Claus Lüers

Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure

Aims We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output. Methods and results In 17 patients with HFNEF (median age 69 years, 13 female) and seven age-matched control patients, systolic and diastolic function was analysed by pressure–volume loops at baseline heart rate and during atrial pacing to 100 and 120 min−1. At baseline, relaxation was prolonged and end-diastolic left ventricular stiffness was higher in HFNEF, whereas all parameters of systolic function were not different from control patients. This resulted in smaller end-diastolic volumes, higher end-diastolic pressure, and a lower stroke volume and cardiac index in HFNEF vs. control patients. During pacing, frequency-dependent upregulation of contractility indices (+dP/dtmax and Ees) occurred similarly in HFNEF and control patients, but frequency-dependent acceleration of relaxation (dP/dtmin) was blunted in HFNEF. In HFNEF, end-diastolic volume and stroke volume decreased with higher heart rates while both remained unchanged in control patients. Conclusion In HFNEF, frequency-dependent upregulation of cardiac output is blunted. This results from progressive volume unloading of the left ventricle due to limited relaxation reserve in combination with increased LV passive stiffness, despite preserved force–frequency relation.

The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction

Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF‐15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF‐15 plasma levels in HFnEF.

Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent

OBJECTIVE Stretch induces functional and trophic effects in mammalian myocardium via various signal transduction pathways. We tested stretch signal transduction on immediate and slow force response (SFR) in rabbit myocardium. METHODS Experiments were performed in isolated right ventricular muscles from adult rabbit hearts (37 degrees C, 1 Hz stimulation rate, bicarbonate-buffer). Muscles were rapidly stretched from 88% of optimal length (L88) to near optimal length (L98) for functional analysis. The resulting immediate and slow increases in twitch force (first phase and SFR, respectively) were assessed at reduced [Na+]o or without and with blockade of stretch activated ion channels (SACs), angiotensin-II (AT1) receptors, endothelin-A (ET(A)) receptors, Na+/H+-exchange (NHE1), reverse mode Na+/Ca2+-exchange (NCX), or Na+/K+-ATPase. The effects of stretch on sarcoplasmic reticulum Ca2+-load were characterized using rapid cooling contractures (RCCs). Intracellular pH was measured in BCECF-AM loaded muscles, and action potential duration (APD) was assessed using floating electrodes. RESULTS On average, force increased to 216+/-8% of the pre-stretch value during the immediate phase, followed by a further increase to 273+/-10% during the SFR (n=81). RCCs significantly increased during SFR, whereas pH and APD did not change. Neither inhibition of SACs, AT1, or ET(A) receptors affected the stretch-dependent immediate phase nor SFR. In contrast, SFR was reduced by NHE inhibition and almost completely abolished by reduced [Na+]o or inhibition of reverse-mode NCX, whereas increased SFR was seen after raising [Na+]i by Na+/K+-ATPase inhibition. CONCLUSIONS The data demonstrate the existence of a delayed, Na+- and Ca2+-dependent but pH and APD independent SFR to stretch in rabbit myocardium. This inotropic response appears to be independent of autocrine/paracrine AT1 or ET(A) receptor activation, but mediated through stretch-induced activation of NHE and reverse mode NCX.

Functional Relevance of the Stretch-Dependent Slow Force Response in Failing Human Myocardium

Stretch induces immediate and delayed inotropic effects in mammalian myocardium via distinct mechanosensitive pathways, but these effects are poorly characterized in human cardiac muscle. We tested the effects of stretch on immediate and delayed force response in failing human myocardium. Experiments were performed in muscle strips from 52 failing human hearts (37°C, 1 Hz, bicarbonate buffer). Muscles were stretched from 88% of optimal length to 98% of optimal length. The resulting immediate and delayed (ie, slow force response [SFR]) increases in twitch force were assessed without and after blockade of the sarcoplasmic reticulum (SR; cyclopiazonic acid and ryanodine), stretch-activated ion channels (SACs; gadolinium, streptomycin), L-type Ca2+-channels (diltiazem), angiotensin II type-1 (AT1) receptors (candesartan), endothelin (ET) receptors (PD145065 or BQ123), Na+/H+ exchange (NHE1; HOE642), or reverse-mode Na+/Ca+ exchange (NCX; KB-R7493). We also tested the effects of stretch on SR Ca2+ load (rapid cooling contractures [RCCs]) and intracellular pH (in BCECF-loaded trabeculae). Stretch induced an immediate (<10 beats), followed by a slow (5 to 10 minutes), force response. Twitch force increased to 232±6% of prestretch value during the immediate phase, followed by a further increase to 279±8% during the SFR. RCC amplitude significantly increased, but pHi did not change during SFR. Inhibition of SACs, L-type Ca2+ channels, AT1 receptors, or ET receptors did not affect the stretch-dependent immediate or SFR. In contrast, the SFR was reduced by NHE1 inhibition and almost completely abolished by reverse-mode NCX inhibition or blockade of sarcoplasmic reticulum function. The data demonstrate the existence of a functionally relevant, SR-Ca2+–dependent SFR in failing human myocardium, which partly depends on NHE1 and reverse-mode NCX activation.

Impact of obstructive sleep apnoea on diastolic function

We investigated whether obstructive sleep apnoea (OSA) independently affects diastolic function in a primary care cohort of patients with cardiovascular risk factors. 378 study participants with risk factors for diastolic dysfunction were prospectively included and a polygraphy was performed in all patients. Diastolic dysfunction was assessed by comprehensive echocardiography including tissue Doppler. Sleep apnoea was classified according to apnoea/hypopnoea index (AHI) as none (AHI <5 events·h−1), mild (AHI ≤5 to <15 events·h−1) or moderate-to-severe (AHI ≥15 events·h−1). Patients with central sleep apnoea (n=14) and patients with previously diagnosed sleep apnoea (n=12) were excluded. In the remaining 352 subjects, 21.6% had an AHI ≥15 events·h−1. The prevalence of diastolic dysfunction increased with the severity of sleep apnoea from 44.8% (none) to 56.8% (mild) to 69.7% (moderate-to-severe sleep apnoea) (p=0.002). The degree of diastolic dysfunction also increased with sleep apnoea severity (p=0.004). In univariate regression analysis, age, desaturation index, AHI, cardiac frequency, angiotensin receptor 1 antagonist therapy, body mass index (BMI) and left ventricular mass were associated with diastolic dysfunction. In multivariate regression analysis, only age, BMI, AHI and cardiac frequency were independently associated with diastolic dysfunction. Moderate-to-severe OSA is independently associated with diastolic dysfunction in patients with classical risk factors for diastolic dysfunction.

Impact of diabetes on left ventricular diastolic function in patients with arterial hypertension.

To analyse the effect of diabetes (DM) on diastolic function in hypertensive patients.

Serum levels of interleukin-6 and interleukin-10 in relation to depression scores in patients with cardiovascular risk factors.

It is currently unknown whether elevated cytokine levels in depression are confined to any specific subgroup of depressive patients. In this study, medical out-patients presenting with cardiovascular risk factors (N = 356) were assessed for both cognitive–affective and physical symptoms of depression using the Hospital Anxiety and Depression Scale (HADS) and the Maastricht questionnaire (MQ), respectively. In study participants assigned to the highest (≥21) and lowest (≤5) quartile for the MQ score, serum levels of cytokines were measured. We found highly significant associations between cognitive–affective symptoms of depression and elevated serum levels of interleukin-6 (IL-6; ρ = .231; p = .002) and interleukin-10 (IL-10; ρ = .370; p < .001), respectively. In multiple regression models elevated IL-10 serum concentration was independently related to cognitive–affective symptoms of depression (ρ = .165; p = .002). When all cytokines were included in one model, elevated IL-10 serum concentrations remained a significant predictor for depressive mood (ρ = .157; p = .009). In patients with cardiovascular risk factors and extreme scores for vital exhaustion, elevated serum IL-6 and even more IL-10 concentrations are linked to the presence of depressive mood. Future studies will have to test whether the so far unreported association of IL-10 with depressive mood represents a causal pathway involved in the pathogenesis or in the prognostic effect of depressive mood in cardiac patients.

Natriuretic peptide vs. clinical information for diagnosis of left ventricular systolic dysfunction in primary care

BackgroundScreening of primary care patients at risk for left ventricular systolic dysfunction by a simple blood-test might reduce referral rates for echocardiography. Whether or not natriuretic peptide testing is a useful and cost-effective diagnostic instrument in primary care settings, however, is still a matter of debate.MethodsN-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical information, and echocardiographic data of left ventricular systolic function were collected in 542 family practice patients with at least one cardiovascular risk factor. We determined the diagnostic power of the NT-proBNP assessment in ruling out left ventricular systolic dysfunction and compared it to a risk score derived from a logistic regression model of easily acquired clinical information.Results23 of 542 patients showed left ventricular systolic dysfunction. Both NT-proBNP and the clinical risk score consisting of dyspnea at exertion and ankle swelling, coronary artery disease and diuretic treatment showed excellent diagnostic power for ruling out left ventricular systolic dysfunction. AUC of NT-proBNP was 0.83 (95% CI, 0.75 to 0.92) with a sensitivity of 0.91 (95% CI, 0.71 to 0.98) and a specificity of 0.46 (95% CI, 0.41 to 0.50). AUC of the clinical risk score was 0.85 (95% CI, 0.79 to 0.91) with a sensitivity of 0.91 (95% CI, 0.71 to 0.98) and a specificity of 0.64 (95% CI, 0.59 to 0.67). 148 misclassifications using NT-proBNP and 55 using the clinical risk score revealed a significant difference (McNemar test; p < 0.001) that was based on the higher specificity of the clinical risk score.ConclusionThe evaluation of clinical information is at least as effective as NT-proBNP testing in ruling out left ventricular systolic dysfunction in family practice patients at risk. If these results are confirmed in larger cohorts and in different samples, family physicians should be encouraged to rely on the diagnostic power of the clinical information from their patients.

Association of Cheyne–Stokes respiration and cardiac cachexia in congestive heart failure

In patients with congestive heart failure (CHF) cachexia as well as Cheyne-Stokes respiration (CSR) are well known disorders. The relationship between CSR and cardiac cachexia however, remains unclear so far. Clinical as well as full-night polysomnographic data from 12 cachectic patients were compared to 13 non-cachectic patients with CHF. The non-cachectic patients did not differ significantly in age (57.3+/-11.6 vs 64.8+/-14.5 years), body mass index (26.4+/-4.0 vs 25.2+/-3.2 kg m-(2)) or ejection fraction (21.8+/-5 vs 23.3+/-7%) from cachectic patients. The weight loss was 2.1+/-2.3 kg in non-cachectic vs 11.5+/-2.7 kg in cachectic patients (p<0.0001). A significant difference was detected for the prevalence CSR (5 vs 10 patients, p<0.03). In this study a high prevalence of sleep breathing disorders, in particular of CSR in CHF patients with cachexia was detected.

Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline

BackgroundTo assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function.Methods3304 patients with heart failure from 9 different studies were included (mean age 63 ± 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (≥ 50%) and 994 patients in the whole cohort suffered from diabetes.ResultsThe majority (>90%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function.ConclusionsDiabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.