The diagnostic approach and management of hypertension in the emergency department.

Hypertension urgency and emergency represents a challenging condition in which clinicians should determine the assessment and/or treatment of these patients. Whether the elevation of blood pressure (BP) levels is temporary, in need of treatment, or reflects a chronic hypertensive state is not always easy to unravel. Unfortunately, current guidelines provide few recommendations concerning the diagnostic approach and treatment of emergency department patients presenting with severe hypertension. Target organ damage determines: the timeframe in which BP should be lowered, target BP levels as well as the drug of choice to use. It's important to distinguish hypertensive emergency from hypertensive urgency, usually a benign condition that requires more likely an outpatient visit and treatment.

Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application.

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

Left ventricular ejection fraction as therapeutic target: is it the ideal marker?

Heart failure (HF) consists the fastest growing clinical cardiac disease. HF patients are categorized on the basis of underlying left ventricular ejection fraction (LVEF) into HF with preserved EF (HFpEF), reduced LVEF (HFrEF), and mid-range LVEF (HFmrEF). While LVEF is the most commonly used surrogate marker of left ventricular (LV) systolic function, the implementation of two-dimensional echocardiography in estimating this parameter imposes certain caveats on current HF classification. Most importantly, LVEF could fluctuate in repeated measurements or even recover after treatment, thus blunting the borders between proposed categories of HF and enabling upward classification of patients. Under this prism, we sought to summarize possible procedures to improve systolic function in patients with HFrEF either naturally or by the means of pharmacologic and non-pharmacologic treatment and devices. Therefore, we reviewed established pharmacotherapy, including beta-blockers, inhibitors of renin-angiotensin-aldosterone axis, statins, and digoxin as well as novel treatments like sacubitril-valsartan, ranolazine, and ivabradine. In addition, we assessed evidence in favor of cardiac resynchronization therapy and exercise training programs. Finally, innovative therapeutic strategies, including stem cells, xanthine oxidase inhibitors, antibiotic regimens, and omega-3 polyunsaturated fatty acids, were also taken into consideration. We concluded that LVEF is subject to changes in HF after intervention and besides the aforementioned HFrEF, HFpEF, and HFmrEF categories, a new entity of HF patients with recovered LVEF should be acknowledged. An improved global and refined LV function assessment by sophisticated imaging modalities and circulating biomarkers is expected to render HF classification more accurate and indicate patients with viable-yet dysfunctional-myocardium and favorable characteristics as the ideal candidates for LVEF recovery by individualized HF therapy.

A simple score for early risk stratification in acute heart failure.

INTRODUCTION: The use of many acute heart failure (AHF) risk scores is cumbersome. We therefore developed a simple AHF risk score (AHFRS) for early risk stratification. METHODS: The study consisted of a prospective derivation cohort (PDC; N=104; age, 77[21] years; LVEF (%), 35[29]) and a retrospective validation cohort (RVC; N=141; age, 76[15] years; LVEF (%), 35[25]). Clinical, echocardiography and laboratory assessment was performed at admission. The study end-point was death from any cause or HF-rehospitalization at 1year. RESULTS: In the PDC 46 (44.2%) patients experienced the end-point. Independent prognostic factors of outcome were hypertension (HTN) history, myocardial infarction (MI) history, and admission red cell distribution width (RDW). Multivariate logistic regression indicated 8-, 4-, and 3-times higher odds ratio for development of study end-point in patients without a HTN history, with MI history, and RDW≥15% (median) respectively. Thus in AHFRS, 2 points were assigned for absence of HTN history, 1 point for presence of MI history, and 1 point for RDW values ≥15% (0 best possible, whereas 4 worst possible score). The AHFRS identified patients who developed the end-point in the PDC with an area under the ROC curve (AUC) of 0.80 [95% C.I.: (0.71, 0.87)] denoting a high discriminative ability. These findings were confirmed in the RVC, in which the endpoint occurred in 52 (36.9%) patients and the AUC for the AHFRS was 0.82 [95% C.I.: (0.73, 0.89)]. CONCLUSIONS: AHFRS is easily obtained at admission and accurately risk stratifies AHF patients.

The heart failure pandemic: The clinical and economic burden in Greece.

BACKGROUND: The objective of this study was to identify the epidemiological and clinical characteristics of heart failure (HF) patients in Greece as well as the economic burden and the distribution of costs for the management of the disease. METHODS: Eight Greek secondary and tertiary cardiology centres from different cities have participated in a prospective, observational survey, the ESC HF Pilot Survey. 307 patients with HF, 177 hospitalised and 130 outpatients, have been recruited and monitored for 12months. Clinical and epidemiological data, along with data on mortality, hospitalisations and health care resources used have been collected. The economic evaluation was conducted from the social security system perspective. RESULTS: The annual mortality rate was 24.3% for the hospitalised patients vs 7.7% for the outpatients (P<0.001) and the annual rehospitalisation rate was 42.9% vs 19.2% respectively (P<0.001). Kaplan-Meier analyses revealed that patients with kidney dysfunction, S3 gallop and higher NYHA class have a significantly worse survival. The mean annual economic burden of the social security system per HF patient was estimated at €4411±4764. About two thirds of this cost is due to in-patient care. CONCLUSIONS: Despite the progress in the management of the disease, about one in four hospitalised patients dies and four in ten are rehospitalised in less than one year. Moreover, the disease imposes a significant economic burden for the social security system and national economy. Their findings suggest that there is still need of more effective drug treatment and efficient disease management programs focused in the reduction of the hospital admissions.

Levosimendan meta-analyses: Is there a pattern in the effect on mortality?

BACKGROUND: Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. METHODS: We here review all previously published meta-analyses on levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing levosimendan into the market. RESULTS: Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. CONCLUSION: The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of levosimendan, with data from multiple randomized trials and meta-analyses.

The diagnostic yield of transesophageal echocardiography in patients with cryptogenic cerebral ischaemia: a meta-analysis.

BACKGROUND AND PURPOSE: The diagnostic utility of transesophageal echocardiography (TEE) in patients with cryptogenic ischaemic stroke (IS) or transient ischaemic attack (TIA) remains controversial. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines to estimate the pooled prevalence of potential cardioembolic causes detected by TEE in prospective observational studies of cryptogenic IS/TIA. Cardiac conditions causally associated with cerebral ischaemia were considered to be intramural thrombi and intracardiac tumors according to ASCO phenotyping of IS. RESULTS: Thirty-five eligible studies, comprising 5772 patients (mean age 53.6 years, 56.9% men) were identified. The most common TEE finding was ascending aorta and/or aortic arch atheroma [51.2% (27.4%-74.5%)], followed by patent foramen ovale (PFO) [43.2% (36.3%-50.4%)]. Complex aortic plaques and large PFOs were reported in 14% (10.2%-18.9%) and 19.5% (16.6%-22.8%) of TEE evaluations. The prevalence of atrial septal aneurysm was 12.3% (7.9%-18.7%) and was significantly higher in conjunction with PFO presence (risk ratio 2.04, 95% confidence interval 1.63-2.54, P < 0.001). The prevalence of left atrial thrombus [3.0% (1.1%-8.3%)] and spontaneous echo contrast [3.8% (2.3%-6.2%)] was low. The prevalence of intracardiac tumors was extremely uncommon [0.2% (0%-0.7%)]. Significant heterogeneity was identified (I(2) > 60%) in the majority of analyses. Heterogeneity was not affected by cryptogenic stroke definition (TOAST versus alternative criteria). After dichotomizing available studies using a cut-off of 50 years, PFO was significantly (P = 0.001) more prevalent in younger than in older patients. CONCLUSION: Routine TEE in patients with cryptogenic IS/TIA commonly identifies abnormal findings. However, the prevalence of cardiac conditions considered to be causally associated with cerebral ischaemia (intracardiac thrombi and tumors) is low.

Pharmaco-economics of levosimendan in cardiology: a European perspective.

INTRODUCTION: Heart failure places a significant economic burden on health care. Acute heart failure requires hospitalization and often frequent re-hospitalization in expensive wards where vasoactive rescue therapy is often added on top of standard medications. In these lean times, there is a growing need for cost-effective therapeutic options that supply superior support and in addition shorten the length of stay in hospital and reduce re-hospitalization rates. The inodilator levosimendan represents the latest addition to the vasoactive treatments of acute heart failure patients, and it appears to meet these expectations. Our aim was to answer the question whether the treatment efficacy of levosimendan - when selected as therapy for patients hospitalized for acute heart failure - brings savings to hospitals in various European countries representing different economies. METHODS AND RESULTS: We took a conservative approach and selected some a fortiori arguments to simplify the calculations. We selected seven European countries to represent different economies: Italy, Spain, Greece, Germany, Sweden, Finland and Israel. Data on the costs of medications and on the cost per day were collected and fed in a simple algorithm to detect savings. These saving varied from country to country, from a minimum of €0.50 in Germany to a maximum of €354.64 in Sweden. CONCLUSIONS: The use of levosimendan as a therapy for patients hospitalized for acute heart failure provides a net saving to hospitals driven by a reduction in the length of hospital stay. This finding is true in each of the countries considered in this study.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus.

BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Association of soluble apoptotic markers with impaired left ventricular deformation in patients with rheumatoid arthritis. Effects of inhibition of interleukin-1 activity by anakinra.

Myocardial function is impaired in rheumatoid arthritis (RA). Inhibition of interleukin (IL)-1 activity reduces experimental myocardial infarction by limiting apoptosis. We investigated whether a) soluble apoptotic markers are related with impaired left ventricular (LV) performance and b) treatment with anakinra, an IL-1 receptor antagonist, reduces apoptotic markers leading to improved LV performance in RA. We studied 46 RA patients. In an acute, double-blind cross-over trial, 23 patients were randomised to a single injection of anakinra or placebo and after 48 hours (h) to the alternative treatment. In a chronic trial, 23 patients who received anakinra for 30 days were compared with 23 patients who received prednisolone. At baseline, 3 h and 30 days after treatment, we measured circulating IL-1ß, tumour necrosis factor (TNF)-α, Fas, Fas-ligand and caspase-9 to assess apoptosis. At baseline and 30 days after treatment, we assessed LV longitudinal strain, strain rate and E/Em ratio using 2D-speckle tracking and tissue Doppler echocardiography. At baseline, increased apoptotic markers were related with reduced LongSRS and increased E/Em (p<0.05). After 3 h and 30 days of anakinra, there was a reduction in Fas (median 481 vs. 364 vs. 301 pg/ml), Fas-ligand (median 289 vs. 221 vs. 190 pg/ml), caspase-9 (median 1.90 vs. 1.40 vs. 1.07 ng/ml), TNF-α and IL-1ß (p<0.05 for all comparisons). E/Em, LongS and LongSRS were improved after anakinra (p<0.01) and their percent changes were related with the corresponding changes of Fas and caspase-9 (p<0.05). No changes of the examined parameters were observed after prednisolone. In conclusion, inhibition of IL-1 activity by anakinra reduces apoptotic markers leading to improved LV performance in RA.

Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF).

PURPOSE: We performed a survey on acute heart failure (AHF) in nine countries in four continents. We aimed to describe characteristics and management of AHF among various countries, to compare patients with de novo AHF versus patients with a pre-existing episode of AHF, and to describe subpopulations hospitalized in intensive care unit (ICU) versus cardiac care unit (CCU) versus ward. METHODS AND RESULTS: Data from 4,953 patients with AHF were collected via questionnaire from 666 hospitals. Clinical presentation included decompensated congestive HF (38.6%), pulmonary oedema (36.7%) and cardiogenic shock (11.7%). Patients with de novo episode of AHF (36.2%) were younger, had less comorbidities and lower blood pressure despite greater left ventricular ejection fraction (LVEF) and were more often admitted to ICU. Overall, intravenous (IV) diuretics were given in 89.7%, vasodilators in 41.1%, and inotropic agents (dobutamine, dopamine, adrenaline, noradrenaline and levosimendan) in 39% of cases. Overall hospital death rate was 12%, the majority due to cardiogenic shock (43%). More patients with de novo AHF (14.2%) than patients with a pre-existing episode of AHF (10.8%) (p = 0.0007) died. There was graded mortality in ICU, CCU and ward patients with mortality in ICU patients being the highest (17.8%) (p < 0.0001). CONCLUSIONS: Our data demonstrated the existence of different subgroups based on de novo or pre-existing episode(s) of AHF and the site of hospitalization. Recognition of these subgroups might improve management and outcome by defining specific therapeutic requirements.

Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study.

OBJECTIVE: We sought to quantify left atrial longitudinal function by tissue Doppler (TDI) and two-dimensional (2D) strain in patients with hypertrophic cardiomyopathy (HCM). DESIGN: Case-control study. SETTING: Tertiary university hospital. PATIENTS: 43 consecutive patients with familial HCM, aged 49 (SD 18) years, along with 21 patients with non-HCM left ventricular hypertrophy (LVH, aged 52 (12) years) and 27 healthy volunteers (aged 42 (13) years). INTERVENTIONS: Subjects were studied by both TDI and 2D left atrial strain during all three atrial phases (reservoir, conduit, contractile), as well as by left ventricular systolic strain; total atrial deformation (TAD) was defined as the sum of maximum positive and maximum negative strain during a cardiac cycle. MAIN OUTCOME MEASURES: Left atrial longitudinal function. RESULTS: Both TDI and 2D atrial strain and TAD were significantly reduced in HCM, compared to the other two groups in all atrial phases (p<0.001 in most cases); left ventricular systolic strain was also significantly reduced in HCM (p<0.001). Adding 2D contractile atrial strain to a model of conventional echo measurements (including left atrial diameter and volume index, interventricular septal thickness and E/A ratio and E/e' ratios) increased its prognostic value in differentiating HCM from non-HCM LVH (p value of the change <0.001), while addition of TDI atrial strain or left ventricular strain did not. A cut-off for 2D contractile strain of -10.82% discriminated HCM from non-HCM LVH with a sensitivity of 82% and a specificity of 81%. Intra-observer and inter-observer variabilities for atrial strain in HCM were 16% and 17.5% for TDI and 8% and 9.5% for 2D, respectively. Processing time per case in HCM was 12.5 (2.6) minutes for TDI versus 3.8 (1.2) minutes for 2D strain (p<0.001). CONCLUSION: Left atrial longitudinal function is reduced in HCM compared to non-HCM LVH and healthy controls. In addition, 2D atrial strain has an additive value in differentiating HCM from non-HCM LVH and it is more reproducible and less time consuming than TDI strain.

Clinical and prognostic implications of self-rating depression scales and plasma B-type natriuretic peptide in hospitalised patients with chronic heart failure.

BACKGROUND: Depression is common among patients with chronic heart failure (CHF) and has been independently associated with a poorer prognosis. PURPOSE: This study evaluated the clinical and prognostic value of depression scales (Beck Depression Inventory (BDI), Zung Self-rating Depression Scale (Zung SDS)) along with plasma B-type natriuretic peptide (BNP) in CHF. METHODS: 155 hospitalised CHF patients (ejection fraction 26.9% (SD 6.4%)) were studied by depression (BDI, Zung SDS) and functional questionnaires (Kansas City Cardiomyopathy Questionnaire (KCCQ), Duke Activity Status Index (DASI)), BNP and 6-minute walk test (6MWT). Patients were followed for 6 months for cardiovascular events, including death from any cause or rehospitalisation for CHF decompensation. RESULTS: Seventy-six (49%) patients with depressive symptoms, as estimated by both scales, had significantly lower DASI and KCCQ scores (13.2 (SD 9.9) vs 23.6 (SD 13.0) and 26.6 (SD 15.0) vs 45.0 (SD 17.0), respectively; p<0.001), higher BNP (921 (SD 889) vs 439 (SD 267) pg/ml, p = 0.001) and reduced 6MWT (270 (SD 130) vs 337 (SD 133); p<0.001). According to logistic regression analysis, Zung SDS and BNP were independently associated with adverse clinical outcomes; values of Zung SDS >or=40 and of BNP >or=290 pg/ml predicted future events with a sensitivity of 82% and 94% and a specificity of 45% and 46%, respectively. The combination of Zung SDS plus BNP had an additive prognostic value, predicting events with a sensitivity of 77% and a specificity of 70% (event-free survival: Zung <40 and BNP <290 pg/ml; 170 (SD 9) days; Zung >or=40 and BNP <290 pg/ml, 159 (SD 14) days; Zung <40 and BNP >or=290 pg/ml, 118 (SD 15) days; Zung >or=40 and BNP >or=290 pg/ml, 73 (SD 8) days, p<0.001). CONCLUSIONS: CHF patients with depressive symptoms have impaired physical activity, associated with excessive neurohormonal activation. Among the studied scales, Zung SDS seemed to independently predict clinical outcome, especially in patients with increased plasma BNP concentration. Hence, the combination of those two modalities provides a practical means for risk stratification in CHF.

Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure.

BACKGROUND: Levosimendan is a novel inodilator that improves central haemodynamics and symptoms of patients with decompensated chronic heart failure. The role, however, of repeated levosimendan infusions in the management of these patients has not yet been properly assessed. PURPOSE: This randomised placebo-controlled trial investigated the effects of serial levosimendan infusions on cardiac geometry and function, and on biomarkers of myocardial injury and neurohormonal and immune activation (troponin T, N-terminal B-type natriuretic pro-peptide (NT-proBNP), C reactive protein (CRP) and interleukin (IL) 6) in patients with advanced heart failure. METHODS: 25 patients with decompensated chronic heart failure were randomised (2:1) to receive five serial 24-h infusions (every 3 weeks) of either levosimendan (n = 17) or placebo (n = 8), and were evaluated echocardiographically and biochemically before and after each drug infusion and 30 days after the final infusion. RESULTS: Following treatment, cardiac end-systolic and end-diastolic dimension and volume indices were significantly reduced only in the levosimendan-treated patients (p<0.01). A significant decrease in NT-proBNP (p<0.01), high-sensitivity CRP (p<0.01) and plasma IL6 (p = 0.05) was also observed in the levosimendan group, whereas these markers remained unchanged in the placebo group; similar changes were observed after each drug infusion. Although the number of patients with a positive troponin T (>or=0.01 ng/ml) was not different between the two groups at baseline, it was significantly higher in the placebo-treated group during the final evaluation (p<0.05). CONCLUSION: Serial levosimendan treatments improved left ventricular performance and modulated neurohormonal and immune activation beneficially in patients with advanced heart failure, without increasing myocardial injury.