Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association.

Heart failure (HF) is a complex clinical syndrome with multiple interactions between the failing myocardium and cerebral (dys-)functions. Bi-directional feedback interactions between the heart and the brain are inherent in the pathophysiology of HF: (i) the impaired cardiac function affects cerebral structure and functional capacity, and (ii) neuronal signals impact on the cardiovascular continuum. These interactions contribute to the symptomatic presentation of HF patients and affect many co-morbidities of HF. Moreover, neuro-cardiac feedback signals significantly promote aggravation and further progression of HF and are causal in the poor prognosis of HF. The diversity and complexity of heart and brain interactions make it difficult to develop a comprehensive overview. In this paper a systematic approach is proposed to develop a comprehensive atlas of related conditions, signals and disease mechanisms of the interactions between the heart and the brain in HF. The proposed taxonomy is based on pathophysiological principles. Impaired perfusion of the brain may represent one major category, with acute (cardio-embolic) or chronic (haemodynamic failure) low perfusion being sub-categories with mostly different consequences (i.e. ischaemic stroke or cognitive impairment, respectively). Further categories include impairment of higher cortical function (mood, cognition), of brain stem function (sympathetic over-activation, neuro-cardiac reflexes). Treatment-related interactions could be categorized as medical, interventional and device-related interactions. Also interactions due to specific diseases are categorized. A methodical approach to categorize the interdependency of heart and brain may help to integrate individual research areas into an overall picture.

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper.

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

COHgb levels predict the long-term development of acute myocardial infarction in CO poisoning.

BACKGROUND: There are several studies evaluating the cardiac effects of carbon monoxide (CO) poisoning during the acute period; however, the number of studies evaluating the long-term cardiac effects is limited. OBJECTIVE: The present study aimed to evaluate the effects of blood carboxyhemoglobin (COHb) levels, elevated due to CO poisoning on the long-term development of acute myocardial infarction (AMI). METHODS: This cross-sectional cohort study included a total of 1013 consecutive patients who presented to the emergency department (ED) due to CO poisoning, between January 2005 and December 2007. The diagnosis of CO poisoning was made according to the medical history and a COHb level of greater than 5%. In terms of AMI development, the patients were followed up for an average of 56 months. RESULTS: At the end of follow-up, 100 (10%) of 1013 patients experienced AMI. Carboxyhemoglobin levels at the time of poisoning were higher among those who were diagnosed with AMI compared to those who were not (55%±6% vs 30%±7%; P<.001). Using a multivariate Cox proportional hazards model with forward stepwise method, age, COHb level, CO exposure time, and smoking remained associated with an increased risk of AMI after adjustment for the variables found to be statistically significant in a univariate analysis. According to a receiver operating characteristic curve analysis, the optimal cutoff value of COHb used to predict the development of AMI was found to be greater than 45%, with 98% sensitivity and 94.1% specificity. CONCLUSION: In patients presenting to the ED with CO poisoning, COHb levels can be helpful for risk stratification in the long-term development of AMI.

Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine.

Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurses and other health care providers have to cooperate to provide optimal benefit. However, many treatment decisions are opinion-based and few are evidenced-based. This consensus paper provides guidance to practicing physicians and nurses to manage acute heart failure in the pre-hospital and hospital setting. Criteria of hospitalization and of discharge are described. Gaps in knowledge and perspectives in the management of acute heart failure are also detailed. This consensus paper on acute heart failure might help enable contiguous practice.

How will 2014 European Society of Cardiology Congress influence our daily practice?

European Cardiology Congress which was held in Barcelona in this year; was a meeting with striking results of the presented scientific studies. Herein, a brief overview of congress highlights is presented.

Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure.

AIMS: The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. METHODS AND RESULTS: We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46% of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11%, isolated abnormal transaminases in 26%, and a combination of abnormal AP and transaminases in 9%. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9%, P = 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4% and 31.6 vs. 22.4%, respectively; both P < 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. CONCLUSION: Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients.

Type I plasminogen activator inhibitor 4G allele frequency is associated with chronic venous insufficiency.

Chronic venous insufficiency (CVI) is a common disease associated with poor quality of life. Genetic polymorphisms causing coagulation abnormalities may account for some of the CVI pathogenesis. Type I plasminogen activator inhibitor (PAI-1) is responsible for fibrinolytic system regulation, and plasma levels of PAI-1 are strongly correlated with PAI-1 4G/5G gene polymorphism. The association between PAI-1 4G/5G gene polymorphism and CVI was investigated. In 34 consecutive patients with clinically overt CVI, the PAI-1 4G/4G polymorphism was detected in three cases (8.8%); the 4G/5G polymorphism was detected in 28 (82.4%). In 34 age- and sex-matched controls, the PAI-1 4G/4G polymorphism was detected in one case (2.9%) and the 4G/5G polymorphism was detected in 14 cases (41.2%). The PAI-1 4G allele was found significantly more frequently in CVI patients than in controls. The 4G allele was associated with a 3.25-fold increase in CVI risk. Thus, a relationship between CVI and the PAI-1 4G allele is apparent.

A comparison of the effects of desflurane, sevoflurane and propofol on QT, QTc, and P dispersion on ECG.

The aim of this prospective, randomized, and double-blinded study was to compare the effects of desflurane, sevoflurane, propofol on both atrial and ventricular wall function by measurement of QT dispersion (QTd), corrected QT dispersion (QTcd), and P dispersion (Pd) on electrocardiogram (ECG). Forty-six patients from the American Society of Anesthesiologists class I-II undergoing noncardiac surgery, were enrolled in this study. Patients were randomly allocated to receive desflurane, sevoflurane or propofol anesthesia. ECG recordings were taken before and after 5 minutes of drug administration. Induction with desflurane significantly increased the QTd compared to baseline (38 +/- 2 ms vs. 62 +/- 6 ms, P 0.05). Sevoflurane and propofol anesthesia was not associated with any changes in QTd. QTcd was increased with desflurane induction and decreased with sevoflurane and propofol induction, but this decrease was only significant in the propofol group (67 +/- 5 ms vs. 45 +/- 3 ms, P 0.05). Pd was significantly increased after induction with desflurane (34 +/- 3 vs. 63 +/- 6 ms, P 0.05). There was a significant increase in QTd and Pd in desflurane group, but this increment did not cause any dangerous arrhythmias. QTcd significantly decreased in propofol group. We believe that further investigations are required for using desflurane as safe as sevoflurane and propofol in noncardiac surgery patients who have high cardiac arrhythmia and ischemia risk.

Acute coronary syndrome: short-term effects of early intravenous metoprolol on maximum P wave duration and P wave dispersion.

In patients with acute coronary syndrome (ACS), the presence of atrial fibrillation (AF) results in worse inpatient outcomes than in those without AF. Two electrocardiographic markers, maximum P wave duration (P(maximum)) and P wave dispersion (P(dispersion)), have been assessed because they reflect conduction abnormalities in patients with paroxysmal AF. b blockers are known to have beneficial effects in patients with ACS. This prospective study was conducted to investigate whether early intravenous (IV) metoprolol injection acutely decreases P(maximum) and P(dispersion) in patients with ACS. This study involved 100 consecutive patients with ACS who were divided into 2 groups according to whether or not they received early IV metoprolol. Group 1 consisted of 19 patients who received IV metoprolol within 3 h after onset of symptoms, and group 2 consisted of 81 patients who did not receive IV metoprolol within 3 h after symptom onset because of late admission. P(maximum) and P(dispersion) were measured on admission and again at 2 h after admission. Two-dimensional echocardiographic examination was also performed. For patients who received early IV metoprolol, P(maximum) and P(dispersion), measured 2 h after admission, were shorter than values at admission (P<.001). Conversely, P(maximum) and P(dispersion), measured 2 h after admission, did not differ significantly from values at admission in patients who did not receive early IV metoprolol (P=.292 and P=.236, respectively). IV administration of metoprolol reduced values for P(maximum) and P(dispersion), measured 2 h after admission, among patients with ACS who were admitted within 3 h after onset of symptoms.

Torsades de pointes with a severely prolonged QT interval induced by an initial low dose sotalol intake.

Many drugs, including sotalol, have been implicated in prolonging QT interval and triggering torsades de pointes, a potentially fatal ventricular arrhythmia, especially during chronic therapy or in case of acute high dose toxicity. We report here a case with a severely prolonged QT interval and torsades de pointes after an initial intake of low dose sotalol (80 mg), indicating a probable inherent individual oversensitivity to sotalol.

Fistulous connection between internal mammary graft and pulmonary vasculature after coronary artery bypass grafting: a rare cause of continuous murmur.

A 58-year-old male who had undergone coronary artery bypass grafting (CABG) using left internal mammary artery and a sequential saphenous vein graft 2 years ago presented with new onset angina. His initial physical examination revealed an unexpected continuous murmur over the left sternal border, and two-dimensional echocardiography has failed to identy the cause. Cardiac catheterization then performed and revealed patent left internal mammary artery and saphenous vein grafts. Besides, selective injection of the left internal mammary artery graft also showed a fistula formation between left internal mammary artery graft and pulmonary vasculature of the left upper lobe. He was managed conservatively because of the severely diseased left anterior descending artery distal to internal mammary artery anastomosis and low pulmonary artery pressure. The development of fistulous connection between internal mammary artery and pulmonary vasculature is an extremely rare complication following CABG. Patients with such fistulae usually present with chest pain due to coronary steal syndrome. A new heart sound, especially a continuous murmur, may be detected during physical examination. Surgical correction is indicated in the event of refractory angina, growing fistula causing heart failure or endarteritis. Otherwise, a conservative approach with instruction of the patient for prophylactic precautions of subacute bacterial endocarditis may be recommended for asymptomatic patients.

Levels of soluble adhesion molecules in various clinical presentations of coronary atherosclerosis.

Adhesion molecules play an important role in the development and course of coronary atherosclerosis. In this study, soluble forms of vascular cell adhesion molecule (VCAM-1) intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin were evaluated in patients with various clinical presentations of coronary atherosclerosis and compared them to those with angiographically documented normal coronary arteries. Venous plasma samples were collected from 43 patients with acute myocardial infarction (AMI), 45 with unstable angina pectoris (UAP), 34 with stable angina pectoris (SAP) and 29 subjects with normal coronary arteries (control). The VCAM-1 level was significantly higher in patients with AMI (mean +/- SEM; 799.8 +/- 26.3 ng/ml) than those with UAP (644.2 +/- 26.7 ng/ml) and SAP (526 +/- 32.5 ng/ml) and controls (270 +/- 26.8 ng/ml). In patients with UAP, VCAM-1 was found to be significantly elevated as compared to the SAP group and controls. VCAM-1 level was also higher in SAP group than the controls. Serum levels ICAM-1 were similar among patients with AMI (424.1 +/- 15.2 ng/ml), UAP (403 +/- 12.3 ng/ml) and SAP (381.2 +/- 16.2 ng/ml); however, levels of ICAM-1 was significantly elevated in these groups as compared to the controls (244.3 +/- 11). The mean level of E-selectin was not different in AMI and UAP groups (47.2 +/- 2.2 vs. 42.6 +/- 2.1 ng/ml; respectively). However, it was significantly higher in acute coronary syndrome groups as compared to SAP (33.4 +/- 2.3 ng/ml) and control subjects (30.7 +/- 1.9 ng/ml). Serum levels of E-selectin were similar in SAP group and controls. For P-selectin, no significant difference was observed between AMI and UAP groups (187.5 +/- 7.2 vs. 181.7 +/- 4.7 ng/ml; respectively), however, it was significantly higher in both groups as compared to SAP group (146.1 +/- 7.4 ng/ml) and controls (108 +/- 6.6 ng/ml). Serum level of P-selectin was significantly higher in patients with SAP than the control group. In conclusion, determination of serum VCAM-1, E-selectin and P-selectin levels seems more useful for detecting coronary plaque destabilization.

Prevalence of angiographically significant coronary artery disease in patients with rheumatic mitral stenosis.

OBJECTIVE: In order to evaluate the prevalence of angiographically significant coronary artery disease (CAD) in patients with predominant mitral stenosis (mitral valve area < or = 1.5 cm2), coronary angiograms of the 837 consecutive patients with mitral stenosis (482 women and 355 men; median age = 50 years [ranging from 35 to 77]) were retrospectively analysed. METHODS AND RESULTS: Significant CAD was defined as at least 50% diameter narrowing of a major coronary artery. Significant CAD was detected in 63 patients (7.5%, 30 men and 33 women). Patients with CAD were significantly older than those without CAD (median: 59 vs. 49 years; p < 0.0001, respectively). With respect to coronary risk factors, diabetes mellitus (28.6% vs. 9.4%; p < 0.0001), hypertension (46% vs. 16.7%; p < 0.0001) and family history of CAD (34.9% vs. 17.3%; p = 0.001) were significantly more frequent in the CAD+ group as compared to the CAD- group. Serum levels of cholesterol were significantly higher in CAD+ group as compared to the CAD-patients (median: 199 vs. 176 mg/dl; p = 0.003). No significant differences were noted between the two groups in both serum levels of HDL-cholesterol (p = 0.12) and triglycerides (p = 0.08). Of the 63 patients with CAD, 21 (33.3%) had angina pectoris (AP) and, in patients free of CAD, AP was present in 106 (13.7%). The sensitivity and specificity of AP for the presence of significant CAD were 33.3% and 86.3%, respectively. The positive predictive value of AP for the presence of CAD was 16.5% and the negative predictive value of its absence was 94.1%. CONCLUSION: It is concluded that routine coronary angiography is not necessarily indicated in predominant mitral stenosis particularly in patients who are younger than 40 years and have no coronary risk factors and typical chest pain.

Maximum p wave duration and p wave dispersion in adult patients with secundum atrial septal defect: the impact of surgical repair.

BACKGROUND: Patients with atrial septal defect (ASD) have an increased risk for atrial fibrillation (AF). Previously it was shown that maximum P wave duration and P wave dispersion in 12-lead surface electrocardiograms are significantly increased in individuals with a history of paroxysmal AF. We studied P maximum and P dispersion in adult patients with ASD during normal sinus rhythm. In addition, the impact of surgical closure of ASD on these variables within 1 year after surgery was evaluated. METHODS: Thirty-four patients (21 women, 13 men; mean age: 35 +/- 11 years) operated on for ostium secundum type ASD and 24 age-matched healthy subjects (13 women, 11 men; mean age: 37 +/- 10 years) were investigated. P maximum, P minimum, and P dispersion (maximum - minimum P wave duration) were measured from the 12-lead surface electrocardiography. RESULTS: P maximum was found to be significantly longer in patients with ASD as compared to controls (115.2 +/- 9 vs 99.3 +/- 14 ms; P < 0.0001). In addition, P dispersion of the patients was significantly higher than controls (37 +/- 9 vs 29.8 +/- 10 ms; P = 0.003). P minimum was not different between the two groups (P = 0.074). After surgical repair of ASD, 10 patients (29%) experienced one or more episodes of paroxysmal AF. Patients with postoperative AF were older (45 +/- 6 vs 30 +/- 10 years; P = 0.001), and had a higher preoperative pulmonary artery peak systolic pressure as compared to those without postoperative AF (51 +/- 11 vs 31 +/- 9 mmHg; P < 0.0001). No significant difference in the pulmonary-to-systemic flow ratio was observed preoperatively between the two groups (P = 0.56). P maximum and P dispersion were significantly higher in patients with postoperative paroxysmal AF at baseline and at postoperative first month, sixth month, and first year as compared to those without it (for P maximum P = 0.027, P = 0.014, P = 0.001, P < 0.0001, respectively; for P dispersion P = 0.037, P = 0.026, P = 0.001, P < 0.0001, respectively). In addition, in patients with postoperative AF, no significant changes were detected in both of these P wave indices during postoperative follow-up. However, in the other group, P maximum and P dispersion were found to be significantly decreased at postoperative 6 months and 1 year as compared to baseline. P minimum was similar throughout the postoperative follow-up as compared to baseline in both groups. CONCLUSIONS: Mechanical and electrical changes in atrial myocardium may cause greater P maximum and P dispersion in patients with ASD. Surgical closure of the ASD can regress these pathological changes of atrial myocardium with a result in decreased P maximum and P dispersion. However, higher P maximum and P dispersion at baseline, which have not decreased after surgery, may be associated with postoperative paroxysmal AF, especially for older patients.

Diagnostic value of aVL derivation for right ventricular involvement in patients with acute inferior myocardial infarction.

BACKGROUND: Right ventricular (RV) involvement is associated with increased morbidity and mortality in patients with acute inferior myocardial infarction (MI). Although electrocardiography is probably the most useful, simple, and objective tool for the diagnosis of acute MI, there are no well-defined criteria in the standard 12-lead electrocardiogram to properly identify RV involvement in patients with acute inferior MI. Our objective was to evaluate the value of ST-segment depression in lead aVL in diagnosing RV involvement in patients with acute inferior MI. MATERIALS AND METHODS: Sixty-seven patients, hospitalized with acute inferior myocardial infarction, were included in this study. The diagnosis of acute inferior myocardial infarction was based on the clinical history, characteristic enzyme pattern of CK-MB values, and the appearance of ST-segment elevation > or = 1 mm in at least two of the leads (leads II, III, aVF). RV infarction was defined by ST-segment elevation > or = 1mm in lead V4R. ST-segment depression in lead aVL that is more than 1 mm was accepted as a diagnostic criterion for RV involvement in patients with acute inferior MI. RESULTS: Thirty-one patients had >1 mm ST-segment depression and 28 of them had right ventricular infarction according to lead V4R. Thirty-six patients showed < or =1 mm ST-segment depression indicating no right ventricular involvement but four of them also had right ventricular infarction according to V4R. CONCLUSION: More than 1 mm ST-segment depression in lead aVL was found to have high sensitivity (87%), specificity (91%), high positive and negative predictive value (90%, 88%, respectively), and high diagnostic accuracy (89%) in diagnosing RV involvement in patients with acute inferior MI. Therefore, by using a simple 12-lead electrocardiographic sign, ST-segment depression >1 mm in lead aVL, obtained on admission, it is possible to identify RV involvement in patients with acute inferior MI.