and HR were significantly higher in FBTCS. From preictal to postictal periods, FBTCS elicited a statistically significant rise in HR and LF/HF, and a statistically significant fall in AVNN, RMSSD, pNN20, and HF. Non-FBTCS only caused statistically significant changes in HR (decrease) and AVNN (increase). SIGNIFICANCE/CONCLUSION: This work emphasizes the greater effect of FBTCS in autonomic cardiac function in patients with refractory epilepsy, compared to other types of seizures, with a significant reduction in vagal tonus, which may be associated with an increased risk of SUDEP.

Heart rate variability in patients with refractory epilepsy: The influence of generalized convulsive seizures.

OBJECTIVE: Patients with epilepsy, mainly drug-resistant, have reduced heart rate variability (HRV), linked to an increased risk of sudden death in various other diseases. In this context, it could play a role in SUDEP. Generalized convulsive seizures (GCS) are one of the most consensual risk factors for SUDEP. Our objective was to assess the influence of GCS in HRV parameters in patients with drug-resistant epilepsy. METHODS: We prospectively evaluated 121 patients with refractory epilepsy admitted to our Epilepsy Monitoring Unit. All patients underwent a 48-hour Holter recording. Only patients with GCS were included (n = 23), and we selected the first as the index seizure. We evaluated HRV (AVNN, SDNN, RMSSD, pNN50, LF, HF, and LF/HF) in 5-min epochs (diurnal and nocturnal baselines; preictal - 5 min before the seizure; ictal; postictal - 5 min after the seizure; and late postictal - >5 h after the seizure). These data were also compared with normative values from a healthy population (controlling for age and gender). RESULTS: We included 23 patients, with a median age of 36 (min-max, 16-55) years and 65% were female. Thirty percent had cardiovascular risk factors, but no previously known cardiac disease. HRV parameters AVNN, RMSSD, pNN50, and HF were significantly lower in the diurnal than in the nocturnal baseline, whereas the opposite occurred with LF/HF and HR. Diurnal baseline parameters were inferior to the normative population values (which includes only diurnal values). We found significant differences in HRV parameters between the analyzed periods, especially during the postictal period. All parameters but LF/HF suffered a reduction in that period. LF/HF increased in that period but did not reach statistical significance. Visually, there was a tendency for a global reduction in our patients' HRV parameters, namely AVNN, RMSSD, and pNN50, in each period, comparing with those from a normative healthy population. No significant differences were found in HRV between diurnal and nocturnal seizures, between temporal lobe and extra-temporal-lobe seizures, between seizures with and without postictal generalized EEG suppression, or between seizures of patients with and without cardiovascular risk factors. SIGNIFICANCE/CONCLUSION: Our work reinforces the evidence of autonomic cardiac dysfunction in patients with refractory epilepsy, at baseline and mainly in the postictal phase of a GCS. Those changes may have a role in some SUDEP cases. By identifying patients with worse autonomic cardiac function, HRV could fill the gap of a lacking SUDEP risk biomarker.

Comparison of levosimendan, NO, and inhaled iloprost for pulmonary hypertension reversibility assessment in heart transplant candidates.

AIMS: Assessing reversibility of pulmonary vascular changes through vasoreactivity testing (VRT) optimizes end-stage heart failure patient selection for heart transplant. All efforts should be made to unload the left ventricle and reduce pulmonary vascular resistance to effectively exclude irreversible pulmonary hypertension. METHODS AND RESULTS: We reviewed our centre's cardiac transplant registry database (2009-2017) for VRT and compared haemodynamic responses with 40 ppm inhaled NO (n = 14), 14-17 µg inhaled iloprost (n = 7), and 24 h 0.1 µg/kg/min intravenous levosimendan (n = 14). Response to levosimendan was assessed by repeat right heart catheterization within 72 h. Baseline clinical and haemodynamic features were similar between groups. VRT was well tolerated in all patients. All drugs effectively reduced pulmonary artery pressures and transpulmonary gradient while increasing cardiac index, although levosimendan had a greater impact on cardiac index increase (P = 0.036). Levosimendan was the only drug that reduced pulmonary artery wedge pressure (P = 0.004) and central venous pressures (P < 0.001) and increased both left and right ventricular stroke work indexes (P = 0.020 and P = 0.042, respectively) and cardiac power index (P < 0.001) compared with NO and iloprost. Right ventricular end-diastolic pressures and central venous pressure were only decreased by levosimendan. The rate of positive responses (≥10 mmHg decrease or final mean pulmonary artery pressure ≤40 mmHg with increased/unaltered cardiac index) was lower with inhaled iloprost (14%) than with either levosimendan or NO (71% and 64%, respectively; P < 0.05). CONCLUSIONS: Levosimendan may be a safe and effective alternative for pulmonary hypertension reversibility assessment or a valuable pre-test medical optimization tool in end-stage heart failure patient assessment for heart transplantation offering extended haemodynamic benefits. Whether it increases the rate of positive responses or allows a better selection of candidates to heart transplantation remains to be established.

Left ventricular pacing with a temporary pacemaker: Case report.

We report a case of temporary pacemaker lead malposition in the left ventricle crossing the interventricular septum (IVS). The majority of described cases occur due to a patent foramen ovale and are frequently incidental findings. A course across the IVS is rarely found and this complication with temporary leads is not even reported in the literature. This very rare location entails a risk of dangerous complications associated with left-to-right flow after lead removal. Echocardiography was an essential tool to diagnose the lead's course inside the heart and enabled secure removal of the lead with cardiac surgery backup.

Myocardial dysfunction in Takotsubo syndrome: More than meets the eye?

INTRODUCTION: Takotsubo syndrome (TTS) is characterized by transient left ventricular (LV) dysfunction, typically mimicking an anterior wall myocardial infarction (MI), without obstructive coronary artery disease. In the few published reports assessing myocardial deformation in TTS and MI, no consistent differences have been described between the two entities. We sought to characterize global and regional function in TTS and to compare it with a population with MI. METHODS: Clinical data, including echocardiography, were gathered from 17 TTS patients and 20 anterior wall ST-segment elevation myocardial infarction (STEMI) controls. Peak systolic longitudinal strain was determined for each LV segment using speckle tracking imaging, and global and mean apical, midventricular and basal longitudinal strain were calculated from these. RESULTS: Both TTS and STEMI patients presented significant LV systolic dysfunction, and there were no significant differences in ejection fraction or global longitudinal strain. Regional longitudinal strain was more severely impaired in basal inferolateral and mid anterolateral segments in the TTS group and in apical anteroseptal segments in the STEMI group. Mean longitudinal strain was worse in the basal segments of TTS patients (-9.8±2.9 vs. -12.4±4.1%, p=0.010), with no significant differences in mid and apical segments. The basal/apical ratio was significantly lower in this group as well (1.51±0.86 vs. 2.94±1.88, p=0.006). CONCLUSIONS: While both TTS and STEMI feature significantly impaired global systolic function, we found a regional pattern of worse basal longitudinal strain and a lower basal/apical ratio in the former. These suggest generalized myocardial impairment in TTS, providing new clues about its pathophysiology and possible specific echocardiographic changes.

Dose-Response Head-to-Head Comparison of Inodilators Dobutamine, Milrinone, and Levosimendan in Chronic Experimental Pulmonary Hypertension.

The choice of inodilator drug in the acute management of patients with pulmonary hypertension (PH) having right ventricular (RV) failure remains unsettled and challenging. Comprehensive experimental evaluations may provide further insight and fundamental translational research clues to support inodilator selection and clinical trial design. Our aim was to compare acute dose-response hemodynamic effects of inodilators dobutamine (DOB), milrinone (MIL), and levosimendan (LEV) in chronic experimental PH. Seven-week-old male Wistar rats were randomly injected with 60 mg·kg-1 monocrotaline (MCT) or vehicle (Ctrl, n = 7) and underwent systemic and pulmonary artery (PA) pressure and RV pressure-volume (PV) hemodynamic evaluation under halogenate anesthesia 24 to 30 days after injection. The MCT-injected animals (n = 7 each) randomly received dose-response infusions of DOB (1, 3, 6 and 12 µg·kg-1·min-1), MIL (MIL: 1, 3, 6 and 12 µg·kg-1·min-1), or LEV (0.3, 0.6, 1.2 and 2.4 µg·kg-1·min-1). Load-independent indexes were obtained by inferior vena cava occlusion at baseline and after the last dose. All inodilators increased RV ejection fraction, preload recruitable stroke work, and ventricular-vascular coupling without jeopardizing perfusion pressure. Dobutamine raised heart rate and PA pressure. Only LEV increased cardiac index and decreased PA elastance and pulmonary vascular resistance (PVR). Moreover, only LEV downward-shifted the end-diastolic PV relationship, thereby improving RV compliance. Adding sildenafil to LEV further decreased PVR. Levosimendan had beneficial acute systolic and diastolic functional effects in experimental chronic PH and RV afterload compared to DOB and MIL. It should be further tested in clinical trials enrolling patients with PH in the perioperative and critical care settings.

Cardiac Catheterization After CABG With BIMA Grafting: Independent Predictors and Mid-term Bypass Viability.

INTRODUCTION: Coronary artery bypass graft (CABG) patency is an important variable, but rarely studied as the main outcome. The best use of bilateral internal mammary artery (BIMA) grafting regarding configuration type or combination with saphenous vein graft (SVG) is still debated. PURPOSE: To find independent predictors for need of cardiac catheterization and for significant lesions in CABG follow-up. METHODS: Retrospective cohort including all patients who underwent isolated CABG with BIMA grafts between 2004 and 2013 in a tertiary center. Preoperative, surgical and postoperative data were collected through clinical files and informatics databases. Kaplan-Meier curves, Cox regression and logistic regression were used to find predictors for the need of catheterization and for significant angiographic lesions after CABG. Secondary end-points studied were mid- term survival and need of re-revascularization either surgically or percutaneously. RESULTS: We included 1030 patients in this analysis. Median follow-up time was 5.5 years and 150 (15%) patients were re-catheterized in that period. Most of these procedures was due to ischemia suspicion (74%) and 61 (41%) were positive for significant angiographic lesions of conduits (IMA: 3.2% and SVG: 3.8%, p=0.488). In multivariate analysis, SVG use was found as an independent predictor of cardiac catheterization on follow-up (HR: 1.610, CI 95%: 1.038-2.499, p=0.034). On the other side, independent predictors of graft lesions were younger age (OR: 0.951, CI 95%: 0.921-0.982, p=0.002), female gender (OR: 2.231, CI 95%: 1.038-4.794, p=0.040), arterial hypertension (OR: 1.968, CI 95%: 1.022-3.791, p=0.043) and 3-vessel disease (OR: 2.820, CI 95%: 1.155-6.885, p=0.023). Among the patients with significant angiographic lesions, 48 underwent repeat revascularization (44 PCI e 4 CABG). Arterial hypertension and younger age were independent predictors of re-revascularization. CONCLUSION: In BIMA patients the addition of SVG predicts the need of catheterization; however prevalence of significant angiographic lesions was similar in IMA and SVG. Our results suggest that arterial hypertension is an independent predictor of graft patency and re-revascularization rate.

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.

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.

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.

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.

Levosimendan: The current situation and new prospects.

Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance. In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions. This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug.

Myocardial and anti-inflammatory effects of chronic bosentan therapy in monocrotaline-induced pulmonary hypertension.

INTRODUCTION AND OBJECTIVES: Endothelin-1 antagonists are increasingly used in the treatment of pulmonary hypertension despite the lack of knowledge of their myocardial and systemic effects. We assessed the right ventricular myocardial and systemic effects of endothelin-1 antagonists in monocrotaline-induced pulmonary hypertension. METHODS: Male Wistar rats (180-200 g, n=57) randomly received 60 mg/kg monocrotaline or vehicle subcutaneously. Two days later, bosentan was randomly started (300 mg/kg/day) by oral route in a subgroup of monocrotaline-injected rats, while the other monocrotaline-injected and control rats received vehicle. At 25-30 days, invasive hemodynamic assessment was performed under anesthesia, arterial blood samples were collected for gas analysis and plasma was extracted for quantification of endothelin-1, cytokines, nitrates and 6-keto-prostaglandin F1α. Right ventricular myocardium was collected for assessment of cyclooxygenase and nitric oxide synthase activity and gene expression. RESULTS: The monocrotaline group developed pulmonary hypertension, low cardiac output, right ventricular hypertrophy and dilation, changes in gene expression and inflammatory activation that were attenuated in the group treated with bosentan. From a functional point of view, this group had improved right ventricular function and preserved ventriculo-vascular coupling, without deterioration in arterial gas parameters or systemic hypotension. In molecular terms, they showed reduced endothelin-1 and cytokine levels, decreased right ventricular inducible nitric oxide synthase and cyclooxygenase-2 activity and increased nitrate plasma levels compared with the non-treated group. CONCLUSIONS: In this study we demonstrate that besides attenuating pulmonary hypertension, bosentan has beneficial hemodynamic, myocardial and anti-inflammatory effects.