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Clinical implications of systemic atherosclerosis in patients with cardiogenic shock (CS) remain unclear. This study investigated the association between polyvascular disease (PVD) and clinical outcome in CS patients.A total of 1247 CS patients was enrolled from the RESCUE registry, a multicenter, observational cohort between January 2014 and December 2018. They were divided into two groups according to presence of PVD, defined as ≥2 coexistence of coronary artery disease, peripheral arterial disease, or cerebrovascular disease. Primary outcome was all-cause death during 12 months of follow-up.136 (10.9%) patients were diagnosed with PVD. The risk of 12-month all-cause death was significantly higher in the PVD group than in the non-PVD group (54.4% versus 40.4%, adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.02-1.69, p = 0.034). There was a significant interaction between PVD and vasoactive inotropic score (VIS) (p for interaction = 0.014). Among the 945 patients with VIS84, PVD was associated with a higher risk of 12-month all-cause death (unadjusted HR 1.77, 95% CI 1.30-2.41, p = 0.030); among the 302 patients with VIS ≥84, the incidence of 12-month all-cause death was similar between the PVD and non-PVD groups (unadjusted HR 1.03, 95% CI 0.68-1.56, p = 0.301).Presence of PVD was associated with 12-month all-cause mortality in patients with CS, especially for less severe forms of CS patients with VIS84. Clinicaltrials.govnumber:NCT02985008.

Background Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). Methods and results 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up. Conclusion Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.

Background: Worsening heart failure complicated by congestion, hypotension, and renal dysfunction is difficult to manage, increasingly common and predicts a poor outcome. Novel therapies are required to facilitate diuresis and implementation of disease-modifying interventions in preparation for hospital discharge. Accordingly, we investigated the haemodynamic and renal effects of the Reitan Catheter Pump (RCP) percutaneous support device in patients admitted with decompensated heart failure (DHF). Methods: This was a prospective observational study of 20 patients admitted with DHF, ejection fraction < 30%, and Cardiac index (CI) < 2.1 L/min/m2 in need of inotropic/mechanical support. Results: Patients underwent RCP support for a mean of 18.3 (±6.3) hours. The RCP increased CI from 1.84 L/min/m2 (±0.27), to 2.41 L/min/m2 (±0.45, p = 0.04), increased urine output (71 mL/h (±65) to 227 ml/h (±179) (p = 0.006) with a concomitant reduction in serum creatinine (188 μmol/L (±87) to 161 μmol/L (±78) (p = 0.0007). There were no clinically significant haemolysis, vascular injury, or thrombo-embolic complications. Conclusions: For patients admitted with DHF, the RCP improves cardiac index, diuresis and renal function without causing important complications.

Background Right heart failure remains a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. Multiple 2D echocardiography derived parameters are associated with right ventricular failure (RV failure), but none of them has been proven to be a reliable predictor to date. We hypothesized that novel 3D-echocardiography (3DE) based parameters are associated with RV failure and predict long term outcome in patients undergoing LVAD implantation. Methods This single-center study retrospectively enrolled 26 patients undergoing continuous-flow LVAD implantation. RV failure was defined as prolonged inotropic support for >14 days after LVAD implantation or consecutive implantation of a right ventricular assist device. Based on transesophageal 3DE datasets acquired prior to surgery right ventricular size, ejection fraction and longitudinal strains were calculated. Results The overall RV failure rate was 19.2%. Patients suffering from RV failure had a significantly impaired 3D-right ventricular ejection fraction (3D-RVEF; 28 ± 2% vs. 19 ± 3%, p = 0.0145) and 3D derived RV free wall longitudinal strain (3D-RV-fws; −13.2 ± 0.97% vs. −6.4 ± 1.98%; p = 0.0056) when compared to patients without RV failure. ROC analysis for 3D-RV-fws (AUC 0.914) and 3D-RVEF (AUC 0.876) showed high discriminative capabilities in regard to detection of RV failure. Kaplan-Meier analysis showed an improved long-term survival of patients with a 3D-RV-fws Conclusions 3D-echocardiography derived RV ejection fraction and RV free wall strain are associated with right ventricular failure and long term outcome in patients undergoing LVAD implantation. These parameters have the potential to be future predictors for right heart failure in LVAD surgery.

Myeloid differentiation factor-2 (MD-2) has been shown to be an important modulator of the innate immune system, but its role in cardiac diseases is unknown. We investigated whether MD-2 plays a role as risk predictor and contributor in dilated cardiomyopathy (DCM).We included 174 patients with reduced left ventricular (LV) ejection fraction (LVEF45%) due to DCM. Coronary artery disease and severe valvular diseases were excluded in all patients by angiography or echocardiography. Cardiac inflammation, viral infection and MD-2 expression were analyzed from right ventricular endomyocardial biopsies. MD-2 was quantified by ELISA in serum upon first hospital admission. Myocyte contractility and inflammatory response after stimulation with recombinant MD-2 protein were analyzed in isolated rat cardiomyocytes. Median follow-up of the patients was 3.51 years (2.73; 4.48) with 34 deaths. Absolute mortality risk increases in patients displaying a MD-2 serum concentration greater than the median (302 ng/ml) was 23% (P 0.0001). Age- and sex-adjusted Cox regression analyses demonstrated that mortality risk was highly related to MD-2 concentrations (P 0.001), but not to age or sex. An increase of 100 ng/ml in the MD-2 level was associated with an absolute mortality risk increase of 50.4%. Receiver operating characteristic (ROC) analyses showed no difference between MD-2 and nterminal-pro brain natriuretic peptide (NT-pro-BNP), while the combination of both MD-2 and NT-pro-BNP resulted in a significantly increased capability of risk prediction when compared to NT-pro-BNP alone (P = 0.014). In-vitro, recombinant MD-2 decreases cell shortening and modulates cytokine activation in isolated cardiomyocytes.MD-2 predicts long-term outcome in DCM patients and improves mortality risk prediction capability compared to NT-pro-BNP alone. In addition, MD-2 exerts direct negative inotropic effects on isolated cardiomyocytes in-vitro. Further randomized trials should confirm MD-2 as a diagnostic and therapeutic target.

Objectives Purpose of this study is to evaluate the clinical significance of major aortopulmonary collateral arteries (MAPCAs) during the early postoperative course after arterial switch operation (ASO) in d-transposition of the great arteries (dTGA). Methods Clinical data of 98 patients with simple dTGA between January 2007 and December 2016 at the University Children's Hospital Zurich, Switzerland were analyzed retrospectively. Results 37 from 98 patients (38%) required cardiac catheterization (CC) due to an early complicated postoperative course or difficult coronary transfer due to special coronary anatomy. In 15 (15%) patients, hemodynamically relevant MAPCAs were found during CC and coil embolization was performed. Patients with relevant MAPCAs had a significantly longer PICU stay (7 versus 6 days, p = 0.021), longer hospital stay (41 versus 27 days, p = 0.005), longer mechanical ventilation time (5 versus 3 days, p = 0.005), longer need for inotropic support (5 versus 4 days, p = 0.001) and delayed chest closure time (3 versus 2 days, p = 0.030) in those in whom it was left open in comparison to all other patients. In patients having CC, pre-surgery oxygen saturation was significantly lower in patients with relevant MAPCAs (58% vs 70%, p 0.019). Echocardiography had a sensitivity of 53% and a specificity of 100% in detecting relevant MAPCAs, accurately. Conclusions MAPCAs are frequently found in dTGA patients and can be associated with lower baseline oxygen saturation and a prolonged postoperative course after ASO. Transthoracic echocardiography cannot replace CC as diagnostic tool. If significant MAPCAs are suspected, early CC should be performed for diagnostic and therapeutic reasons.

Background Targeted treatment for decompensated right heart failure (RHF) with or without left heart failure is lacking. Vasopressin antagonists (vaptans) may offer an option by increasing urine output and fluid mobilization when used in acute decompensated RHF without impacting blood pressure or renal function, both common complications of loop diuretics. Methods and results We searched electronic medical records from 2 institutions over 4 years for patients with RHF treated with vaptans. Urine output, creatinine, BUN and sodium, 1 day pre- versus 1 day post-vaptan initiation were compared. Baseline (admission) pre-vaptan values for patients with RHF who met inclusion criteria (n = 112) were RAP, median (interquartile range) = 19 (13–24) mmHg; cardiac index, mean ± standard deviation = 1.8 ± 0.4 L/min/m2; BNP, 1078 (523–1690) pg/ml; creatinine clearance of 51 (39–69) ml/min, BUN, 37 (26–54) mg/dl, and serum [Na+] 132 (126–135) mEq/L. Most patients (n = 103/112) received intravenous inotrope (prior to vaptan, n = 91). Overall length of stay was 27 (16–43) days. Vaptan treatment (90% tolvaptan, 10% conivaptan) was associated with increased 24 h urine output, 1517 (906–2394) vs 2337 (1425–3744) mL, p = 0.005, and [Na+], 127 (124–130) vs 130 (126–135) mEq/L, p = 0.001, without significant change in Cr or BUN. Furosemide IV dose equivalent decreased or remained unchanged in 75% of patients at 24 h and 64% at 72 h compared to the 24 h prior to vaptan use. Conclusion Vaptans were associated with a significant increase in urine output and serum sodium with an apparent reduction or stabilization of furosemide equivalent dosing in the early treatment period in patients with decompensated RHF. Vaptans may offer a management option for patients failing conventional diuretic-based treatment.

Guidelines recommend serial fetal echocardiograms when congenital heart disease is diagnosed. Necessity, timing, and frequency of serial echocardiograms are based on clinical judgment. Fetuses with hypoplastic left heart syndrome (fHLHS) may undergo multiple studies prior to birth. Goal of this study was to determine if the need for unexpected, emergent cardiac interventions were required immediately post-natally, if there were no concerns on initial fetal echocardiogram. Methods Fetal echocardiograms performed between 2006 and 2018 on fHLHS were reviewed. fHLHS were excluded if initial fetal scan documented any other concerns. Unexpected, emergent catheterization or surgical procedures, intubation, or inotropic support within the first 72 h of life were recorded. Results Total of 80 fHLHS were reviewed. Thirty-two fHLHS were excluded because of concerns on the initial fetal echocardiogram. Sixteen fHLHS had one scan, 14 had two scans, 13 had three scans, and 5 had four scans. No patient underwent an unexpected, emergent catheterization or surgical procedure within the first 72 h of life. Seven patients required intubation and 1 patient received inotropic support within the first 72 h of life. Conclusion No fHLHS underwent an unexpected, emergent catheterization or surgical procedure within the first 72 h of life if the initial fetal echocardiogram had no significant concerns. Medical interventions did occur immediately post-natally, but could not be directly attributed to a missed fetal cardiac diagnosis. Frequent serial fetal echocardiograms may not necessarily be needed to predict the need for an unexpected, emergent procedure.

Acute heart failure (AHF) after ST-segment elevation myocardial infarction (STEMI) is usually treated with inotropic support or vasoactive medications. In this study, we aimed at investigating the role of levosimendan on cardiovascular determinants of contractility and afterload in patients with AHF following STEMI treated with percutaneous coronary intervention (PCI).Forty-eight consecutive STEMI patients were retrospectively enrolled. Non-invasive assessment of left ventricular elastance (Ees) and arterial elastance (Ea) and their relationship, ventriculo-arterial coupling (VAC) was performed before and after levosimendan infusion.After infusion of levosimendan a significant increase in SV was detected in all patients (from 48 ± 17 to 60 ± 21 ml, p 0.001). VAC slightly decreased from 1.74 ± 0.8 to 1.66 ± 0.7 (p = NS) as a result of a profound reduction in arterial elastance (Ea 2.34 ± 1.09 to 1.74 ± 0.5 mm Hg/ml, p 0.001) and in ventricular elastance (Ees 1.57 ± 0.12 to 1.24 ± 0.09 mm Hg/ml, p = 0.021). Ejection fraction (EF) (from 0.29 ± 0.1 to 0.32 ± 0.1, p 0.01) and WMSI, (from 2.16 ± 0.47 to 2.05 ± 0.54, p 0.05) also, significantly improved. Finally, baseline VAC was able to predict the use of norepinephrine (NE) and early and one-year mortality of patients treated.In STEMI patients with AHF the use of levosimendan significantly increases stroke volume after 24-hour treatment through Ea reduction. Baseline VAC seemed to predict early and late mortality and early and prolonged use of NE, however, this needs to be tested in larger series of patients and multivariate adjustments for other prognostic predictors.

This study examines the clinical utility of plasma neutrophil gelatinase-associated lipocalin (NGAL) as an indicator of myocardial dysfunction and mortality in severe sepsis and septic shock.We designed a prospective cohort study in an intensive care unit, and 53 patients with severe sepsis or septic shock were included. Data were used to determine a relationship between NGAL and the development of myocardial dysfunction and mortality. These associations were determined by the Mann-Whitney test, multiple logistic regression, plotting the receiver operating characteristic (ROC) curve, Kaplan-Meier curves and Spearman test.The High NGAL group had higher need for inotropic/vasopressor support (92% vs. 52%, p=0.0186), higher incidence of regional wall motion abnormalities (46% vs. 13%, p=0.0093), higher B-type natriuretic peptide (BNP) level (p=0.0197), higher cardiac troponin I (cTnI) level (p=0.0016), lower ejection fraction (EF) (p0.0001) and higher mortality (p=0.0262) compared to the Low NGAL group. Patients with High NGAL were more likely to manifest electrocardiogram (ECG) abnormalities (p=0.042) and demonstrate clinical myocardial dysfunction (p=0.0186) as evidenced by clinical or radiological evidence of pulmonary edema as compared to those with Low NGAL group. NGAL, BNP, Acute Physiology and Chronic Health Evaluation (APACHE) II score, cTnI, and PaOHigh plasma NGAL correlates with high mortality and myocardial dysfunction in severe sepsis and septic shock.

Platelet aggregation is a crucial feature in coronary artery thrombus formation and is a major causative factor in both acute coronary syndromes (ACS) and reocclusion after percutaneous coronary interventions (PCI). The glycoprotein (GP) IIb/IIIa (αIIbβ3) integrin receptor is the pivotal mediator of platelet aggregation. In late 1990s, the introduction of GP IIb/IIIa inhibitors (GPI) was associated with a reduction of ischemic complication, and a clear clinical benefit in PCI during ACS, for both non ST-elevation (NSTE) and ST-segment elevation myocardial infarction (STEMI). The currently available GPI (abciximab, eptifibatide and tirofiban) tended to be replaced in the current therapy of STEMI by different agents and this is in part related to the effectiveness and to the potential adverse effects (thrombocytopenia and bleeding). There might be a certain level of variability among these agents and here we have reviewed only abciximab in detail. Interestingly, however, the story may not be entirely different from that of positive inotropic agents in the context of acute ischemia where the potent action to sustain left ventricular function had an arrhythmogenic counterpart to evaluate and take into consideration and therefore therapeutically it will always be necessary to weigh benefits and harms if actions are expected by relatively potent agents.

Objective Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy (SCM) resembles a reversible cardiomyopathy that is characterized by localized wall motion abnormalities in the absence of stenotic coronary vascular disease. Patients typically present with apical ballooning of the left ventricle (LV), however the right ventricle (RV) is also affected in up to 50.0% of patients. Long-term prognosis of classical SCM resembles that of patients after ST elevation myocardial infarction. Data on long-term prognosis of biventricular compared to classical SCM is controversial. The aim of this study was therefore to analyze patients with biventricular SCM regarding in-hospital outcome and long-term prognosis. Materials and methods 114 consecutive patients with SCM were retrospectively analyzed. 88 patients presented with classical SCM, 26 patients (22.8%) were diagnosed with biventricular SCM. Follow-up was conducted for a total of 4.4years. Mean age was 67.1years with 83.3% of patients being female. The primary endpoint was a composite of all-cause mortality, recurrence of SCM and re-hospitalization due to heart failure. Results Although patients with biventricular SCM presented with a tendency towards an increased rate of cardiogenic shock (30.8% vs. 15.9%; p=0.09) and significantly more usage of inotropic support upon hospital admission (34.6% vs. 13.6%; p=0.01), there was no difference concerning the primary endpoint in both groups (50.0% vs. 44.3%; p=0.31). Furthermore, there was no difference in mortality both in-hospital (7.7% vs. 7.9%; p=0.66) and during long-term follow-up (27.3% vs. 23.1%; p=0.46). Conclusion Patients with biventricular SCM have the same in-hospital and long-term outcome compared to classical SCM.

Heart rate plays a major role in myocardial ischemia. A high heart rate increases myocardial performance and oxygen demand and reduces diastolic time. Ivabradine reduces heart rate by inhibiting the If current of sinoatrial-node cells. In contrast to beta-blockers, ivabradine has no negative inotropic and lusitropic effect for a comparable heart rate reduction. Consequently, diastolic duration is increased with ivabradine compared to beta-blockers. This has potential consequences on coronary blood flow since compression of the vasculature by the surrounding myocardium during systole impedes flow and coronary blood flow is mainly diastolic. Moreover, ivabradine does not unmask alpha-adrenergic vasoconstriction and, unlike beta-blockers, maintains coronary dilation during exercise. In comparison with beta-blockers, ivabradine increases coronary flow reserve and collateral perfusion promoting the development of coronary collaterals. Ivabradine attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through reduced formation of reactive oxygen species. In conclusion, ivabradine differs from other anti-anginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective anti-anginal and anti-ischemic agent for the treatment of patients with coronary artery disease.

Ambulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients.185 AAHF NYHA class III-IV patients, with ≥2 HF hospitalizations/emergency visits in the previous 6 months and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2 μg/kg/min) without prior bolus every 3-4 weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6 months before and after treatment start.Infusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6 months before to the 6 months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p 0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), p = 0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, p = 0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant.In AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.

The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on ‘calcium sensitizers’ instead of ‘calcium mobilizers’. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.

End of life is an unfortunate but inevitable phase of the heart failure patients' journey. It is often preceded by a stage in the progression of heart failure defined as advanced heart failure, and characterised by poor quality of life and frequent hospitalisations. In clinical practice, the efficacy of treatments for advanced heart failure is often assessed by parameters such as clinical status, haemodynamics, neurohormonal status, and echo/MRI indices. From the patients' perspective, however, quality-of-life-related parameters, such as functional capacity, exercise performance, psychological status, and frequency of re-hospitalisations, are more significant. The effects of therapies and interventions on these parameters are, however, underrepresented in clinical trials targeted to assess advanced heart failure treatment efficacy, and data are overall scarce. This is possibly due to a non-universal definition of the quality-of-life-related endpoints, and to the difficult standardisation of the data collection. These uncertainties also lead to difficulties in handling trade-off decisions between quality of life and survival by patients, families and healthcare providers. A panel of 34 experts in the field of cardiology and intensive cardiac care from 21 countries around the world convened for reviewing the existing data on quality-of-life in patients with advanced heart failure, discussing and reaching a consensus on the validity and significance of quality-of-life assessment methods. Gaps in routine care and research, which should be addressed, were identified. Finally, published data on the effects of current i.v. vasoactive therapies such as inotropes, inodilators, and vasodilators on quality-of-life in advanced heart failure patients were analysed. This project did not receive any financial support, apart for covering the logistic expenses related to the organisation of the consensus meeting in Munich on January 23, 2015, which was achieved by collecting unrestricted educational grants from Orion Pharma (Finland), AbbVie (U.S.A.), Medis d.o.o. (Slovenia) and Biomed JR Ltd. (Israel). The attendees did not receive any honoraria. PP and MK are employees of Orion Pharma.

Background Angiotensin-(1–12) [Ang-(1–12)] is a chymase-dependent source for angiotensin II (Ang II) cardiac activity. The direct contractile effects of Ang-(1–12) in normal and heart failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1–12) may modulate [Ca 2+ ] i regulation and alter cardiomyocyte contractility in normal and HF rats. Methods and results We compared left ventricle (LV) myocyte contractile and calcium transient ([Ca 2+ ] iT ) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and 16 age-matched controls. In normal myocytes, versus baseline, Ang II (10 −6 M) superfusion significantly increased myocyte contractility (dL/dt max : 40%) and [Ca 2+ ] iT (29%). Ang-(1–12) (4 × 10 −6 M) caused similar increases in dL/dt max (34%) and [Ca 2+ ] iT (25%). Compared with normal myocytes, superfusion of Ang II and Ang-(1–12) in myocytes obtained from rats with isoproterenol-induced HF caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dt max and [Ca 2+ ] iT . Chymostatin abolished Ang-(1–12)-mediated effects in normal and HF myocytes. The presence of an inhibitory cAMP analog, Rp-cAMPS prevented Ang-(1–12)-induced inotropic effects in both normal and HF myocytes. Incubation of HF myocytes with pertussis toxin (PTX) further augmented Ang II-mediated contractility. Conclusions Ang-(1–12) stimulates cardiomyocyte contractile function and [Ca 2+ ] iT in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1–12) and Ang II in HF myocytes are mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.

Levosimendan is used in acute heart failure (HF) and increasingly as planned repetitive infusions in stable chronic HF, but the extent of this practice is unknown. The aim was to assess the use of levosimendan vs. conventional inotropes and the use as planned repetitive vs. acute treatment, in Sweden.We performed a descriptive study with individual patient validation assessing the use of levosimendan and conventional intravenous inotropes, indications for levosimendan, clinical characteristics and survival in the Swedish Heart Failure Registry between 2000 and 2011. For repetitive levosimendan, we assessed potential indications for alternative interventions.Of 53,548 total registrations, there were 655 confirmed with inotrope use (597 levosimendan, 37 conventional, 21 both) from 22 hospitals responding to validation, and 6069 in-patient controls with New York Heart Association III-IV and ejection fraction40%. The indications for levosimendan were acute HF in 384 registrations (306 patients), and planned repetitive in 234 registrations (87 patients). Planned repetitive as a proportion of total levosimendan registrations ranged 0-65% and of total levosimendan patients ranged 0-54% in different hospitals. Of planned repetitive patients without existing cardiac resynchronization therapy, implantable cardioverter defibrillator, transplant and/or assist device, 46-98% were potential candidates for such interventions.In HF in cardiology and internal medicine in Sweden, levosimendan was the overwhelming inotrope of choice, and the use of planned repetitive levosimendan was extensive, highly variable between hospitals and may have pre-empted other interventions. Potential effects of and indications for planned repetitive levosimendan need to be evaluated in prospective studies.

GLP-1 and exendin-4, which are used as insulin sensitizers or weight reducing drugs, were shown to improve glucose uptake in the heart. However, the direct effects of GLP-1 or exendin-4 on normal hearts in the presence of fatty acids, the main cardiac substrates, have never been investigated. We therefore assessed the effects of GLP-1 or exendin-4 on myocardial glucose uptake (GU), glucose oxidation (GO) and cardiac performance (CP) under conditions of fatty acid utilization. Methods and results Rat hearts were perfused with only glucose (5mM) or glucose (5mM) plus oleate (0.4mM) as substrates for 60min. After 30min, GLP-1 or exendin-4 (0.5nM or 5nM) was added. In the absence of oleate, GLP-1 increased both GU and GO. Exendin-4 increased GO but showed no effect on GU. Neither GLP-1 nor exendin-4 affected CP. However, when oleate was present, GLP-1 failed to stimulate glucose utilization and exendin-4 even decreased GU. Furthermore, now GLP-1 reduced CP. In contrast to prior reports, this negative inotropic effect could not be blocked by the protein kinase A inhibitor H-89. We then measured myocardial GO and CP in rats receiving a 4-week GLP-1 infusion. Interestingly, this chronic treatment resulted in a significant reduction in both GO and CP. Conclusions Under the influence of oleate, GLP-1 reduces contractile function and fails to stimulate glucose utilization in normal hearts. Exendin-4 may acutely reduce cardiac glucose uptake but not contractility. We suggest advanced investigation of heart function and metabolism in patients treating with these peptides.

Objective Right heart failure is associated with increased mortality and morbidity. The optimal treatment for patients with RV failure is not established. The aim of this study is to conduct a systematic review of the literature to assess the relative benefits and harms of digoxin therapy in patients with RV failure. Methods We performed a literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) on Nov. 4, 2014. We did not use publication type, period or language restrictions to the search strategy. Exclusions included: trials that excluded patients with RV failure, included patients requiring mechanical or intravenous inotropic support, review papers and case reports. The primary outcome was long-term efficacy outcomes of digoxin in right heart failure. Two reviewers screened titles and abstracts of identified citations independently and in duplication using calibration exercises and standardized screening forms. Results The search strategy identified 4097 citations, and 4 studies were included in this analysis (n=76 patients). Of the four studies, two assessed improvements in RVEF, two studies compared exercise capacity indexes, and one assessed symptoms with digoxin compared with placebo. No study assessed mortality outcomes. Overall, there was no statistically significant improvement in RVEF, exercise capacity, NYHA class, heart failure score, or body weight. Conclusions There are few studies evaluating Digitalis use for RV failure, which are limited to patients with cor pulmonale. In these patients, Digitalis use provides no improvement in RVEF, exercise capacity, or NYHA class. Randomized clinical trials are needed to address this question.

Aims Inotrope treatment is often necessary in refractory to optimal management end stage heart failure, when signs of end-organ hypoperfusion appear. The effect of specific inotropes on patient outcome remains controversial. The aim of the study was to compare the effect of levosimendan versus dobutamine, alone or in combination with levosimendan, on the outcome of end-stage heart failure patients, requiring inotropic therapy. Methods and results We studied 63 patients in NYHA class IV, refractory to optimal medical therapy, recently hospitalized for cardiac decompensation and stabilized by an intravenous inotrope. They were randomly assigned to intermittent infusions of either a) dobutamine, 10mg/kg/min, versus b) levosimendan, 0.3mg/kg/min, versus c) dobutamine, 10mg/kg/min+levosimendan 0.2mg/kg/min, each administered weekly, for 6h, over a 6-month period. All patients received amiodarone, 400mg/day, to suppress the proarrhythmic effects of the inotropes. Baseline characteristics of the 3 groups were similar. At 6months, survival free from death or urgent left ventricular device implantation was 80% in the levosimendan, 48% in the dobutamine ( P =0.037 versus levosimendan), and 43% in the levosimendan+dobutamine ( P= 0.009 versus levosimendan) group. At 3months, NYHA class improved significantly in all 3 groups, whereas pulmonary capillary wedge pressure decreased (27±4 to 19±8mmHg, P= 0.008) and cardiac index increased (1.5±0.3 to 2.1±0.3l/min/m 2 , P= 0.002) significantly only in patients assigned to levosimendan. Conclusions In patients with refractory end-stage heart failure, intermittent administration of levosimendan conferred survival and hemodynamic benefits in comparison to a regimen of intermittent infusions of dobutamine, alone or in combination with levosimendan.

Levosimendan is a new calcium sensitizer with positive inotropic properties. In previous studies, it has recently been shown that levosimendan improves the Doppler echocardiographic parameters of the left ventricular (LV) diastolic function in patients with anterior acute myocardial infarction. We sought to evaluate the effects of levosimendan compared to dobutamine on LV diastolic function, using conventional transmitral Doppler, in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) who subsequently developed cardiogenic shock.We randomized 22 consecutive STEMI patients with cardiogenic shock after primary PCI to levosimendan or dobutamine infusion and we also analyzed the diastolic function using conventional transmitral Doppler flow.Twenty-four hours after the initiation of the drug infusion, patients treated with levosimendan (n=11) showed a significant reduction of the isovolumetric relaxation time (116+/-15.2-70.4+/-10.8 ms; P.001), and a significant increase of the E/A ratio (0.6+/-0.3-1.4+/-0.5; P.001). In the dobutamine group (n=11), no statistically significant differences were noted in the echocardiographic Doppler indexes.Levosimendan seems to be effective in improving the Doppler echocardiographic parameters of LV diastolic function in patients with STEMI revascularised by primary PCI who developed cardiogenic shock.

Levosimendan and dobutamine are comparable inotropic drugs as regards their hemodynamic effects and clinical outcomes in decompensated heart failure (HF). The aim of this study was to compare the effects of levosimendan and dobutamine treatment on NT-proBNP levels in patients with decompensated HF. Forty-four patients with decompensated HF and ejection fraction n =26) or dobutamine ( n =18). NT-proBNP was measured at baseline and 12 h, 24 h and 48 h after the initiation of drug infusion. NT-proBNP levels at baseline, 12 h, 24 h and 48 h were 16,879±2437, 16,004±2635, 12,881±2305 and 11,078±2092 pg/ml, respectively, in the levosimendan group and 16,031±3463, 15,908±3806, 12,271±3299 and 14,840±4009 pg/ml, respectively, in the dobutamine group. NT-proBNP decreased significantly at 24 h in response to both levosimendan and dobutamine treatment ( p p p =n.s. vs. baseline), in contrast, NT-proBNP reduction continued for up to 48 h in the levosimendan group ( p

This study evaluated the effects of exercise training on myocardial function and ultrastructure of rats submitted to different levels of food restriction (FR). Male Wistar-Kyoto rats, 60 days old, were submitted to free access to food, light FR (20%), severe FR (50%) and/or to swimming training (one hour per day with 5% of load, five days per week for 90 days). Myocardial function was evaluated by left ventricular papillary muscle under basal condition (calcium 1.25 mM), and after extracellular calcium elevation to 5.2 mM and isoproterenol (1 microM) addition. The ultrastructure of the myocardium was examined in the papillary muscle. The training effectiveness was verified by improvement of myocardial metabolic enzyme activities. Both 20% and 50% food restriction protocols presented minor body and ventricular weights gain. The 20%-FR, in sedentary or trained rats, did not alter myocardial function or ultrastructure. The 50%-FR, in sedentary rats, caused myocardial dysfunction under basal condition, decreased response to inotropic stimulation, and promoted myocardial ultrastructural damage. The 50%-FR, in exercised rats, increased myocardial dysfunction under basal condition but increased response to inotropic stimulation although there was myocardial ultrastructural damage. In conclusion, the exercise training in severe restriction caused marked myocardial dysfunction at basal condition but increased myocardial response to inotropic stimulation.

Both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) bind preferentially to the natriuretic peptide A receptor. Therefore, we hypothesized that the positive inotropic and lusitropic effects of ANP might be blunted in patients with moderate congestive heart failure and high BNP levels. Micromanometers and conductance catheters were used to obtain relatively load-insensitive left ventricular pressure-volume analysis in order to compare the myocardial and load-altering actions of ANP in 20 patients with low and high plasma BNP levels. In the low-BNP group (plasma BNP levels230 pg/ml), ANP infusion significantly decreased end-systolic pressure and end-diastolic pressure and volume, increased end-systolic elastance, and shortened left ventricular relaxation. By contrast, in the high-BNP group (plasma BNP levels230 pg/ml), the effect of ANP infusion on LV contractility was blunted but its beneficial effects on LV diastolic function and LV-arterial coupling remained. Thus, ANP infusion may improve LV diastolic function even in patients with moderate heart failure and high plasma BNP levels.

Digoxin has been used for hundreds of years to aid rate control in atrial fibrillation and as a positive inotrope in heart failure. Our familiarity with digoxin has allowed it to become easily prescribed even though there are data suggesting that use of digoxin may in fact result in increased mortality and pro-arrhythmia. Within this review we explain some of the outcome data associated with digoxin use to determine if it is time to take the gloves off and examine if we should still be using this drug in the 21st century.

Objective: The objectives of this study were to determine myocardial injury in patients with septic shock by measuring serum cardiac troponin I (cTnI), to evaluate relationship between elevated cTnI and myocardial dysfunction and to determine if cTnI is a predictor of outcome in these patients. Methods: Thirty-seven consecutive patients with septic shock were included in the study. Serum cTnI was measured at study entry and after 24 and 48 h. Transthoracic echocardiogram, electrocardiogram and regular biochemical and hemodynamic assessments were performed. Results: Sixteen (43%) patients had elevated serum cTnI. These patients had higher need for inotropic/vasopressor support (94% vs. 53%, p =0.018), higher APACHE II score (28 vs. 20, p =0.004), higher incidence of regional wall motion abnormalities on echocardiography (56% vs. 6%, p =0.002), lower ejection fraction (46% vs. 62%, p =0.04) and higher mortality (56% vs. 24%, p =0.04) compared to normal cTnI patients. By multiple logistic regression analysis, serum cTnI and APACHE II score were independent predictor of death and length of stay in intensive care unit. Serum cTnI, APACHE II score, anion gap and serum lactate were independent predictor of need for inotropic/vasopressor support. Receiver-operating characteristics of serum cTnI as a predictor of death in septic shock were significant. The elevated serum level of cTnI correlated with the lower left ventricular ejection fraction ( p Conclusions: Myocardial injury can be determined in patients with septic shock by serum cTnI. Serum cTnI concentration correlates with myocardial dysfunction in septic shock. High serum cTnI predicts increased severity of sepsis and higher mortality. A close monitoring of patients with septic shock and elevated levels cTnI is warranted.

Acute Chagas' disease corresponds to the initial period of a Trypanosoma cruzi infection. Levosimendan is a positive inotropic drug with vasodilatory properties that is indicated for acute heart failure. We describe two cases of myocarditis due to acute Chagas' disease, resulting from oral intake of sugar cane juice infected with T. cruzi and resulting complications. Both developed acute decompensated heart failure refractory to Dobutamine. We describe for the first time in the medical literature the use of Levosimendan for myocarditis due to acute Chagas' disease, with excellent clinical and hemodynamic results.

This study sought to determine independent predictors of all-cause mortality for patients with Chagas' disease heart failure listed for heart transplantation. Need of inotropic support (p=0.01; hazard ratio=14.68, 95% Confidence Interval 1.86 to 115.82) and the Transpulmonary Gradient (p=0.02; HR=1.15, 95% Confidence Interval 1.03 to 1.30) were established independent predictors of all-cause mortality.

The intrinsic cardiac responses to 2-months Nigella sativa (black seed) oral supplementation (800 mg/kg) in rats were investigated. The isolated hearts were perfused in a Langendorff preparation to demonstrate the effects of N. sativa on the baseline inotropic and chronotropic functions and the myocardial flow rate. N. sativa supplementation induced moderate global (homogenous) cardiac hypertrophy, evident by significant increases in left ventricular and whole heart weights as well as the relative heart weight/body weight ratio. The isolated perfused hearts of Nigella-treated rats showed enhanced levels of baseline peak tension, maximum rate of tension development, heart rate and myocardial flow rate. Moreover, there was a significant increase in the tension developed per gram left ventricular weight. The present study provides the first evidence of a physiological cardiac hypertrophy in rats induced by long term N. sativa supplementation. © 2007 Elsevier Ireland Ltd. All rights reserved.

One hundred and twenty-three patients had coronary artery bypass grafting (CABG) within 30 days of acute myocardial infarction (AMI) from May 1992 to November 1997. Commonest infarct was anterior transmural (61.8%) and commonest indication of surgery was post-infarct persistent or recurrent angina (69.1%). Ten patients were operated within 48 h and 36 between 48 h to 2 weeks of having MI. Out of these, nine patients were having infarct extension and cardiogenic shock at the time of surgery. Pre-operatively fourteen patients were on inotropes of which six also had intra-aortic balloon pump (IABP) support. All patients had complete revascularisation with 3.8+/-1.2 distal anastomoses per patient. By multivariate analysis, we found that independent predictors of post-operative morbidity [inotropes48 h, use of IABP, ventilation24 h, ICU stay5 days] and complications [re-exploration, arrhythmias, pulmonary complications, wound infection, cerebrovascular accident (CVA)] were left ventricular ejection fraction (LVEF)30%, Q-wave MI, surgery48 h after AMI, presence of pre-operative cardiogenic shock and age60 years (Por = 0.01). Mortality at 30 days was 3.3%. LVEF30%, Q-wave MI, surgery48 h after AMI, presence of pre-operative cardiogenic shock and age60 years were found to be independent predictors of 30 days mortality (Por = 0.01). Ninety patients were followed up for a mean duration of 33 months (1 to 65 months). There were three late deaths and five patients developed recurrence of angina. To conclude, CABG can be carried out with low risk following AMI in stable patients for post-infarct angina. Patients who undergo urgent or emergent surgery and who have pre-operative cardiogenic shock, IABP, poor left ventricular functions, age60 years and Q-wave MI are at increased risk.

The hemodynamic effects of levosimendan have been shown to be maintained or even enhanced by beta blockers. Furthermore, levosimendan has recently been reported to represent mortality benefit in patients receiving beta blockers. However, it is not clear whether these favorable effects of levosimendan under beta blockade are also suggested by a better neurohormonal response. We evaluated neurohormonal response to levosimendan in patients receiving beta blocker in our study population on the basis of the comments of Giamouzis and colleagues on previously published article, in which both levosimendan and dobutamine were found to be very effective inotropic agents in achieving favorable neurohormonal response but levosimendan had a better and prolonged effect. The findings of recent subgroup analysis suggested that levosimendan treatment trended toward a greater reduction in NT-proBNP levels and therefore may provide a better neurohormonal response in patients receiving beta blockers as compared with those patients not receiving beta blocker.

Current treatment goals in heart failure (HF) aim to improve both survival and quality of life (QoL) of patients. In this brief communication, we reviewed randomized controlled trials that assessed the impact of pharmacological treatment on QoL, and we discussed some methodological limitations of QoL assessment in HF. Studies that assessed QoL with a disease-specific questionnaire were included. We found that at present there is a paradox in HF treatment. Life prolonging therapies, such as angiotensin-converting-enzyme-inhibitors, and angiotensin receptor blockers improve modestly or only delay the progressive worsening of QoL in HE Treatment with beta blockers does not affect QoL in any way. However, this neutral effect of beta blockers may also be due to some methodological limitations, such as the small number of patients included in beta blocker trials or the short duration of follow-up. Disease-specific questionnaires may also have some limitations, e.g. are not sensitive enough to detect small changes in QoL. On the other hand, therapies that significantly improve QoL in HF (e.g. inotropic agents) do not seem beneficial in relation to survival. We conclude that QoL in HF remains an open field, in which new therapies but also clarification of methodology is required. In the mean time, the use of life prolonging therapies appears as a safe measure to modestly improve or maintain QoL. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

use in primary care: the Framingham heart study. Circulation 2008;117:743–53. [6] Verdecchia P, Angeli F. Does brachial pulse pressure predict coronary events? Adv Cardiol 2007;44:150–9. [7] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol 2002;39:257–65. [8] Ghiadoni L, Faita F, Salvetti M, et al. Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study. J Hypertens 2012;30:1399–405. [9] Ghiadoni L, Versari D, Giannarelli C, Faita F, Taddei S. Non-invasive diagnostic tools for investigating endothelial dysfunction. Curr Pharm Des 2008;14:3715–22. [10] Witte DR, van der Graaf Y, Grobbee DE, Bots ML. Measurement of flow-mediated dilatation of the brachial artery is affected by local elastic vessel wall properties in high-risk patients. Atherosclerosis 2005;182:323–30.

In the normally contracting heart, the contractile apparatus consumes the great majority of myocardial energy metabolites and oxygen. In fact, non-contractile myocardial functions, including cardiac action potentials as well as maintenance of cellular homeostasis, require less than 20% as much oxygen [1]. It is therefore apparent that shutting down the hearts' mechanical activities during severe oxygen deprivation could preserve energy metabolites. In fact, this is what happens during ischemic stunning. We believe that the same mechanisms are at play in takotsubo, another conditions in which the cardiomyocytes sense relative oxygen deprivation. The heart relies almost entirely on aerobic metabolism and is dependent on a continuous supply of oxygen. In healthy subjects the heart can increase regional blood flow at least 5-fold through socalled autoregulatory mechanisms and can therefore tolerate fluctuations in myocardial oxygen demand. However, situations can arise where autoregulatory mechanisms fail to maintain adequate tissue perfusion. This leads to myocardial ischemia. If the supply:demand mismatch is of sufficient magnitude and duration cardiomyocyte cell death ensues. Following complete occlusion of a coronary artery, cardiomyocytes supplied by that artery stop contracting within seconds. Energy metabolites decrease to 50% of their initial levels within 10 min and within 20 min irreversible cell injury ensues. Thus, contractile activities cease well before the cell is depleted of energy, a phenomenon coined “ischemic stunning”. Such a hierarchical order of cellular functions is reasonable from an evolutionary perspective and is common in biology. By downprioritizing contractile activities the cell preserves energy and is able to sustain longer periods of oxygen deprivation. Hence, although it inherently leads to impaired cardiac function with potential complications, ischemic stunning is likely an important protective mechanism in acute ischemic syndromes, including acute myocardial infarction. Pre-, perand postconditioning are terms used to describe the protective effect on the myocardium of brief episodes of ischemia against subsequent, simultaneous, or preceding greater ischemic insults. A great myriad of molecules have been postulated to mediate conditioning but none have been successfully translated to clinical praxis. It is clear from earlier studies that ischemic conditioning phenomena entail more thanmerely ischemic stunning, i.e. preservation of energy metabolites otherwise destined to be consumed by the contractile apparatus. Studies have shown that brief episodes of ischemia preceding an ischemic event are associated with cardioprotection independent on the degree of functional impairment still present at the onset of the indexevent [2]. This is not surprising since ischemic stunning likely ensues immediately upon coronary artery occlusion. Thus, since little energy is lost before stunning ensues, little if any benefit would be expected if the myocardium was already stunned beforehand. Instead, conditioning more likely probes the heart towards more efficient “stunning” once the ischemic insult occurs. This is most likely accomplished by complex intracellular alterations, some of which have been thoroughly studied. Takotsubo is characterized by regional contractile dysfunction that develops in the absence of an explanatory vascular culprit lesion and that often extends beyond the territory supplied by a single main coronary artery. Catecholamines are strongly implicated in the pathogenesis and a strong emotional and/or physical stressor can be identified in the majority of patients [3]. Although the mechanisms underlying takotsubo are incompletely understood, there is indirect support in the literature for a causative role of relative ischemia. First, microvascular resistance has been shown to be increased in patients with takotsubo [4]. Second, and more important, left ventricular outflow obstruction can be observed at the time of echocardiographic assessment in approximately 1/4 of patients that present with typical takotsubo, i.e. apical akinesia with preserved basal function [5]. The combination of strong inotropic drive and outflow obstruction could be expected to greatly increase LV afterload, particularly in apical regions. Cardiomyocytes within

The therapeutic effects of calcium channel blockers on heart failure are controversial. However, a recent clinical trial demonstrated a favorable effect of amlodipine on survival rates in patients with heart failure resulting from nonischemic dilated cardiomyopathy. There are a number of studies showing that cytokines generated by activated immune cells cause an increase in nitric oxide (NO) via induction of NO synthase (NOS), which results in a direct negative inotropic effect and a modulation of inotropic responsiveness. Increases in inflammatory circulating cytokines have been detected in patients with heart failure and cardiomyopathy, elevated plasma levels of nitrite/nitrate in patients with heart failure have been reported, and inducible NOS (iNOS) has been found in ventricular tissue from patients with dilated cardiomyopathy. In our recent study, amlodipine improved histopathological lesions in the heart and survival rates in a murine model of nonischemic heart failure induced by encephalomyocarditis virus. Amlodipine inhibited NO production in vitro and decreased the number of iNOS positive cells in vivo. In this model, the therapeutic effect of amlodipine on myocardial injury is considered in part to result from inhibition of overproduction of NO. In this review, the possible roles of cytokines and NO in the pathophysiology of heart failure are discussed, along with the opportunities for therapeutic intervention.

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.

Background Advanced congestive heart failure (CHF) therapies include intravenous inotropic agents, change in class of diuretics, and venous ultrafiltration or hemodialysis. These modalities have not been associated with improved prognosis and are limited by availability and cost. Compared to high-dose furosemide alone, concomitant hypertonic saline solution (HSS) administration has demonstrated improved clinical outcomes with good safety profile. Methods A literature search was conducted for randomized controlled trials that investigated the use of HSS in patients admitted to hospital with acute CHF. Results 1032 patients treated with HSS and 1032 controls, demonstrated decreased all-cause mortality in patients treat with HSS with RR of 0.56 (95% CI 0.41–0.76, p =0.0003). 1012 patients treated with HSS and 1020 controls, demonstrated decreased heart failure hospital readmission with RR of 0.50 (95% CI 0.33–0.76, p =0.001). Patients treated with HSS also demonstrated decreased hospital length of stay ( p =0.0002), greater weight loss ( p p Conclusion The results of this meta-analysis demonstrate that in patients with advanced CHF concomitant hypertonic saline administration improved weight loss, preserved renal function, and decreased length of hospitalization, mortality and heart failure rehospitalization. A future adequately powered, multi-centre, placebo controlled, randomized, double dummy, blinded trial is needed to assess the benefit of hypertonic saline in patients with renal dysfunction, in diverse patient populations, as well using a patient population on optimal current heart failure treatment. Pending further validation, there is promise for hypertonic saline as an advanced therapy for the management of acute advanced CHF.

Cardiac dysfunction is common in ICU patients and is a poor prognostic factor [1,2]. Acute myocardial infarction (AMI) is commonly diagnosed in ICU patients and cardiospecific proteins are detected in up to 47% of these patients. An AMI diagnosis is often based only on detection of cardiospecific proteins in plasma and/or ECG and echocardiographic findings. Angiographic evidence is rarely present [2]. Furthermore, reported plasma troponin levels are often mildly to moderately elevated, a laboratory finding that is consistent not only with a small or moderately sized AMI but also with stress-induced cardiomyopathy (SIC). It is thus possible that many or perhaps most cases of myocardial infarction diagnosed in the ICU may in fact be SIC. SICwas first described in 1990 but is nowan increasingly recognized acute cardiac syndrome and an important differential diagnosis in patients presenting with chest pain [3]. SIC is characterized by severe regional myocardial hypokinesia or akinesia, often but not always involving apical segments, in the absence of an explanatory coronary lesion [4]. Although the pathomechanisms behind SIC is believed to differ substantially from that of AMI the two conditions appear clinically similar and cannot, as yet, be differentiated by non-invasive modalities [5]. However, plasma troponin levels are typically mildly to moderately elevated in SIC and extreme values are rare. SIC is typically preceded by an emotional or somatic stressor and although the pathophysiology of SIC is poorly understood, there exist strong evidence for an important role of catecholamine overstimulation [5]. Among the evidence indicating catecholamines in the pathogenesis of SIC are the observations that plasma levels of epinephrine and norepinephrine are severely elevated in SIC patients, also compared to AMI patients, and several reports where iatrogenously administered beta-adrenergic agonists have triggered SIC or worsened the patients' condition [5,6]. Furthermore, we have shown that i.p. administration of isoprenaline, a nonselective β-adrenoreceptor agonist, induces SIC-like left ventricular apical akinesia in rats [7]. We believe that there is reason to believe that SIC may be particularly prevalent among patients admitted because of severe non-cardiac disease, conditions associated with internal somatic stress and a strong adrenergic drive. A recent report showed that N20% of patients admitted to an intensive care unit (ICU) displayed SIC-like left ventricular apical ballooning. Development of SIC-like cardiac dysfunction was particularly likely in sepsis, a condition associated with a profound endogenous stress response [1]. Considering the liberal use of inotropic support in ICU patients, including catecholamine, detection of SIC patients in this setting may be of particular importance and may merit re-evaluation of treatment strategies [6,8]. Cardiac output is often inadequate in ICUpatients despite optimization of filling pressures and afterload. These patients therefore require additional support tomaintain adequate tissue perfusion. Typical regimens include positive inotropes and/or vasopressor substances, manyofwhich are catecholamines.Webelieve that further stimulation of adrenergic signaling pathways may exacerbate cardiac dysfunction in somepatients andmay lead toparadoxical deterioration of these patients condition (Fig.1). In patients suffering from severe heart failure inotropic support by the β-adrenoreceptor agonist dobutamine was associated with a near statistically significantly increased mortality compared to placebo [8]. We believe that suspicion of stress-induced cardiac dysfunction should deter the anesthesiologist towards switching to non-catecholamine vasopressors. Similarly, non-catecholamine vasopressors may also be preferable in these patients. We propose that many so-called AMIs detected in the ICU may in fact be SIC and in many cases these SICs may have been caused or exacerbated by iatrogenously administered inotropic agents, especially β-adrenoreceptor agonist. Non-catecholamine inotropes and/or vasopressors or mechanical assist may be preferable in patients at risk of developing SIC. Until SIC is better understood and these patients can be identified we argue for judicious use of catecholamine inotropes and liberal use of mechanical assist, particularly in patients displaying signs of cardiac dysfunction or injury.

We studied the mechanism of the positive inotropic action of cocaine in isolated guinea pig atria superfused with Tyrode's solution at 31 degrees C while attached to a force transducer to measure peak tension developed, maximum velocity of development of tension, and time to peak tension. Cocaine 2.9 microM enhanced peak tension developed and velocity of development of tension, and prolonged time to peak tension. The increase in peak tension developed produced by cocaine was not affected by propranolol. On the other hand, the cocaine-induced increase in velocity of development of tension was reduced, but not abolished. In the presence of propranolol and phentolamine combined, the cocaine-induced prolongation of time to peak tension was abolished and the increases of both peak tension developed and velocity of development of tension were significantly smaller than those observed in the absence of the two adrenergic blockers. For all practical purposes, nifedipine completely abolished the increase in peak tension developed induced by cocaine. It is concluded that the positive inotropic effect of cocaine in the guinea pig atrial muscle is predominantly the result of adrenergic-dependent, both alpha- and beta- receptor mediated, as well as adrenergic-independent increases in calcium influx through the L-type calcium channels in the sarcolemma.

The phosphodiesterase (PDE) III inhibitor, E-1020 (loprinone hydrochloride), has positive inotropic and vasodilating effects. This study evaluated the positive inotropic effect of intracoronary E-1020 in eight patients with coronary artery disease and hypertensive heart disease. A direct intracoronary infusion of the PDE III inhibitor minimizes its vasodilating effect. After baseline hemodynamic measurements and coronary arteriography, a micromanometer-tipped 8F conductance catheter was introduced into the left ventricle to determine the hemodynamic effects of E-1020. Saline and vehicle were infused into the left main coronary artery at a rate of 2 ml/min. The dose of intracoronary E-1020 increased from 2.5 to 5.0 and 7.5 micrograms/min. The inotropic effect of E-1020 was defined as the change in the slope of the end-systolic pressure-volume relationship (Emax), which was independent of afterload and preload. Emax significantly increased at infusion rates of 7.5 micrograms/min from control. Peak +dP/dt increased at an infusion rate of 5.0 micrograms/min or higher, while left-ventricular end-diastolic pressure (LVEDP) decreased significantly at a rate of 5.0 and 7.5 micrograms/min. Intracoronary infusion of E-1020 at a rate of 2.5 micrograms/min produced a plasma concentration of 20 ng/ml, which was identical to the minimum effective plasma concentration seen in previous study by intra venous infusion. However, at a plasma concentration of 20 ng/ml, E-1020 has more vasodilating effects than inotropic effects. Clinically, E-1020 appears to have a positive inotropic effect that depends on the extent of myocardial perfusion.

Cardiac endothelium modulates underlying cardiac muscle performance probably by releasing certain regulatory factors. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cyclic GMP (cGMP), may be involved in this cardiac modulation. Many recent studies have examined inotropic effects of NO utilizing NO donors and NO-synthase inhibitors, both in vitro and in vivo, with apparently contradictory results. We examined the myocardial effects of NO-releasing nitrovasodilators (sodium nitroprusside (SNP), SIN-1 and S-nitrosoacetyl penicillamine (SNAP)), a cGMP analogue, 8-bromo-cGMP, and the cGMP phosphodiesterase inhibitor zaprinast, in isolated cat papillary muscle. A novel concentration-dependent positive inotropic effect of SNP and SIN-1 in muscles with damaged endocardial endothelium (EE) was observed which contrasted to their negative inotropic effect in muscles with intact EE. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. Concentration response curves with addition of SNAP and 8-bromo-cGMP resulted in a biphasic inotropic response. While administration of low concentrations of SNAP and 8-bromo cGMP induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Administration of zaprinast caused a monophasic concentration-dependent positive inotropic effect. We conclude that basal release of NO and consequent modest (physiological?) elevation in cGMP may preserve myocardial function, while large (pathological?) increases would depress myocardial function.

A49year-oldwomanwasreferredforincreasingdyspnoeaonexer-tion.Shehadsevereobesityanduncontrolledtype-2diabetesandwasacurrent smoker. Transthoracic echocardiogram was performed, show-ingseveresystolicdysfunction(EF0.30),moderatemitralregurgitation,elevated left ventricular filling pressures and moderate pulmonaryhypertension.Thus,coronaryangiogramwasindicated.Rightdominantcoronary artery showed no significant lesions and filled retrogradelyboth left anterior descending and circumflex arteries up to the leftmain. Several diagnostic catheters failed to intubate left main artery.Aortography revealed total left main occlusion.The patient was referred for surgery and a left internal mammaryartery (LIMA) bypass graft to left anterior descending artery (LAD)was performed. Patient experienced severe heart failure requiringhigh doses of inotrope and loop diuretics and was discharged 3 weeksafter admission. Unfortunately, 5-days after discharge the patient wasadmitted with severe biventricular failure. A second coronary angio-gram confirmed LIMA occlusion. We considered in a multidisciplinarymeeting to attempt the LM occlusion percutaneously with retrogradeinjections via right coronary artery.We faced the first problem of the absence of both radial pulses (longIntensiveCareadmission)andtheabsenceofleftfemoralpulse(severeperipheral disease). Thus, we made a “blind” antegrade approach via 6Fright femoral approach. A Judkins-left 4 6-Fr guiding catheter was placedin the left aortic sinus and we patiently advanced a Fielder XT guidewire(Ashahi Intecc Co., Japan) where we “guessed” the LM might be.