Biljana Putnikovic

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS‐ELD trial

Various beta‐blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta‐blockers in elderly patients with heart failure.

Relationship of reduced cerebral blood flow and heart failure severity in elderly males

Introduction. Brain detrimental effects are under-recognised complication of chronic heart failure (CHF). One of the major causes may be cerebral hypoperfusion. This study was designed to investigate the relationship between cerebral blood flow (CBF) and severity of CHF as well as to evaluate its determinants among different parameters of cardiac dysfunction. Methods. Seventy-one CHF males with NYHA class II and III and 20 control subjects age ≥ 55 years were recruited. CBF was evaluated by colour duplex sonography of extracranial arteries. Echocardiography, 6-min walk test, quality of life and endothelial function were also assessed. Serum NT-pro-BNP and adipokines levels (adiponectin and leptin) were measured. Results. CBF was significantly reduced in elderly patients with CHF compared to healthy controls (677 ± 170 vs 783 ± 128 ml/min, p = 0.011). Reduced CBF was associated with reduced left ventricular ejection fraction (LVEF) (r = 0.271, p = 0.022), lower 6-min walk distance (r = 0.339, p = 0.004), deteriorated quality of life (r = −0.327, p = 0.005), increased serum adiponectin (r = −0.359, p = 0.002), and NT-pro-BNP levels (r = −0.375, p = 0.001). In multivariate regression analysis, LVEF and adiponectin were independently associated with reduced CBF in CHF patients (R2 = 0.289). Conclusion. CBF was reduced in elderly males with mild-to-moderate CHF, and was associated with factors that represent the severity of CHF including high serum adiponectin and NT-pro-BNP levels, decreased LVEF, impaired physical performance, and deteriorated quality of life.

Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged >55 yr were recruited. PTH, 25-hydroxyvita-min D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77±33 vs 40±11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17±9 vs 10±2 µg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NT-pro-BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Insulin, Thrombin, ERK1/2 Kinase and Vascular Smooth Muscle Cells Proliferation

Vascular smooth muscle cells (VSMC) respond to arterial wall injury by intimal proliferation and play a key role in atherogenesis by proliferating and migrating excessively in response to repeated injury, such as hypertension and atherosclerosis. In contrast, fully differentiated, quiescent VSMC allow arterial vasodilatation and vasoconstriction. Exaggerated and uncontrolled VSMC proliferation appears therefore to be a common feature of both atherosclerosis and hypertension. Signal transduction pathways in eukaryotic cells integrate diverse extracellular signals, and regulate complex biological responses such as growth, differentiation and death. One group of proline-directed Ser/Thr protein kinases, the mitogen-activated protein kinases (MAPKs), plays a central role in these signalling pathways. Much attention has focused in recent years on subfamilies of MAPKs, the extracellular signal regulated kinases (ERKs). Here we overview the work on ERKs 1 to 2, emphasising when possible their biological activities in VSMC proliferation. It is clear from numerous studies including our own, that ERK1/ERK2 pathway has an important role in VSMC proliferation induced by insulin (INS) and thrombin. Despite the physiological and pathophysiological importance of INS and thrombin, possible signal transduction pathways involved in INS and thrombin regulation of VSMCs proliferation remains poorly understood. Thus, this review examines recent findings in signaling mechanisms involved in INS and thrombin- triggered VSMCs proliferation with particular emphasis on ERK1/2 signaling pathways. Future investigations should now focus on the mechanisms of MAPK activation which might therefore represent a new mechanism involved in the antiproliferative effect revealed in this review.

Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension.

Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.

Primary PCI for acute myocardial infarction in a patient with idiopathic thrombocytopenic purpura. A case report and review of the literature.

Background and Purpose:The occurrence of acute myocardial infarction (AMI) in patients with idiopathic thrombocytopenic purpura (ITP) is rare, especially when the platelet count is low. Since only few case reports have been published, there are no recommendations for the management of thrombocytopenic patients with AMI. The aim of the present study is to discuss different aspects of this challenging issue and to review limited data available in the literature.Case Study:An 80-year-old patient with ITP (platelet count 5 . 109/l) is presented who developed an AMI (ST segment elevation myocardial infarction) and was successfully treated by primary percutaneous coronary intervention (PCI).Conclusion:Considering the high bleeding risk in patients with ITP and AMI, careful balance between usual anticoagulation and antiplatelet therapy on the one hand, and efforts to raise platelet count on the other hand are needed.ZusammenfassungHintergrund und Fragestellung:Akute Myokardinfarkte (AMI) bei Patienten mit idiopathischer thrombozytopenischer Purpura (ITP, Morbus Werlhof) sind seltene Ereignisse. Da in der Literatur nur einige wenige Fälle beschrieben sind, existieren auch keine Therapieempfehlungen für diese Konstellation. In der vorliegenden Studie sollen unterschiedliche Aspekte dieser herausfordernden Situation diskutiert und die verfügbaren Daten aus der Literatur zusammenfassend beschrieben werden.Fallbericht:Geschildert wird der Fall eines 80-jährigen Patienten mit ITP (Thrombozytenzahl 5 . 109/l), der einen AMI (ST-Strecken-Hebungsinfarkt) erlitten hatte und mit primärer perkutaner Koronarintervention (PCI) erfolgreich behandelt wurde.Schlussfolgerung:Das hohe Blutungsrisiko bei Patienten mit ITP und AMI erfordert eine sorgfältige Balance zwischen Antikoagulation bzw. Plättchenhemmung einerseits und Anhebung der Thrombozytenzahl andererseits.

Frequency and significance of unrecognized chronic obstructive pulmonary disease in elderly patients with stable heart failure

Background and aims: Due to prolonged life-spans and modern therapeutic approaches, there has been an increase in the number of patients aged ≥65 years with chronic heart failure (CHF). The duration and quality of life in elderly patients with CHF also depend on accompanying diseases. Although frequency of chronic obstructive pulmonary disease (COPD) in patients with CHF is about 30%, it is hard to find similar data in the elderly population. COPD is defined as a spirometrically assessed ratio of a post-dilatory forced expiratory volume in the first second, divided by forced vital capacity (FEV1/FVC) <70%. The aims of our study were to assess the prevalence of previously undiagnosed COPD in outpatients (≥65 yrs) with stable CHF and to determine the effect of the combination of COPD and CHF on patients’ functional capacity as measured by a 6-minute walking test. Methods and Results: Of the 174 study patients, 126 (72.4%) were men. In 48 patients (27.6%) we found previously unrecognized COPD. They were significantly older (75.6±5.8 vs 73±4.5 years, p<0.01) and more frequently had abdominal obesity and a greater waist circumference (98.8±10.2 vs 94.9±9.1 cm, p<0.05). Patients with COPD had significantly shorter 6-min walking distance (275.5±112.9 vs 291.3±96.7 m, p<0.05). Only patient’s age had a positive prognostic association with unrecognized COPD (OR=1.16; 95% CI 1.01–1.34, p<0.01). Patients with COPD showed a significant correlation between actual/predicted FEV1 and the 6-min walking distance (r=0.39, p<0.01). Conclusions: We found a high prevalence of unrecognized COPD in elderly patients with CHF and central obesity. Chronic obstructive pulmonary disease influenced functional capacity in CHF patients, as determined by the 6-minute walking test. Closer co-operation between pulmonologists and cardiologists is necessary to optimize management of this large proportion of CHF patients.

Primary PCI for Acute Myocardial Infarction in a Patient with Idiopathic Thrombocytopenic Purpura

Background and Purpose:The occurrence of acute myocardial infarction (AMI) in patients with idiopathic thrombocytopenic purpura (ITP) is rare, especially when the platelet count is low. Since only few case reports have been published, there are no recommendations for the management of thrombocytopenic patients with AMI. The aim of the present study is to discuss different aspects of this challenging issue and to review limited data available in the literature.Case Study:An 80-year-old patient with ITP (platelet count 5 . 109/l) is presented who developed an AMI (ST segment elevation myocardial infarction) and was successfully treated by primary percutaneous coronary intervention (PCI).Conclusion:Considering the high bleeding risk in patients with ITP and AMI, careful balance between usual anticoagulation and antiplatelet therapy on the one hand, and efforts to raise platelet count on the other hand are needed.ZusammenfassungHintergrund und Fragestellung:Akute Myokardinfarkte (AMI) bei Patienten mit idiopathischer thrombozytopenischer Purpura (ITP, Morbus Werlhof) sind seltene Ereignisse. Da in der Literatur nur einige wenige Fälle beschrieben sind, existieren auch keine Therapieempfehlungen für diese Konstellation. In der vorliegenden Studie sollen unterschiedliche Aspekte dieser herausfordernden Situation diskutiert und die verfügbaren Daten aus der Literatur zusammenfassend beschrieben werden.Fallbericht:Geschildert wird der Fall eines 80-jährigen Patienten mit ITP (Thrombozytenzahl 5 . 109/l), der einen AMI (ST-Strecken-Hebungsinfarkt) erlitten hatte und mit primärer perkutaner Koronarintervention (PCI) erfolgreich behandelt wurde.Schlussfolgerung:Das hohe Blutungsrisiko bei Patienten mit ITP und AMI erfordert eine sorgfältige Balance zwischen Antikoagulation bzw. Plättchenhemmung einerseits und Anhebung der Thrombozytenzahl andererseits.

Detection of Massive Pulmonary Embolism by Transesophageal Echocardiography

Transesophageal echocardiography is a new echocardiographic technique with indications that are still expanding and being redefined. Recently, the usefulness of transesophageal echocardiography in pulmonary embolism has been demonstrated in several case reports. In this article, we present 3 cases with pulmonary embolism diagnosed by transesophageal echocardiography and discuss its diagnostic value in this clinical setting.

Effect of beta blockade on natriuretic peptides and copeptin in elderly patients with heart failure and preserved or reduced ejection fraction: Results from the CIBIS-ELD trial☆ , ☆☆

BACKGROUND We sought to investigate the effect of beta-blocker (BB) up-titration on serum levels of NT-proBNP and copeptin in patients with heart failure (HF) with reduced (HFREF) or preserved ejection fraction (HFPEF). METHODS Serial measurements of NT-proBNP and copeptin were obtained after initiation of BB up-titration in 219 elderly patients with HFREF or HFPEF. RESULTS After initial increasing trend of NT-proBNP at 6 weeks in HFREF patients, there was a subsequent decrease at 12 weeks of BB treatment up-titration (p=0.003), while no difference was found compared to baseline levels. In contrast to NT-proBNP, there was a continuous decreasing trend of copeptin in HFREF patients (at 12 weeks: p=0.026). In HFPEF patients, NT-proBNP significantly decreased (p=0.043) compared to copeptin after 12 weeks of BB up-titration. CONCLUSIONS After 12 weeks of BB optimization copeptin might reflect successful up-titration faster than NT-proBNP in HFREF, while the opposite was found in patients with HFPEF.