Pragmatic diagnostic and therapeutic algorithms to optimize new potassium binder use in cardiorenal disease.

BACKGROUND: Pivotal randomized trials demonstrating efficacy, safety and good tolerance, of two new potassium binders (patiromer and sodium zirconium cyclosilicate) led to their recent approval. A major hurdle to the implementation of these potassium-binders is understanding how to integrate them safely and effectively into the long-term management of cardiovascular and kidney disease patients using renin angiotensin aldosterone system inhibitors (RAASi), the latter being prone to induce hyperkalaemia. METHODS: A multidisciplinary academic panel including nephrologists and cardiologists was convened to develop consensus therapeutic algorithm(s) aimed at optimizing the use of the two novel potassium binders (patiromer and sodium zirconium cyclosilicate) in stable adults who require treatment with RAASi and experience(d) hyperkalaemia in a non-emergent setting. RESULTS: Two dedicated pragmatic algorithms are proposed. The lowest intervention threshold (i.e. 5.1 mmol/L or greater) was the one used in the patiromer and sodium zirconium cyclosilicate) pivotal trials, both drugs being indicated to treat hyperkalaemia in a non -emergent setting. Acknowledging the heterogeneity across specialty guidelines in hyperkalaemia definition and thresholds to intervene when facing hyperkalaemia, we have been mindful to use soft language i.e. "it is to consider", not necessarily "to do". CONCLUSIONS: Providing the clinical community with pragmatic algorithms may help optimize the management of high-risk patients by avoiding the risks of both hyper and hypokalaemia and of suboptimal RAASi therapy.

Macrophage-modulating cytokines predict adverse outcome in heart failure.

Cytokines regulating the mobilisation, recruitment and survival of mononuclear cells may play an important role in progression of heart failure. Therefore, we investigated the role of granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF) in patients with advanced heart failure. G-CSF, MCP-1 and M-CSF were determined in plasma of 351 patients with advanced heart failure by specific ELISAs. During a median follow up period of 16 months (95% confidence interval [CI]: 15-17 months) 175 patients (50%) experienced the composite endpoint rehospitalisation and all-cause mortality. M-CSF tertiles were associated with a gradually increasing risk with hazard ratios (HR) of 2.2 (95% CI: 1.5-3.2; for trend, p<0.001) for the composite endpoint and 2.6 (95% CI: 1.5-4.6; for trend, p=0.002) for all-cause mortality comparing third and first tertile. These associations remained significant in a multivariable Cox regression model after adjustment for BNP and other known risk factors (p=0.043 and p=0.024). High MCP-1 concentrations were associated with an increased risk of all-cause mortality with an adjusted HR of 1.9 (third vs. first tertile, 95% CI: 1.1-3.3; for trend, p=0.034). In contrast, G-CSF tertiles were not significantly associated with the composite endpoint or all-cause mortality in multivariable Cox regression. In conclusion, the independent and concentration-dependent association of macrophage-modulating cytokines and in particular of M-CSF with adverse outcome in advanced HF patients suggests that these cytokines may play an important pathophysiological role in progression of cardiomyopathy.

Interactions of glucose metabolism and chronic heart failure.

BACKGROUND: We evaluated insulin sensitivity and beta cell function in patients with chronic heart failure (CHF), and investigated a possible correlation of these metabolic parameters with specific biomarkers of heart failure. Additionally, we investigated the effects of two angiotensin receptor blockers (ARBs), namely telmisartan and candesartan, that were administered over a 5 month treatment period, as additional therapy to standard care. METHODS AND RESULTS: The study group consisted of 94 CHF patients. Insulin sensitivity (OGIS index) and insulin secretion parameters were investigated by frequently sampled oral glucose tolerance tests and consecutive mathematical modelling. In total, 94.6 % of patients had clinically overt diabetes, impaired glucose tolerance or insulin resistance at the time of enrolment HbA1c was found to correlate to NT-proBNP, MR-proADM, CT-proET-1, and MR-proANP, but not to Copeptin. NT-proBNP correlated inversely to OGIS. None of the metabolic parameters were altered significantly after candesartan or telmisartan treatment in either the patient or standard care group. CONCLUSION: Insulin sensitivity and insulin secretion are impaired in CHF and biomarkers of heart failure and atherosclerotic disease correlate to glucose metabolism.

Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure.

BACKGROUND: Natriuretic peptides, particularly brain natriuretic peptide (BNP), are elevated in heart failure and therefore considered to be excellent predictors of outcome. Vasopressin is also known to be related to the severity of heart disease. Copeptin--an inactive fragment of the vasopressin precursor--has not been previously investigated in the context of heart failure. MATERIALS AND METHODS: We prospectively studied 268 patients with advanced heart failure after they had been discharged from the hospital. We investigated the ability of BNP and copeptin to predict death, re-hospitalization due to heart failure, and a combination of the two endpoints. RESULTS: Over a mean follow-up period of 15.8 months (up to 24 months), 83 patients died, 122 patients experienced worsening of heart failure, and 145 patients achieved the combined endpoint. Univariate predictors of death were copeptin, BNP, age and impaired kidney function. In multivariate analysis, copeptin (chi(2) = 16, P < 0.0001) and age (chi(2) = 4, P < 0.05) were independent predictors. Univariate predictors of re-hospitalization due to heart failure were copeptin, BNP, age and impaired kidney function. Furthermore, in multivariate analysis BNP (chi(2) = 18, P < 0.0001), age (chi(2) = 11.8, P < 0.001) and copeptin (chi(2) = 4.2, P < 0.05) were found to be independent predictors. CONCLUSION: Our study is the first to show that copeptin is an excellent predictor of outcome in advanced heart failure patients. Its value is superior to that of BNP in predicting death and a combined endpoint, although BNP is still suitable for predicting chronic heart failure (CHF) re-hospitalization. Our data imply that vasopressin antagonism might be a new target to improve outcome in this population.

Comparison of transesophageal Doppler coronary flow reserve measurements with thallium-201 single-photon emission computed tomography imaging in assessment of left anterior descending artery stenoses.

BACKGROUND AND HYPOTHESIS: Recent studies demonstrate the feasibility of coronary flow reserve measurements by transesophageal echocardiographic (TEE) Doppler recordings of coronary sinus or left anterior descending (LAD) coronary artery flow velocity for detecting stenoses of the LAD artery. This study compares coronary flow reserve measurements by Doppler TEE with thallium-201 (201Tl) single-photon emission computed tomography (SPECT) in patients with proximal single-vessel LAD stenosis. METHODS: Nineteen patients with various degrees of LAD stenosis (mean area stenosis 71 +/- 24%; range 24-96%) were studied. Area stenosis by quantitative coronary angiography was < 75% in 7 patients and > 75% in 12 patients. Transesophageal LAD and coronary sinus Doppler measurements were performed at baseline and after intravenous dipyridamole. Coronary flow reserve was calculated as the ratio of hyperemic to baseline average peak velocities. Predefined coronary flow reserve cut-off values of 1.8 for the coronary sinus method and of 2.0 for the LAD method were used for diagnosis of significant LAD stenosis. Results were compared with qualitative 201Tl dipyridamole SPECT. RESULTS: Overall predictive accuracy for diagnosis of > 75% LAD stenosis was 79% for 201Tl SPECT, 77% for the transesophageal LAD and 79% for the transesophageal coronary sinus technique. Concordant results between 201Tl SPECT and the LAD and coronary sinus Doppler methods were observed in 79% and 71% of patients, respectively. CONCLUSIONS: Thallium-201 SPECT and transesophageal Doppler assessment of coronary flow reserve have similar accuracy for diagnosing significant proximal LAD stenosis. Therefore, both transesophageal Doppler techniques might constitute another widely available, noninvasive method for assessment of left coronary artery disease, if disease location is proximal.

Transesophageal versus intracoronary Doppler measurements for calculation of coronary flow reserve.

OBJECTIVE: The present study was performed to compare coronary flow reserve by transesophageal Doppler echocardiography and intracoronary Doppler flow wire measurements in patients with LAD disease. METHODS: 17 patients with various degree of LAD stenosis were studied. Intracoronary LAD Doppler measurements were performed at baseline and after intracoronary injection of 18 micrograms adenosine. Transesophageal coronary sinus and LAD Doppler measurements were performed at baseline and after intravenous dipyridamole (0.6 mg/kg/5 min). Coronary flow reserve was calculated as the ratio of hyperemic to baseline average peak velocities. RESULTS: Coronary flow reserve was 2.44 +/- 0.62 and 2.19 +/- 0.76 for proximal and distal intracoronary measurements and was 2.25 +/- 0.64 and 1.74 +/- 0.63 for transesophageal LAD- and coronary sinus measurements. Proximal intracoronary flow reserve significantly correlated with transesophageal coronary sinus (r = 0.73, p < or = 0.001) and LAD (r = 0.70, p < or = 0.005) measurements, whereas distal intracoronary flow reserve only correlated with transesophageal coronary sinus flow reserve (r = 0.56, p < or = 0.02). Receiver operating characteristic curve analysis demonstrated similar diagnostic accuracy of all applied techniques for detection of a significant LAD stenosis. CONCLUSIONS: Coronary flow reserve by both transesophageal techniques correlated with intracoronary Doppler flow wire measurements, however considerable discrepancies may occur in the individual patient.

Estimation of coronary flow reserve by transesophageal coronary sinus Doppler measurements in patients with syndrome X and patients with significant left coronary artery disease.

OBJECTIVES: This study sought to determine the feasibility of coronary sinus flow velocity analysis by transesophageal Doppler echocardiography for estimation of coronary flow reserve in patients with syndrome X and patients with coronary artery disease. BACKGROUND: Coronary flow reserve provides useful information in patients with coronary artery disease and patients with syndrome X. Current methods of measuring coronary flow reserve are invasive or require extensive laboratory equipment, or both. Transesophageal Doppler recordings of coronary sinus flow velocity before and after vasodilator application may allow noninvasive determination of coronary flow reserve. METHODS: We obtained coronary sinus flow velocity recordings before and after dipyridamole administration (0.6 mg/kg body weight per 5 min) in 9 patients with syndrome X, 14 with significant left coronary artery disease and 22 age-matched control patients. We used the formula anterograde minus retrograde flow velocity time integral times heart rate as an index of coronary sinus flow. Coronary flow reserve was calculated by dividing coronary sinus flow variables after dipyridamole administration by the respective baseline values. RESULTS: Technically adequate recordings were obtained in 44 (98%) of 45 patients. Compared with that in the control group (2.78 +/- 0.95 [mean +/- SD]), coronary flow reserve was significantly lower in patients with syndrome X (1.21 +/- 0.23, p < or = 0.001) as well as in those with coronary artery disease (1.47 +/- 0.7, p < or = 0.001). Using a cutoff coronary flow reserve value of 1.8, sensitivity, specificity and overall predictive value of coronary flow reserve determinations were, respectively, 100%, 91% and 94% for syndrome X and 86%, 91% and 89% for coronary artery disease. CONCLUSIONS: Coronary flow reserve calculation by transesophageal coronary sinus flow velocity recordings is feasible in a large proportion of patients and might be useful for the noninvasive evaluation of patients with syndrome X and patients with severe left coronary artery disease.

[Change in the patient profile in coronary heart disease at the time of initial evaluation with coronary angiography between 1975 and 1989]. / Veränderung des Patientenprofils mit koronarer Herzkrankheit zum Zeitpunkt der Erstevaluierung mittels Koronarangiographie zwischen 1975 und 1989.

BACKGROUND AND METHOD: After the introduction of coronary angioplasty in the late 1970s, diagnostic coronary angiography has been performed for reasons other than to evaluate patients for bypass surgery. The aim of this study was to evaluate the change of the patient-profile at the time of the first angiographic evaluation of coronary artery disease. Therefore, 6456 patients in the period from 1975 to 1989 were included. RESULTS: The observation period of 15 years was divided into three parts of 5 years each (group 1 1975-79, N = 1130); group 2 1980-84, N = 2412; and group 3 1984-89, N = 2914). The mean age (53.3 +/- 7.4 vs. 54.4 +/- 8.4 vs. 57.8 +/- 9.3; p < 0,0001) as well as the number of patients of age > 64 years (6.4% vs. 9.6% vs. 25.9%, p < 0.0001) increased significantly over the 15 years. Women were found twice as often in group 3 vs. group 1 (10% vs. 16% vs. 19%; p < 0.0001). In the observation period the left ventricular ejection fraction (51.1 +/- 15.9 vs. 53.8 +/- 14.4 vs. 55.4 +/- 16.2) and one-vessel disease (37.2% vs. 38.2% vs. 42.4%) increased significantly (p < 0.0001), whereas multi-vessel disease decreased (57.7% vs. 56.6% vs. 52.6%). CONCLUSION: Between 1975 and 1989 significantly more women, more patients over 64 years of age, and more patients with lower degree of coronary disease were first evaluated with coronary angiography. The change of patient-profile may have been influenced by increased risk-factors among women and the possibility to offer patients an alternative therapy to bypass surgery.