Kyu-Hyung Ryu

Adrenergic Control of the Force-Frequency Relation

This article briefly reviews recent experimental studies which show that beta-adrenergic receptor stimulation produces an important enhancement of the force-frequency relation on myocardial contractility. The basic property of the force-frequency effect to progressively enhance myocardial contractility as heart rate increases is augmented at each level of increasing adrenergic stimulation. This newly described intrinsic mechanism for the control of cardiac inotropic state, graded beta-adrenergic amplification of the force-frequency relation, is strongly manifested during normal exercise and infusion of a beta-adrenergic agonist at rest, and it influences both systolic and diastolic ventricular function. Significant impairment of adrenergic amplification of the force-frequency relation is observed in experimental heart failure and could contribute to impaired cardiac function during stress or exercise in this setting.

Improvement of hyponatraemia during hospitalisation for acute heart failure is not associated with improvement of prognosis: an analysis from the Korean Heart Failure (KorHF) registry

Objective Hyponatraemia predicts poor prognosis in patients hospitalised for acute heart failure (AHF). Yet, the association of hyponatraemia improvement with better postdischarge outcome has not been elucidated. Here, we determined the clinical impact of hyponatraemia improvement during hospitalisation on postdischarge outcome in patients admitted for AHF. Design Prospective cohort study. Setting Nation-wide twenty-four academic hospitals in Korea (mean follow-up of 1.7 years after discharge). Patients 2888 patients hospitalised for AHF. Main outcome measures Primary endpoints were composite of death or rehospitalisation due to heart failure. Results Hyponatraemia was present in 575 of total 2888 patients hospitalised for AHF at admission. Hyponatraemia was normalised in 274 patients (47.7%) at discharge. During mean follow-up of 1.7 years total 735 rehospitalisations and 397 deaths were documented. Persistent hyponatraemia during hospitalisation was significantly associated with increased incidence of composite endpoint of death or rehospitalisation in multivariate analysis compared with normonatraemia at admission (HR 1.345, 95% CI 1.075 to 1.683, p=0.010). However, improvement of hyponatraemia during hospitalisation was not significantly associated with lower incidence of composite endpoint of death or rehospitalisation in multivariate analysis (HR 1.084, 95% CI 0.709 to 1.659, p=0.709). Improved hyponatraemia was not associated with better prognosis in analysis with propensity score matching, either (HR 1.111, 95% CI 0.588 to 2.100, p=0.746). Conclusions In patients hospitalised for AHF, hyponatraemia on admission is associated with a worse prognosis compared with normonatraemia, irrespective of whether hyponatraemia improves during hospitalisation.

Prognostic value of NT-proBNP in heart failure with preserved versus reduced EF

Objective Plasma level of N-terminal–pro-brain natriuretic peptide (NT-proBNP) is a reliable prognostic factor in patients with heart failure (HF). However, it is unclear how differently the biomarker predicts adverse outcomes in HF with preserved EF (HFpEF) versus HF with reduced EF (HFrEF). Methods From the Korean Heart Failure registry, a prospective multicentre cohort for consecutive patients who were hospitalised for acute HF syndrome, those with available NT-proBNP and LVEF measurements were extracted. Patients with LVEF ≥50% were categorised as the HFpEF group (N=528) and those with ≤40% as the HFrEF group (N=1142). Results Patients with HFpEF had significantly lower NT-proBNP level than those with HFrEF (median 2723 vs 5644 ng/L, p<0.001). Event-free survival did not differ between the two groups either in terms of death from any cause (88.4% vs 86.9%; p=0.471) or the composite of death or HF readmission at 1 year (73.8% vs 70.6%; p=0.225). High levels of NT-proBNP were significantly associated with poor outcomes. However, the relationship was not different among the HFpEF and HFrEF groups (interaction p=0.956 for all-cause death; p=0.351 for the composite of all-cause death or HF hospitalisation). Conclusions Plasma level of NT-proBNP is the most powerful prognostic factor in both HFpEF and HFrEF. Although patients with HFpEF have lower NT-proBNP levels, the prognosis of a patient with HFpEF expected from a given NT-proBNP level is similar with his/her counterpart with HFrEF.

Relative contributions of different cardiovascular risk factors to significant arterial stiffness

BACKGROUND Although arterial stiffness has been known to be related to many cardiovascular (CV) risk factors, the level of contribution of each risk factor to significant arterial stiffness is not yet clear. METHODS We studied an out-patient cohort of 835 subjects who were without a history of CV disease. Brachial-ankle pulse wave velocity (baPWV) measurement and Framingham risk score (FRS) calculation were performed for all subjects. RESULTS baPWV was well correlated with FRS (r=0.523, P<0.001) and it could independently predict it (P<0.001) after adjusting for the conventional CV risk factors. We defined a baPWV>1710 cm/s as significant arterial stiffness on the basis of its ability to detect a high 10-year risk of coronary heart disease (FRS>20%). Multiple logistic regression analysis revealed that the adjusted odds ratios of significant arterial stiffness for an age >60 years, hypertension, male gender, smoking and diabetes were 6.2 (95% CI 4.4-8.7), 3.4 (95% CI 2.1-5.3), 1.9 (95% CI 1.3-2.8), 1.9 (95% CI 1.2-3.2) and 1.6 (95% CI 1.1-2.4), respectively. Hyperlipidemia and obesity were not statistically significant. CONCLUSIONS Old age and hypertension were the strongest independent predictors of significant arterial stiffness. Male gender, smoking and diabetes followed in order of strength as independent predictors.

Force-Frequency Relations in the Failing Rabbit Heart and Responses to Adrenergic Stimulation

BACKGROUND Recent experiments have documented the importance of beta-adrenergic regulation of the force-frequency relation (FFR) in the normal and failing heart. As in isolated human cardiac muscle, a descending limb of the FFR occurs at high frequencies in the intact rabbit heart, and therefore a new model of atrial pacing-induced heart failure was developed in the rabbit. Responses of the FFR to beta-adrenergic stimulation were then assessed in the conscious state before and after the induction of heart failure. METHODS AND RESULTS Rapid atrial pacing for an average of 19.5 days in instrumented rabbits produced severe left ventricular dilation with reduced cardiac output (echocardiography) and depressed myocardial contractility and relaxation rate (left ventricular dP/dt, catheter-tip micromanometer), associated with reductions in beta-adrenergic receptor density and adenylyl cyclase activity. Before heart failure, heart rate was slowed in the conscious animal from 280 +/- 30 (SD) to about 225 beats/min using a sinus node inhibitor (zatebradine), and heart rate was then increased in steps by atrial pacing from 250 to 450 beats/min; the heart rate-versus-left ventricular dP/dtmax (FFR) response showed an ascending response (increasing contractility), with a descending limb at rates greater than 375 beats/min, and dobutamine infusion amplified the ascending limb of the FFR (increased slope) and attenuated the descending limb. In heart failure the basal FFR was severely depressed with a descending limb over 350 beats/min; dobutamine shifted the FFR upward somewhat without change in the slope of the ascending limb, whereas dobutamine prevented the descending limb of the FFR. Similar responses were observed in the relations between heart rate and cardiac output. CONCLUSIONS A new model of heart failure in the conscious rabbit was developed using rapid atrial pacing and applied to study force-frequency effects. In heart failure, normal beta-adrenergic amplification of the ascending limb of the FFR by dobutamine was absent, but a marked descending limb of the FFR at higher heart rates was prevented by dobutamine. Observed reductions in components of the beta-adrenergic receptor system likely were responsible for impaired beta-adrenergic FFR amplification, but the mechanism(s) for the descending limb and its correction by dobutamine are not yet established. These responses of the FFR may influence importantly the ability of the failing heart to respond to exercise and stress.

Hemoconcentration is a good prognostic predictor for clinical outcomes in acute heart failure: Data from the Korean Heart Failure (KorHF) Registry☆

BACKGROUND Hemoconcentration is a surrogate marker of effective decongestion and diuresis therapy. Recently, hemoconcentration has been associated with decreased mortality and rehospitalization in heart failure (HF) patients. However, the prognostic power of hemoconcentration in a large sample-sized HF cohort was limited until now. METHODS AND RESULTS We analyzed data from hospitalized patients with acute heart failure (AHF) that were enrolled in the Korean Heart Failure Registry(n=2,357). The primary end point was a composite of all-cause mortality and HF rehospitalization during the follow-up period (median=347, interquartile range=78-744 days).Hemoconcentration, defined as an increased hemoglobin level between admission and discharge, was presented in 1,016 AHF patients (43.1%). In multivariable logistic regression, hemoglobin, total cholesterol, and serum glucose levels at admission, and ischemic HF, were significant determinants for hemoconcentration occurrence. The Kaplan-Meier curve showed that event-free survival was significantly higher in the hemoconcentration group compared to the non-hemoconcentration group (65.1% vs. 58.1%, log rank p<0.001). In multiple Cox proportional hazard analysis, hemoconcentration was an independent predictor of the primary end point after adjusting for other HF risk factors (hazard ratio=0.671, 95% confidence interval=0.564-0.798, p<0.001). CONCLUSIONS Hemoconcentration during hospitalization was a prognostic marker of fewer clinical events in the AHF cohort. Therefore, this novel surrogate marker will help in the risk stratification of AHF patients.

Effects of a sinus node inhibitor on the normal and failing rabbit heart

The effects on cardiac function of slowed frequency produced by a sinus node inhibitor (zatebradine, or UL-FS 49) were studied in the conscious rabbit under control conditions (n=16) and after heart failure was produced by rapid atrial pacing for an average of 18.5 days (n=8). Echocardiography was used to verify severe left ventricular (LV) dysfunction, and high-fidelity micromanometry and cardiac output measurements (Doppler echo) were performed. Echocardiographic fractional shortening was 40.3±4.1% (SD) in controls; in heart failure it was 18.0±1.6%, and the LV was enlarged. In controls, as heart rate (HR) was decreased from 279 beats per minute (bpm) by incremental doses of zatebradine (up to 0.75 mg/kg), maximal changes occurred when the heart reached 218 bpm with a maximum decrease of the first derivative of LV pressure (LV dP/dtmax) of 15.9%; LV enddiastolic pressure (EDP) increased from 4.3 to 8.4 mmHg along with a significant decrease in cardiac index (CI) of 15.2%, while LV systolic pressure (SP) was stable. In heart failure, LV dP/dtmax and CI were markedly reduced compared to controls and with reduction of HR from 257 to 221 with reduction of HR from 257 to 221 bpm LV dP/dtmax was unchanged, LVEDP increased slightly (NS), LVSP was unchanged and CI fell by 13.5% at the highest dose. In subgroups (control n=9, failure n=6), in order to eliminate the hemodynamic effects of cardiac slowing by zatebradine the sinus rate present before zatebradine was matched by atrial pacing; this procedure eliminated all hemodynamic abnormalities accompanying cardiac slowing in both groups. In conclusion, slowed HR due to a sinus node inhibitor was well tolerated in severe heart failure, and all negative hemodynamic responses in both controls and in heart failure were due entirely to a negative forcefrequency effect, without a direct depressant action of zatebradine on the myocardium.

The CKD-EPI is more accurate in clinical outcome prediction than MDRD equation in acute heart failure: Data from the Korean Heart Failure (KorHF) Registry

complex suggest AV-nodal pathway is located in the ischemic or infarction area. Prolonged PR and PJ interval or the third degree AV-nodal tract block suggest that the normal A–V conduction system and the anomalous bypass tract is anatomically closely connected and is simultaneously affected by the same disease process in the ischemic or necrotic area. In the presence of a WPW pattern, “infarct Q waves” should not be diagnosed unless the pattern is reverted. Exercise testing which can increase conduction through the atrioventricular nodal pathway or pharmacologic interventions which can decrease conduction through accessory pathway have been used for a long time to abolish preexcitation. Programmed atrial stimulation could produce block in the accessory pathway and unmask the underlying QRS morphology. Intermittent preexcitation syndrome and orthodromic atrioventricular reentrant tachycardia utilize the normal A–V pathway exclusively and allow a proper recognition and location of old MI [6]. We would like to thank all the people who participated in the study.

Low Serum Total Cholesterol Level is a Surrogate Marker, But Not a Risk Factor, for Poor Outcome in Patients Hospitalized With Acute Heart Failure: A Report From the Korean Heart Failure Registry

BACKGROUND Hypercholesterolemia is a major risk factor for incident coronary artery disease and the prevalence of heart failure (HF). The causal relationship between low total cholesterol (TC) levels and poor clinical outcome in patients with acute HF has not been investigated. This study evaluated the effect of cholesterol levels on the long-term outcome in patients hospitalized due to acute HF. METHODS AND RESULTS We analyzed a cohort of 2,797 HF patients who were eligible for analysis in 3,200 patients of the Korean Heart Failure Registry. Patients were stratified into quartiles of TC (Q1 <133, Q2 133-158, Q3 159-190, and Q4 >190 mg/dL). Propensity score matching was performed with the patients in Q1 and Q4. Patients with lower serum TC had lower blood pressure, lower hemoglobin, lower serum sodium, and higher natriuretic peptide levels than patients with higher TC levels. Low TC was associated with increased risks for death and readmission due to HF; the adjusted hazard ratio (HR) of Q1 compared with Q4 was 1.57 (95% confidence interval [CI] 1.30-1.90). However, propensity score matching analysis revealed that low cholesterol itself did not affect outcome (HR 1.12, 95% CI 0.85-1.48). CONCLUSIONS Low TC is strongly associated with mortality and morbidity in patients with HF. However, low TC seemed to be a secondary result of the patients state rather than an independent risk factor for poor outcome.

Efficacy of fixed-dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study

BackgroundThe objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.ResultsIn this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group (36.5 mmHg vs. 31.6 mmHg; p = 0.0117). The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks (52.1% vs. 33.3%; p = 0.0213) but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.ConclusionThese results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.Trial RegistrationClinicalTrials.gov: NCT01127217