Acute Coronary Syndrome in the COVID-19 Era-Differences and Dilemmas Compared to the Pre-COVID-19 Era.

The COVID-19 pandemic has led to numerous negative implications for all aspects of society. Although COVID-19 is a predominant lung disease, in 10-30% of cases, it is associated with cardiovascular disease (CVD). The presence of myocardial injury in COVID-19 patients occurs with a frequency between 7-36%. There is growing evidence of the incidence of acute coronary syndrome (ACS) in COVID-19, both due to coronary artery thrombosis and insufficient oxygen supply to the myocardium in conditions of an increased need. The diagnosis and treatment of patients with COVID-19 and acute myocardial infarction (AMI) is a major challenge for physicians. Often the presence of mixed symptoms, due to the combined presence of COVID-19 and ACS, as well as possible other diseases, nonspecific changes in the electrocardiogram (ECG), and often elevated serum troponin (cTn), create dilemmas in diagnosing ACS in COVID-19. Given the often-high ischemic risk, as well as the risk of bleeding, in these patients and analyzing the benefit/risk ratio, the treatment of patients with AMI and COVID-19 is often associated with dilemmas and difficult decisions. Due to delays in the application of the therapeutic regimen, complications of AMI are more common, and the mortality rate is higher.

Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure.

Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1∗B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 "risk-associated" genotype (OR = 2.8, p = 0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p = 0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.

Long-term mortality is increased in patients with undetected prediabetes and type-2 diabetes hospitalized for worsening heart failure and reduced ejection fraction.

BACKGROUND: We assessed the prevalence of newly diagnosed prediabetes and type-2 diabetes mellitus (T2DM), and their impact on long-term mortality in patients hospitalized for worsening heart failure with reduced ejection fraction (HFrEF). METHODS: We included patients hospitalized with HFrEF and New York Heart Association (NYHA) functional class II-III. Baseline two-hour oral glucose tolerance test was used to classify patients as normoglycaemic or having newly diagnosed prediabetes or T2DM. Outcomes included post-discharge all-cause and cardiovascular mortality during the median follow-up of 2.1 years. RESULTS: At baseline, out of 150 patients (mean-age 57 ± 12 years; 88% male), prediabetes was diagnosed in 65 (43%) patients, and T2DM in 29 (19%) patients. These patients were older and more often with NYHA class III symptoms, but distribution of comorbidities was similar to normoglycaemic patients. Taking normoglycaemic patients as a reference, adjusted risk of all-cause mortality was significantly increased both in patients with prediabetes (hazard ratio, 2.6; 95% confidence interval (CI), 1.1-6.3; p = 0.040) and in patients with T2DM (hazard ratio, 5.3; 95% CI, 1.7-15.3; p = 0.023). Likewise, both prediabetes (hazard ratio, 2.9; 95% CI, 1.1-7.9; p = 0.041) and T2DM (hazard ratio, 9.7; 95% CI 2.9-36.7; p = 0.018) independently increased the risk of cardiovascular mortality compared with normoglycaemic individuals. There was no interaction between either prediabetes or T2DM and heart failure aetiology or gender on study outcomes (all interaction p-values > 0.05). CONCLUSIONS: Newly diagnosed prediabetes and T2DM are highly prevalent in patients hospitalized for worsening HFrEF and NYHA functional class II-III. Importantly, they impose independently increased long-term risk of higher all-cause and cardiovascular mortality.

Evaluation of Oxidative Stress Markers and Catecholamine Changes in Patients with Dilated Cardiomyopathy Before and After Cardiopulmonary Exercise Testing.

INTRODUCTION: The aim of this study was to evaluate oxidative stress markers (OSM) and catecholamine levels in patients with dilated cardiomyopathy (DCM) before and after cardiopulmonary exercise testing, and to investigate the association between changes in these markers and the New York Heart Association classification (NYHA) and left ventricular ejection fraction (LVEF) in these patients. METHODS: We evaluated 74 patients with DCM and 80 control subjects without DCM. Patients were grouped according to NYHA stages I/II or III/IV. Eligible participants were considered to be those with LVEF values <45%. The OSM analysed included superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPX). The catecholamines analysed included adrenaline, noradrenaline, and dopamine. Vitamin C was also evaluated. All values were obtained before and after cardiopulmonary exercise testing. RESULTS: There was a significant increase in GR, adrenaline, and noradrenaline after testing in the DCM patients. A significant difference between controls and patients in CAT and evaluated catecholamines was observed after testing. A significant increase in GR, GPX, adrenaline, and noradrenaline for patients in NYHA I/ II, and in CAT, GR, adrenaline, noradrenaline, and dopamine for patients in NYHA III/IV, was found between the different times of observation. LVEF before testing showed a significant positive correlation with GPX, and a negative correlation with noradrenaline and adrenaline. After testing a significant negative correlation was found with SOD and GR. CONCLUSIONS: The results of our study demonstrate the complexity of the neurohumoral mechanisms and physiological alterations in the failing heart in DCM patients. Further studies are needed, including other biomarkers and larger samples of patients, in order to improve our understanding of the aetiopathogenesis of DCM development and progression.

Mineralocorticoid receptor antagonists, a class beyond spironolactone--Focus on the special pharmacologic properties of eplerenone.

The renin-angiotensin-aldosterone system can be blocked at specific levels by using different classes of pharmacologic agents, including angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers and mineralocorticoid receptor antagonists. Broad use of the latter, such as spironolactone, has been limited by significant incidence of gynecomastia and other sex-related adverse effects. These problems can be overcome with use of eplerenone, a selective mineralocorticoid receptor antagonist. Eplerenone has been specifically developed to bind selectively to the mineralocorticoid receptors in order to minimize binding to the progesterone and androgen receptors. In the last decade, multiple scientific evidences have been accumulated showing the efficacy and safety of the drug in multiple clinical conditions, including heart failure and arterial hypertension. Eplerenone is generally well tolerated, with the most frequent adverse event being hyperkalemia, with sexual adverse events (i.e. gynecomastia) being more uncommon, due to the selectivity of eplerenone. This review focuses on the pharmacodynamic and pharmacokinetic properties of eplerenone, thus providing the scientific basis to fully understand drug-to-drug interactions, in particular, and its efficacy and tolerability, in general. Noteworthy, the activity of eplerenone in special conditions and different patient populations is summarized.

The role of glycemia in acute heart failure patients.

Acute heart failure (AHF) is one of the most important cardiovascular syndromes associated with high cardiovascular morbidity, and is the major cause of admission in emergency departments worldwide. The clinical complexity of AHF has significantly increased, mostly due to the comorbidities: diabetes, arterial hypertension, dyslipidemia, obesity, peripheral vascular disease, renal insufficiency and anemia. Numerous clinical trials have demonstrated a frequent association of AHF and diabetes. Since AHF is a very heterogeneous condition, it is important to identify clinical and laboratory parameters useful for risk stratification of these populations. Hyperglycemia may be one of the most convenient, since it is widely measured, easily interpreted, and inexpensive. Acute coronary syndrome (ACS), arrhythmias and poor compliance to chronic medications are considered to be the most frequent precipitating factors of AHF in diabetics. Several studies identified diabetes as the most prominent independent predictor of morbidity and mortality in both acute and chronic heart failure (HF) patients. The following parameters were identified as the independent predictors of in-hospital mortality in patients with AHF and diabetes: older age, systolic blood pressure <100 mmHg, ACS, non-compliance, history of hypertension, left ventricular ejection fraction (LVEF) <50%, serum creatinine >1.5 mg/dL, marked elevation of natriuretic peptides, hyponatremia, treatment at admission without ACE inhibitors/ARBs/ß-blockers, and no percutaneous coronary intervention (PCI) as a treatment modality. The most frequent cause of AHF is ACS, both with ST segment elevation (STEMI) or without (NSTEMI). Hyperglycemia is very common in these patients and although frequently unrecognized and untreated, has a large in-hospital and mortality significance.

Correlation of atherogenic risk factors with retinal artery occlusion in adults.

AIM: To evaluate correlation of atherogenic risk factors between patients with retinal artery occlusion (RAO) and matched population, including those with central RAO and branch RAO. METHODS: Seventy-two participants from 2 groups were evaluated: a group with diagnosed RAO (first group; 45 participants) and a matched control group including those without RAO or any other ophthalmological disease (second group; 27 participants). From those with diagnosed RAO patients with central RAO and patients with branch RAO were evaluated separately. Additional parameters that were observed included body mass index (BMI), blood pressure, fasting glucose levels, triglycerides, LDL and HDL cholesterol fractions levels, presence of metabolic syndrome and hyperlipoproteinemia. RESULTS: There was a significant increase of LDL mean values in the group of patients with RAO. Hypertension (88.9%), hyperlipoproteinemia (68.9%) and metabolic syndrome (53.3%) were significantly more frequent in patients with RAO, while gender and diabetes mellitus were not in direct correlation with the development of RAO. The group of patients with RAO had no significantly higher values of BMI compared to the control. High density lipoprotein fraction was significantly higher in the group of patients with central RAO as compared with those with branch RAO. CONCLUSION: Patients with atherogenic risk factors are more prone to the development of RAO. Furthermore, we demonstrated that HDL had more protective effects on smaller blood vessels (branch retinal artery) than on larger blood vessels (central retinal artery).

Influence of intravitreal injection of bevacizumab on systemic blood pressure changes in patients with exudative form of age-related macular degeneration.

INTRODUCTION: The aim of our study was to examine blood pressure (BP) changes in hypertensive and nonhypertensive patients after intravitreal bevacizumab injections and to assess whether intravitreal bevacizumab carries an associated vascular risk in patients with exudative ocular disease. We also aimed to estimate the influence of gender. METHODS: The study included 57 patients with age-related macular degeneration who received an intravitreal injection of 1.25 mg (0.1 mL) of bevacizumab. We analyzed systolic and diastolic BP values separately. Patients were divided into males and females, and into hypertensives and normotensives based on their BP values. BP was measured before bevacizumab administration, and 10 minutes, 1 hour, 2 days, 7 days and 6 weeks after the injection. RESULTS: Males had a statistically significant decline in systolic BP values 1 hour and 6 weeks after drug administration (p<0.05). The most notable significant decline in diastolic BP values was for males and for normotensive participants 1 hour after drug administration (p<0.05), while the most notable decline in diastolic BP values for females and for hypertensive participants was 7 days after drug administration, with statistical significance only for hypertensive patients (p<0.01). For males it was noticed that a statistically significant decline in diastolic BP persisted after 6 weeks (p<0.05). CONCLUSIONS: An intravitreal bevacizumab injection is safe as regards BP changes over 6 weeks post administration. Regular follow up for 6 weeks should be mandatory in order to promptly recognize individuals who have changes in BP values and include them in BP treatment in order to prevent complications.

Pericardial syndromes: an update after the ESC guidelines 2004.

Despite a myriad of causes, pericardial diseases present in few clinical syndromes. Acute pericarditis should be differentiated from aortic dissection, myocardial infarction, pneumonia/pleuritis, pulmonary embolism, pneumothorax, costochondritis, gastroesophageal reflux/neoplasm, and herpes zoster. High-risk features indicating hospitalization are: fever >38 °C, subacute onset, large effusion/tamponade, failure of non-steroidal anti-inflammatory drugs (NSAIDs), previous immunosuppression, trauma, anticoagulation, neoplasm, and myopericarditis. Treatment comprises 10-14-days NSAID plus 3 months colchicine (2 × 0.5 mg; 1 × 0.5 mg in patients <70 kg). Corticosteroids are avoided, except for autoimmunity, as they facilitate the recurrences. Echo-guided pericardiocentesis (±fluoroscopy) is indicated for tamponade and effusions >2 cm. Smaller effusions are drained if neoplastic, purulent or tuberculous etiology is suspected. In recurrent pericarditis, repeated testing for autoimmune and thyroid disease is appropriate. Pericardioscopy and pericardial/epicardial biopsy may clarify the etiology. Familial clustering was recently associated with tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A gene mutation). Treatment includes 10-14 days NSAIDs with colchicine 0.5 mg bid for up to 6 months. In non-responders, low-dose steroids, intrapericardial steroids, azathioprine, and cyclophosphamide can be tried. Successful management with interleukin-1 receptor antagonist (anakinra) was recently reported. Pericardiectomy remains the last option in >2 years severely symptomatic patients. In constriction, expansion of the heart is impaired by the rigid, chronically inflamed/thickened pericardium (no thickening ~20 %). Chest radiography, echocardiography, computerized tomography, magnetic resonance imaging, hemodynamics, and endomyocardial biopsy indicate the diagnosis. Pericardiectomy is the only treatment for permanent constriction. Predictors of poor survival are prior radiation, renal dysfunction, high pulmonary artery pressures, poor left ventricular function, hyponatremia, age, and simultaneous HIV and tuberculous infection.

Anthropometric and lipid parameters trends in school children: one decade of YUSAD Study.

INTRODUCTION: Athersclerosis is a multifactorial disease that begins in childhood. There are few reports regarding influence of risk factors on the atherosclerotic processes in early period of life and adolescence. OBJECTIVE: The aim of this study was to present and analyze risk factor trends in school children over a 10-year period that were included and followed-up by the Yugoslav Study of Atherosclerosis Precursors in School Children (YUSAD Study). METHODS: There were three examinations of selected population from 13 centres. The first examination was performed when children were 10 years of age (first group; N = 6381 participants), the second examination on the same population when they were 15 years of age (second group; N = 5017) and third when children were 19/20 years of age (third group; N = 1293). Evaluated parameters included: BMI, waist circumference (WaC) and lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride). RESULTS: A significant elevation of values (p < 0.001) of BMI, WaC and triglycerides and a significant decline (p < 0.001) of total cholesterol and LDL cholesterol in boys over 5 and 10-year period was noticed. There was a significant elevation (p < 0.001) of BMI, WaC and HDL values and a significant decline in LDL cholesterol values in girls over the 5 and 10-year period. CONCLUSION: Our results point out that girls between 10 and 19/20 years have a better lipid profile during growth. It should be stressed out that childhood and adolescence can be more beneficial in the observation of risk factor influences on pathological, genetic and clinical levels.

[Evaluation of body mass index and lipid fractions levels in patients with retinal artery occlusion].

BACKGROUND/AIM: There are studies stressing out that atherosclerosis is most common associated systemic condition in patients with retinal artery occlusion. The aim of this study was to analyze values of body mass index and lipid fractions in healthy individuals and patients with retinal artery occlusion. METHODS: This study included 90 participants during a 6-year period. The population was divided into 2 groups: the group with the diagnosed retinal artery occlusion and the group without retinal artery occlusion. The observed parameters were as follows: body mass index, low and high density lipoproteins and triglycerides. RESULTS: The study revealed no significant difference regarding body mass index and triglycerides values between the two evaluated groups, while low and high density lipoproteins values were significantly higher in the group of patients with retinal artery occlusion. CONCLUSIONS: The study demonstrated that body mass index and triglycerides have less important role in atherogenic pathogenesis of retinal artery occlusion, while low density lipoprotein is the fraction that is shown to be most potent in such etiological processes.

Physical activity evaluation in Yugoslav Study of the Precursors of Atherosclerosis in School Children - YUSAD study.

INTRODUCTION: It is observed that there is a lack of physical activity and exercise in children, stressing higher prevalence of childhood obesity. The purpose of the study was to evaluate duration of physical activity in a child population and correlation of dynamics in physical activity during 5 years of follow-up in the same population. MATERIAL AND METHODS: We evaluated 3243 school children from 12 regional centres across Serbia. The first examination was done when the children were 10 years old (baseline group), while the second examination was done on the same population when children were 15 years old. Physical activity was classified as recreational activity after school. We analysed 3 groups regarding physical activity: a group of children who were physically active less than 1 hour per day (group I), a second group active from 1 hour to < 3 hours per day (group II), and a third group active ≥ 3 hours per day (group III). RESULTS: In our study we have found on examination that the majority of children were physically active between 1 and 3 hours per day. Our results indicate that there is significant movement from groups I and III toward group II on the second examination regarding the proportion in the baseline group. There is a significant increase in the number of children in group I as they get older. CONCLUSIONS: School children in Serbia are physically active predominantly between 1 and 3 hours per day at the age between 10 and 15 years.

Renal effects of ularitide in patients with decompensated heart failure.

BACKGROUND: Renal function frequently deteriorates in decompensated heart failure (DHF) patients, and one determinant is reduced renal blood flow. This may, in part, result from low cardiac output (CO), reduced mean arterial pressure (MAP), and venous congestion. The combined impact of both venous congestion (elevated right atrial pressure [RAP]) and low MAP are reflected by a reduced pressure gradient MAP-RAP. This study investigated the renal effects of ularitide, a synthetic version of the renal natriuretic peptide urodilatin in DHF patients. METHODS: In SIRIUS II, a double-blind phase II trial, 221 patients hospitalized for DHF (with dyspnea at rest or minimal activity, cardiac index or=18 mm Hg) were randomized to a single 24-hour infusion of ularitide (7.5, 15, or 30 ng/kg per minute) or placebo added to standard therapy. RESULTS: Estimated glomerular filtration rate, serum creatinine, creatinine clearance, and blood urea nitrogen (BUN) were not impaired by ularitide throughout infusion and during a 2-day follow-up period. At 24 hours, 15 ng/kg per minute ularitide reduced BUN levels (-4.07 +/- 12.30 vs -0.20 +/- 7.50 for placebo, P < .05). Ularitide at 15 and 30 ng/kg per minute rapidly elevated CO with sustained effects. Although 15 ng/kg per minute ularitide preserved the pressure gradient MAP-RAP, 30 ng/kg per minute ularitide reduced MAP-RAP by -7.8 +/- 10.6 mm Hg vs -2.4 +/- 9.8 mm Hg for placebo (P < .01, at 6 hours). A strong inverse correlation between MAP-RAP and BUN levels (Corr = -0.50579, P = .00015) was observed with 15 ng/kg per minute ularitide. CONCLUSIONS: Single 24-hour infusions of ularitide at 15 ng/kg per minute preserved short-term renal function in DHF patients possibly by both elevating CO and maintaining the MAP-RAP pressure gradient.

[Diabetic cardiomyopathy: old disease or new entity?].

Cardiovascular manifestation of diabetes has remarkable therapeutic and prognostic implications. Diabetic cardiomyopathy is a distinct heart muscle disease in patients with well-controlled diabetes mellitus that cannot be ascribed to coronary artery disease, hypertension or any other known cardiac disease. It is characterized by left ventricular diastolic dysfunction that can be detected in 52-60% of well-controlled type II diabetic subjects using contemporary Doppler techniques. Pathophysiologically, hyperglycaemia causes myocardial necrosis and fibrosis, as well as the increase of myocardial free radicals and oxidants, which decrease nitric oxide levels, worsen the endothelial function and induce myocardial inflammation. Insulin resistance with hyperinsulinaemia and decreased insulin sensitivity are responsible for left ventricular hypertrophy. Clinical manifestations of diabetic cardiomyopathy are dispnoea, arrhythmias, atypical chest pain or dizziness. The treatment of diabetic cardiomopathy should be initiated as early as diastolic dysfunction is identified. Various therapeutic options include improving diabetic control with both diet and drugs (metformin and thiazolidinediones), use of ACE inhibitors, beta blockers and calcium channel blockers. Daily physical activity and reduction in body mass index may improve glucose homeostasis by reducing the glucose/insulin ratio, and the increase of both insulin sensitivity and glucose oxidation by the skeletal and cardiac muscles. Metformin and thiazolidinendiones are used to treat insulin resistance, but have different mechanisms of action. Metformin reduces free fatty amino acids effluvium from fat cells, thereby suppressing hepatic glucose production and indirectly improving peripheral insulin sensitivity and the endothelial function. In contrast, thiazolidinediones improve peripheral insulin sensitivity by reducing circulating free fatty amino acids, but also increasing production of adiponectin, which improves insulin sensitivity. Beta-adrenoceptor blocking agents are effective in preventing or reversing myocardial dilatation and remodelling, while ACE inhibitors facilitate blood flow through microcirculation in coronary vascular bed, fat and skeletal muscle, as well as improve insulin action at the cellular level.

Management strategies in pericardial emergencies.

BACKGROUND: The most frequent pericardial emergency is cardiac tamponade, but complications of an acute coronary syndrome and aortic dissection may also involve the pericardium. Acute pericarditis can also represent a medical emergency due to chest pain of upsetting intensity. Decompensations in chronic advanced constriction and in the clinical course of purulent pericarditis necessitate critical care as well. DIAGNOSIS AND MANAGEMENT: The diagnosis of cardiac tamponade is based on clinical presentation and physical findings, confirmed by echocardiography and cardiac catheterization. Tamponade is an absolute indication for urgent drainage, either by pericardiocentesis or surgical pericardiotomy. The approach for pericardiocentesis can be subxiphoid or intercostal using echocardiographic or fluoroscopic guidance. Urgent drainage, combined with intravenous antibiotics, is also mandatory in suspected purulent pericarditis. If confirmed, it should be combined with intrapericardial rinsing (best by a surgical drainage). Pericardiocentesis is contraindicated in cardiac tamponade complicating aortic dissection. This condition should immediately lead to cardiac surgery. Although pericardiectomy is the only treatment for permanent constriction, this procedure is contraindicated when extensive myocardial fibrosis and/or atrophy are demonstrated. CASE STUDY: Iatrogenic tamponade may occur during percutaneous mitral valvuloplasty, implantation of pacemakers, electrophysiology and radiofrequency ablation procedures, right ventricular endomyocardial biopsy, percutaneous coronary interventions, and rarely during Swan-Ganz catheterization. The authors report on a 79-year-old who suffered coronary perforation and cardiac tamponade during elective stent implantation. Tamponade was successfully treated with pericardiocentesis and implantation of a membrane-covered graft stent. Subsequent recurrent pericarditis/postpericardial injury syndrome with moderate pericardial effusion was initially treated with aspirin and then with aspirin and colchicine. At 6 months, the patient is in stable remission even after withdrawal of colchicine. CONCLUSION: Natural history of pericardial diseases can be complicated with pericardial emergencies requiring prompt diagnosis, intensive care with hemodynamic monitoring, and early aggressive management. Medical supportive measures, drainage of pericardial effusion, surgical pericardiotomy, and pericardiectomy should be applied when needed with no delay. This procedural approach also applies to iatrogenic interventions leading to tamponade.

Haemodynamic and clinical effects of ularitide in decompensated heart failure.

AIMS: Ularitide is a synthetic form of urodilatin, a natriuretic peptide produced in the kidney with vasodilating, natriuretic, and diuretic effects, that offers promise for the management of decompensated heart failure (DHF). We assessed the efficacy and safety of ularitide in treating patients with DHF. METHODS AND RESULTS: In this Phase II randomized, double-blind, placebo-controlled trial, 221 DHF patients received either placebo (n=53) or ularitide at 7.5 ng/kg/min (n=60), 15 ng/kg/min (n=53), or 30 ng/kg/min (n=55) as a 24-h continuous infusion. At 6 h, ularitide demonstrated a significant decrease in pulmonary capillary wedge pressure (P=0.052, P=0.000004, P=0.000002, respectively) and improved dyspnoea score in the 7.5, 15, and 30 ng/kg/min ularitide group (P=0.0026, P=0.0026, P=0.0013, respectively). Ularitide reduced systemic vascular resistance and increased cardiac index for the 15 and 30 ng/kg/min groups (P=0.017, P=0.00002, respectively). Systolic blood pressure (BP) decreased dose dependency. Heart rate and serum creatinine were unchanged through day 3. Most frequently reported drug-related adverse events through day 3 in all ularitide groups were dose-dependent BP decrease and hypotension. CONCLUSION: Ularitide lowered cardiac filling pressures and improved dyspnoea without apparent early deleterious effects on renal function in DHF patients. These results suggest that ularitide may play a role in the management of DHF.

[Influence of heart failure severity on heart rate variability].

INTRODUCTION: Autonomic regulation of cardiovascular functions in congestive heart failure is characterised by enhanced sympathetic and diminished parasympathetic activity. The long term predominance of sympathetic tone is a significant factor in arrhythmogenesis, sudden cardiac death, and progressive pump failure. Heart rate variability (HRV) is a noninvasive method for estimating the sympatho vagal balance in cardiovascular control. AIM: The aim of this study was to analyse the influence of heart failure severity on HRV. METHOD: HRV was estimated through the spectral analysis of short term ECG (Cardiovit AT 60, Schiller, CH) in 63 patients (78% male, mean age 56.9 +/- 10.9 years) and 14 healthy volunteers (57.1% male, mean age 53.1 +/- 8.2 years). The following spectral components were measured: VLF (very low frequency), LF (low frequency), HF (high frequency), and total power (Tot Power). RESULTS: All spectral componentswere statistically, significantly lower in patients with heart failure in comparison to healthy controls (VLF: 159.89 +/- 147.02 vs. 285.50 +/- 202.77 ms2; p = 0.023, LF: 161.48 +/- 204.01 vs. 474.57 +/- 362.93 ms2; p < 0.001, HF: 88.58 +/- 102.47 vs. 362.71+/- 318.28 ms2; p < 0.001), as well as total power (Tot Power: 723.39 +/- 644.52 vs. 1807.29 +/- 1204.74 ms2; p < 0.001). A significant, negative correlation between HRV parameters and NYHA class was detected in heart failure patients (VLF: r = -0.391; p = 0.002, LF: r = -0.401; p = 0.001, and Tot Power r = -0.372; p = 0.003). Ejection fraction proved to be in significant, positive correlation to VLF (r = 0.541; p = 0.002), LF (r = 0.531; p = 0.003), HF (r = 0.418; p = 0.020), and Tot Power (r = 0.457; p = 0.013). CONCLUSION: Significant HRV reduction is a precursor to incipient heart failure (NYHA I). In heart failure progression, total power as well as the power of all spectral components is progressively reduced. LF and Tot Power are the most prominent parameters for discriminating between the different stages of heart failure. These results could promote HRV as an important decision-making tool in heart failure treatment as well as in monitoring the results of that treatment.