Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy

PurposeDiabetic cardiac neuropathy, which is characterized by reduced heart rate variability (HRV), frequently coexists with peripheral neuropathy. Gabapentin has been used for the treatment of diabetic neuropathy. We aimed to evaluate the possible effect of gabapentin treatment on autonomic function in patients with type 2 diabetes via HRV.MethodsThirty patients with type 2 diabetes mellitus and peripheral neuropathy and 28 age- and sex-matched healthy controls were consecutively registered. Each patient underwent HRV measurements, and diabetic patients were administered gabapentin. After 3 months of gabapentin therapy, HRV parameters were measured again.ResultsBaseline HRV parameters were blunted in patients with diabetes mellitus according to the controls [standard deviation of all NN intervals (SDNN, ms): 106.3±29.9 vs. 148.8±36.5, P=.001; power spectrum of the high-frequency band (HF, ms²): 133.6±98.3 to 231.4±197.6, P=.02; power spectrum of the low-frequency band (LF, ms²): 341.8±247.8 to 511.5±409.4, P=.048; LF/HF ratio: 3.3±2.4 to 2.6±1.5, P=.33]. After 3 months of treatment with gabapentin, some HRV parameters showed some improvement. SDNN (106.2±29.8 to 119.4 ± 25, P=.016) and HF (133.6±98.3 to 167.6±118.3, P=.021) increased significantly. LF/HF ratio decreased (from 3.3±2.4 to 2.3±1.9, P=.039) and LF remained unchanged (341.8±247.8 to 352.3±228.9, P=.88).ConclusionsTherapeutic doses of gabapentin not only alleviate neuropathic symptoms but also improve cardiac autonomic function in diabetic patients with peripheral neuropathy.     

Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction

BackgroundResults on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and β-blocker therapy.Methods and ResultsNineteen patients with IDCM (age 58 ± 8 years, ejection fraction 33 ± 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [¹⁵O]H₂O, [¹¹C]acetate and [¹¹C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of β-blockade was estimated with a β-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 ± 2 versus 57 ± 12 mm Hg·L·g⁻¹, P < .0001) and reduced myocardial FFA uptake (5.5 ± 2.0 versus 6.4 ± 1.2 μmol·100 g⁻¹·min⁻¹, P < .05), but the FFA β-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction (r = −0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA β-oxidation rate constant correlated positively with the HOMA index (r = 0.53, P < .05). In patients on β-1 selective β-blockers, β-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective β-blocker.ConclusionsMyocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.     

Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure

BackgroundWe assessed the effects of candesartan in addition to angiotensin-converting enzyme (ACE) inhibitors on N-terminal pro-type natriuretic peptide (Nt-proBNP), systemic markers of inflammation and oxidative stress as well as on glucose regulation in patients with heart failure (HF).Methods and ResultsEighty patients with HF ages 62.5 ± 8.4 years presenting mostly with New York Heart Association class II symptoms (class II = 57.5%, III = 41.3%), and mean left ventricular ejection fraction 27.1 ± 7.3% were recruited. The patients were randomized to receive candesartan titrated to 32 mg 1 per day versus placebo in double-blind fashion for 6 months. Nt-proBNP, markers of inflammation and oxidative stress, glucose, insulin, and fasting insulin resistance index were analyzed. Candesartan decreased Nt-proBNP (median value = 12.4% versus −20.4%; [candesartan] P = .05), and high-sensitivity C-reactive protein (hsCRP) (+5.32% versus −20.3% [candesartan]; P = 0.046), without significantly influencing serum interleukin-6, interleukin-18, adhesion molecules, or markers of oxidative stress. Blood glucose decreased in patients treated with candesartan with a significantly greater effect in patients with higher blood glucose levels (P < .01 for interaction).ConclusionsThe addition of candesartan to ACE inhibitor and β-blocker decreases Nt-proBNP and hsCRP, but does not change the other markers of inflammation or oxidative stress in patients with heart failure. Dual angiotensin-II suppression also decreased blood glucose with a greater impact in patients with higher blood glucose level.     

Comparison of muscle sympathetic activity in ischemic and nonischemic heart failure

BackgroundThe magnitude of sympathetic activation in chronic heart failure is assumed to be independent of its cause. However, because a higher sympathetic component of heart rate variability (HRV) in patients with ischemic cardiomyopathy (ICM) has been reported, we hypothesized that patients with ICM would have a higher resting muscle sympathetic nerve activity (MSNA) than patients with nonischemic dilated cardiomyopathy (DCM).Methods and ResultsResting MSNA was assessed by microneurography and HRV concurrently by coarse-graining spectral analysis in 30 treated normotensive patients with chronic heart failure (12 with ICM and 18 with DCM), matched for age and left ventricular ejection fraction, and 23 healthy normal control subjects, matched for age and blood pressure. Peak oxygen uptake was determined during graded cycling (17 W/min) to maximum effort. MSNA was significantly different between groups (P < .001; ICM 60 ± 3; DCM 47 ± 3; control subjects 35 ± 3 bursts/min). Compared with control subjects, the total spectral power and the high-frequency component of HRV were lower in both ICM and DCM groups, but fractal and low-frequency power were lower only in the ICM group (P < .05). Peak oxygen uptake (milliliters per kilogram of body weight per minute) was significantly less in the ICM group than in the DCM group (P = .04) and lower in both groups than in the control subjects (P < .001).ConclusionsThese observations suggest an additional ischemic stimulus to sympathetic activation in heart failure, which may impair exercise capacity reflexively.     

The effects of fasting on heart rate variability in hypertensive patients

ABSTRACT

Heart rate variability (HRV) is an independent indicator of increased mortality in patients with myocardial infarction and congestive heart failure. The effects of fasting on the HRV are not known in hypertensive patients. Therefore, studying the effects of Ramadan fasting on hypertensive patients’ HRV seems reasonable to address.

We conducted a prospective study including 20 hypertensive patients with sinus rhythm. HRV was determined twice by ambulatory 24-hour Holter recordings at fasting during and after Ramadan.

Subjects mean age was 55 ± 11.8 years. Sex-ratio was 1.5. When two groups compared, statistically significant differences were found in terms of SDNN (113 ± 71 vs 140 ± 38, p = 0.001), SDANN (109.7 ± 45 vs 134.8 ± 48.3, p = 0.008), T power (2368.7 ± 121.3 vs 3660.5 ± 170.9, p = 0.03) and LF (552.2 ± 31.3 vs 903.7 ± 48.9, p < 0.0001) values.

HRV parameters were found to be decreased in Ramadan. Thus, Ramadan fasting enhances the activity of the sympathetic system in hypertensive patients.     

Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation

BackgroundLong-term impact of levosimendan on renal function remains undefined. Prospectively, we evaluated effects of levosimendan on renal function in patients with advanced chronic heart failure awaiting cardiac transplantation.Methods and ResultsOf 40 patients, 20 were randomized to receive levosimendan (10-minute bolus 12 μg/kg, followed by 0.1 μg/kg/min for 24 hours; LS Group), and 20 received no levosimendan (Controls). The groups did not differ in age, heart failure etiology, left ventricular ejection fraction, and plasma brain natriuretic peptide. Patients were followed for 3 months. At baseline, the groups did not differ in serum creatinine (1.92 ± 0.13 mg/dL in LS Group versus 1.91 ± 0.12 mg/dL in Controls, P = .81) and creatinine clearance (43.7 ± 2.9 mL/min versus 43.9 ± 2.8 mL/min, P = .84). At 3 months, we found a decrease in serum creatinine and an increase in creatinine clearance in LS Group, but not in Controls, leading to a significant intergroup difference in serum creatinine (1.60 ± 0.26 mg/dL in LS Group versus 1.90 ± 0.14 mg/dL in Controls, P = .005) and creatinine clearance (53.6 ± 8.6 mL/min versus 44.0 ± 3.3 mL/min, P = .005). An improvement in creatinine ≥0.5 mg/dL occurred in 50% patients from LS Group compared with 10% of Controls (P = .005).ConclusionsLevosimendan improves long-term renal function in advanced chronic heart failure patients awaiting cardiac transplantation.     

A Pilot Study on the Role of Autoantibody Targeting the β1-Adrenergic Receptor in the Response to β-blocker Therapy for Congestive Heart Failure

BackgroundAutoantibodies directed against the β1-adrenergic receptor exert agonistlike actions by inducing receptor uncoupling and cause myocardial damage as well as fatal ventricular arrhythmias. Previous studies have shown that β-blockers can modulate these actions of the autoantibodies. We investigated the influence of such autoantibodies in patients with congestive heart failure (CHF) receiving β-blocker therapy.Methods and ResultsEighty-two CHF patients were randomly assigned to treatment with metoprolol or carvedilol for 16 weeks. Autoantibodies were detected in 20 patients (24%) by enzyme-linked immunosorbent assay. Left ventricular function in response to β-blocker therapy did not differ significantly by the presence of the autoantibody in global analysis. However, changes of the left ventricular end-diastolic dimension (P = .04), end-systolic dimension (P < .01), and ejection fraction on radionuclide ventriculography (P = .02) were significantly larger in autoantibody-positive patients than antibody-negative patients. Changes in the plasma level of brain natriuretic peptide tended to be larger in autoantibody-positive patients (P = .09). The increase of heart rate normalized by the increase of plasma norepinephrine during exercise (an index of adrenergic responsiveness) showed a greater decrease in autoantibody-positive patients than autoantibody-negative patients (P = .035).ConclusionOur data suggest that β-blocker therapy might be more effective in CHF patients with autoantibodies targeting the β1-adrenergic receptor.     

Modified orthostatic load for spectral analysis of short-term heart rate variability improves the sensitivity of autonomic dysfunction assessment

AimTo evaluate the impact of orthostatic load for sensitivity of short-term spectral analysis of heart rate variability (HRV) assessment of potential early autonomic dysfunction in diabetes mellitus.MethodsComparison of results of short-term time- and frequency-domain analysis of HRV during single positions and during modified orthostatic load (supine 1–standing–supine 2, each position 300 s) in diabetic subjects with good glycemic control (n=80, age 38±14, diabetes duration 16±10 years) and without autonomic neuropathy as assessed by a standard bedside reflex test battery, and in nondiabetic controls (n=150, age 40±13 years).ResultsNone of the short-term frequency-domain parameters [absolute and logarithmic (LN) values of spectral powers in total- (TF), low- (LF), and high-frequency (HF) bands and its centroid frequencies] as obtained in single positions “supine” or “standing” revealed a significant difference between well-controlled patients and healthy controls (P>.3). However, during modified orthostatic load, significant differences in ΔLN TF_{(supine 1–supine 2)} and in ΔLN LF_{(supine 1–supine 2)} as well as in ΔLN LF_{(standing–supine 2)} values between diabetic and healthy subjects were recorded [?0.2±0.5 vs. ?0.1±0.4 LN (ms²), P=.05; ?0.3±0.8 vs. 0.1±0.7 LN (ms²), P=.001 and 0.2±1.0 vs. 0.4±0.9 LN (ms²), P=.05, respectively] with insignificant intergroup differences in related centroid frequencies. This finding suggests a delayed recovery of LF spectral power in diabetic subjects after orthostatic challenge.ConclusionsWhen compared with single position measurements, the modified orthostatic load protocol improves the sensitivity of short-term HRV examination. In well-controlled diabetic subjects without cardiovascular autonomic neuropathy (as excluded by standard cardiovascular reflex testing), the delayed recovery of LF band spectral power after orthostatic load with standing up indicates diminished parasympathetic activation.     

Caffeine prolongs exercise duration in heart failure

BackgroundCaffeine increases submaximal exercise performance in healthy young subjects; its effects on exercise tolerance in heart failure (HF) have not been characterized.Methods and ResultsTo determine whether caffeine increases exercise tolerance in HF, caffeine (4 mg/kg intravenously, equivalent to 2 cups of coffee) or vehicle were infused into 10 treated HF patients (left ventricular ejection fraction 25 ± 2 %), and 10 age-matched normal subjects (N) on 2 separate days in a double-blind, randomized, crossover design. We measured heart rate, blood pressure, and ventilation at rest and during graded cycling (15 W/minute) to peak effort. Peak oxygen consumption was unaffected in either group. Mean exercise time was unchanged in N (1013 ± 87 versus 988 ± 107 seconds; P = .86) but was significantly increased by caffeine in HF (from 511 ± 28 to 560 ± 37 seconds; P = .004) despite an increase in peak minute ventilation (P < .05). Resting and peak blood pressures were higher after caffeine (P < .05) in HF, not N.ConclusionCaffeine allows HF patients to exercise longer at peak effort.     

Effect of Acute β-blocker Withholding on Ventilatory Efficiency in Patients With Advanced Chronic Heart Failure

BackgroundThis is the first study to examine the effect of acute (24-hour) β-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure (CHF) during maximal incremental treadmill cardiopulmonary exercise test.Methods and ResultsSeventeen CHF patients were studied either 3 hours after administration of β-blocker (BB_ON) or 27 hours after the last β-blocker ingestion (BB_OFF). The ventilatory efficiency was measured via the slope of the linear relationship between ventilation (V′_E) and carbon dioxide production (V′CO₂) (ie, V′_E/V′CO₂ slope). Measurements were also made at rest, anaerobic threshold (AT), maximal end-tidal pressure for carbon dioxide (P_ETCO_2max), respiratory compensation point (RC), and peak exercise. Compared with BB_ON, the V′_E/V′CO₂ slope was significantly increased during BB_OFF (30.8 ± 7.4 vs. 29.1 ± 5.4, P = .04). At peak exercise, oxygen uptake (V′O₂, 16.0 ± 2.7 vs. 15.6 ± 2.8 mL·kg·min) and V′CO₂ (1458 ± 459 vs. 1414 ± 429 mL/min) were not different between the 2 conditions, whereas V′_E was higher during BB_OFF (49.5 ± 10.7 vs. 46.1 ± 9.6 L/min, P = .04). No differences were noted at AT and RC in V′O₂, V′CO₂, V′_E, V′_E/V′O₂, and V′_E/V′CO₂ ratios during the 2 conditions. At P_ETCO_2max, used to noninvasively estimate the CO₂ set point, V′_E was higher (33.9 ± 7.6 vs. 31.7 ± 7.3 L/min, P = .002) and P_ETCO₂ was lower (37.4 ± 4.8 vs. 38.5 ± 4.0 mm Hg, P = .03), whereas V′CO₂ was unchanged (1079 ± 340 vs. 1050 ± 322 mL/min) during BB_OFF.ConclusionAcute β-blocker withholding resulted in decreased ventilatory efficiency mostly from an increase of V′CO₂-independent regulation of V′_E and less likely from a change in ventilation/perfusion mismatching.     

Clinical significance of heart rate during acute decompensated heart failure to predict left ventricular reverse remodeling and prognosis in response to therapies in nonischemic dilated cardiomyopathy

Although an increased heart rate (HR) is a strong predictor of poor prognosis in cases of chronic heart failure (HF), the clinical value of HR as a predictor in acute decompensated HF (ADHF) is unclear. Seventy-eight patients with nonischemic dilated cardiomyopathy (NIDCM) with sinus rhythm who were first hospitalized for ADHF from 2002 to 2010 were retrospectively investigated after exclusion of patients with tachycardia-induced cardiomyopathy. The patients were divided into two groups stratified by HR on admission with a median value of 113 beats/min (Group H with HR ≥ 113 beats/min; Group L with HR < 113 beats/min). Despite similar backgrounds, including pharmacotherapy for HF, HR changes responding to titration of β-blocker (BB) therapy and myocardial interstitial fibrosis, left ventricular (LV) ejection fractions improved more significantly 1 year later in Group H than in Group L (57 % ± 11 % vs. 46 % ± 12 %, P < 0.001). Cardiac event-free survival rates were also significantly improved in Group H (P = 0.038). Multiple regression analysis revealed that only the peak HR on admission was an independent predictor of LV reverse remodeling (LVRR) 1 year later (β = 0.396, P = 0.005). High HR on first admission for ADHF is a strong predictor of LVRR, with a better prognosis in the event of NIDCM in response to optimal pharmacotherapy, independent of pre-existing myocardial damage and subsequent HR reduction by BB therapy.     

A randomised,controlled, double-blind,cross-over pilot study assessing the effects of spironolactone,losartan and their combination on heart rate variability and QT dispersion in patients with chronic heart failure

Background and objective

The blocking of aldosterone or angiotensin II receptors improves mortality in patients with chronic heart failure. We explored whether combining losartan and spironolactone would have any added benefit on the known surrogate of mortality by using heart rate variability (HRV) and QT dispersion as our endpoints.

Methods

We designed a three-phase, consecutive, randomised, controlled, double-blind, cross-over pilot study to assess the effects of losartan alone (50 mg/day), spironolactone (25 mg/day) with angiotensin converting enzyme (ACE) inhibitor and, finally, losartan with spironolactone, on HRV and QT dispersion. We enrolled eight patients (aged 47 to 72 years, mean = 63.7 years), with New York Heart Association (NYHA) class II–III heart failure and ejection fraction (EF) < 35%, in the study at a university-affiliated hospital in Dundee, Scotland. Digital 24-hour Holter recordings were analysed for time-domain HRV and the 12-lead ECG was optically scanned and digitised for analysis of QT dispersion. Evaluations were done at baseline, and at six, 12 and 18 weeks from baseline.

Results

Losartan and spironolactone showed statistically significant, favourable effects on HRV, QT dispersion and mean heart rate (p < 0.05).

Conclusion

The data showed that in these patients with heart failure, the addition of spironolactone to an ACE inhibitor, or the use of losartan on its own, or the combination of losartan plus spironolactone induced a favourable sympathovagal balance. The drugs significantly improved HRV indices and QT dispersion further, and the combination appeared to be safe. However, no significant differences were seen between the effects of each of these regimes on HRV and QT dispersion.     

The Effects of Race on Peak Oxygen Consumption and Survival in Patients With Systolic Dysfunction

BackgroundThe relationship of peak exercise oxygen consumption (VO₂) to survival in black heart failure (HF) patients is not well established. We examined the effects of race on peak VO₂ values and survival in HF patients with systolic dysfunction.Methods and ResultsThis study evaluated consecutive ambulatory HF patients who underwent symptom-limited stress tests with breath-by-breath expired gas analyses using ramped treadmill protocols. The relationship between cardiopulmonary exercise parameters and patient transplant-free survival was assessed by race. This study included 580 HF patients (mean age 52 ± 12 years; 28% females; 22% blacks; mean left ventricular ejection fraction 26 ± 12%; mean body mass index 28.7 ± 5.4; 73% on β-blocker). Black patients had a significantly lower peak VO₂ than white patients (14.2 ± 5.2 versus 16.4 ± 7.0; P < .0001), despite adjusting for identified covariates. However, there was no significant difference in the 1-year transplant-free survival between black and white HF patients (87% versus 85%; P = NS). Peak VO₂ was significantly associated with survival in both racial groups.ConclusionsBlack HF patients had significantly lower peak VO₂, but yet had equivalent survival rates at 1 year. Further study is warranted to clarify the impact of these racial differences on the timing of cardiac transplantation black HF patients.     

Chronotropic incompetence in adolescents and adults with congenital heart disease after cardiac surgery

BackgroundChronotropic incompetence (CI) is one of the major problems in adults with congestive heart. Little is known about CI in adults with congenital heart disease (ACHD) after cardiac surgery. The purpose of our study was to investigate the presence and risk factors of CI in ACHD patients.Methods and ResultsClinical and echocardiographic data, NT-pro brain natriuretic peptide (N-BNP), and peak oxygen uptake (VO_2peak) during spiroergometry were obtained in 345 consecutive ACHD patients. CI was defined as the failure to achieve ≥80% of the predicted maximal heart rate. A total of 117 (34%) of study patients fulfilled the CI criterion. These patients were in a higher New York Heart Association class (1.7 ± 0.06 versus 1.4 ± 0.03, P < .0001; mean ± SEM), had significantly higher N-BNP levels (230 ± 31 versus 121 ± 10 pg/mL, P < .0001) and a more pronounced impairment of VO_2peak (23.8 ± 0.6 versus 28.4 ± 0.5 mL·kg·min, P < .0001) than those without CI. Elevated odds ratios for CI were found in patients with a single ventricle (4.03), Mustard operation for transposition of the great arteries (3.11), and aortic coarctation (2.14).ConclusionsOur results indicate that CI in ACHD patients is a frequent problem and is related to the severity of the heart failure as measured by symptom assessment (New York Heart Association class), plasma N-BNP level and peak oxygen uptake.     

Association Between β-Blockers and Outcomes in Heart Failure With Preserved Ejection Fraction: Current Insights From the SwedeHF Registry

Backgroundβ-Blockers have an uncertain effect in heart failure with a preserved ejection fraction of 50% or higher (heart failure with preserved ejection fraction [HFpEF]).Methods and ResultsWe included patients with HFpEF from the Swedish Heart Failure Registry (SwedeHF) enrolled from 2011 through 2018. In a 2:1 propensity-score matched analysis (β-blocker use vs nonuse), we assessed the primary outcome first HF hospitalization, the coprimary outcome cardiovascular (CV) death, and the secondary outcomes of all-cause hospitalization and all-cause death. We performed intention-to-treat and a per-protocol consistency analyses. There were a total of 14,434 patients (median age 79 years, IQR 71–85 years, 51% women); 80% were treated with a β-blocker at baseline. Treated patients were younger and had higher rates of atrial fibrillation and coronary artery disease, and higher N-terminal pro-B-type natriuretic peptide levels. In the 4412:2206 patient matched cohort, at 5 years, 42% (95% CI 40%–44%) vs 44% (95% CI 41%–47%) had a HF admission and 38% (IQR 36%–40%) vs 40% (IQR 36%–42%) died from CV causes. In the intention-to-treat analysis, β-blocker use was not associated with HF admissions (hazard ratio 0.95 [95% CI 0.87–1.05, P = .31]) or CV death (hazard ratio 0.94 [95% CI 0.85–1.03, P = .19]). In the subgroup analyses, men seemed to have a more favorable association between β-blockers and outcomes than did women. There were no associations between β-blocker use and secondary outcomes.ConclusionsIn patients with HFpEF, β-blocker use is common but not associated with changes in HF hospitalization or cardiovascular mortality. In the absence of a strong rational and randomized control trials the case for β-blockers in HFpEF remains inconclusive.Bullet points● The effect of β-blockers with heart failure with preserved ejection fraction of 50% or greater is uncertain.● In a propensity score–matched heart failure with preserved ejection fraction analysis in the SwedeHF registry, β-blockers were not associated with a change in risk for heart failure admissions or cardiovascular deaths.Lay summaryThe optimal treatment for heart failure with a preserved pump function remains unknown. Despite the lack of scientific studies, β-blockers are very commonly used. When matching patients with a similar risk profile in a large heart failure registry, the use of β-blockers for the treatment of heart failure with a preserved pump function was not associated with any changes in heart failure hospital admissions or cardiovascular death.     

The Arg16Gly polymorphism of the β2-adrenergic receptor and left ventricular systolic function

Backgroundβ-Adrenergic receptors (ARs), including β1- and β2-AR, are involved in modulation of cardiac contractility and heart rate. Arg16Gly, a functional polymorphism in the β2-AR gene, has been reported to influence exercise capacity in heart failure patients. This study examined the association of the β2-AR Arg16Gly polymorphism with left ventricular (LV) systolic function in a biethnic population-based sample.MethodsEchocardiograms and the β2-AR Arg16Gly polymorphism were analyzed in 267 normotensive (54% African Americans) and 252 severe hypertensive (53% African Americans) adults without coronary heart disease or diabetes.ResultsThe frequencies of Gly16Gly16, Arg16Gly16, and Arg16Arg16 were 28.1%, 54.3%, and 17.6%, respectively, in normotensives, and 31.4%, 47.6%, and 21.0%, respectively, in hypertensives. In normotensives, the Gly16Gly16 homozygotes displayed greater fractional shortening (35.9% ± 4.3% v 34.1% ± 4.7% v 34.0% ± 3.9%, P = .01), ejection fraction (65.0% ± 5.8% v 62.5% ± 6.4% v 62.6% ± 5.4%, P = .01), midwall shortening (18.6% ± 1.6% v 17.9% ± 1.9% v 18.0% ± 1.6%, P = .02), and stress-corrected midwall shortening (110.1% ± 9.3% v 106.1% ± 10.6% v 108.1% ± 10.8%, P = .03) compared to the Arg16Gly16 and Arg16Arg16 groups. These associations were independent of age, sex, ethnicity, heart rate, body mass index, systolic blood pressure, LV end-diastolic dimension, and field center. No significant associations between the β2-AR Arg16Gly polymorphism and echocardiographic measures were found in hypertensives.ConclusionsThe Arg16Gly polymorphism of β2-AR may be a marker for LV chamber function and contractility in normotensive adults.     

Outpatient continuous parenteral inotropic therapy as bridge to transplantation in children with advanced heart failure

BackgroundAdvanced heart failure in children is associated with high morbidity and mortality and is often refractory to standard medical therapy. The purpose of this study was to review our institutional experience with the use of outpatient parenteral inotropic therapy (PIT) for advanced chronic heart failure in children.Methods and ResultsWe reviewed the medical records of all patients treated with PIT as outpatients. Seven patients received outpatient PIT from 2/99 to 1/05 (mean age was 14.6 years ± 3.7). Median duration of therapy was 10 weeks (range 4–84 weeks). The mean number of emergency department visits per patient was greater before starting PIT than after starting PIT (2.3 ± 1.8 versus 1.1 ± 2.2, P < .05). The mean number of hospital admissions from exacerbation of heart failure symptoms decreased after starting PIT (2.1 ± 1.3 versus 0.6 ± 0.8, P < .05). Mean EF% in patients with systolic dysfunction improved while on therapy (30 ± 14% before versus 39 ± 16% after, P < .05). There was 1 death and 5 complications in 2 patients. Six patients were successfully bridged to transplantation.ConclusionOutpatient continuous parenteral inotropic therapy may serve as a successful bridge to cardiac transplantation in selected pediatric outpatients.     

Effects of passive tilt and submaximal exercise on spectral heart rate variability in ventricular fibrillation patients without significant structural heart disease

It has been shown that tilt and exercise elicit significant changes in autonomic activity in normal subjects and that submaximal exercise causes a greater reduction in heart rate variability (HRV) in animals susceptible to ventricular fibrillation (VF). Whether there is an abnormal HRV response to tilt and exercise in patients at risk of sudden cardiac death (SCD) remains unknown. Short-term HRV before and during passive tilt and exercise was studied in 12 survivors of out-of-hospital cardiac arrest with documented VF and compared with 12 age- and sex-matched normal controls. No patient had significant structural heart disease or left ventricular dysfunction. HRV was computed as total-frequency (TF, 0.01 to 1.00 Hz), low-frequency (LF, 0.04 to 0.15 Hz) and high-frequency (HF, 0.15 to 0.40 Hz) components. There was no significant difference between normal controls and SCD survivors in HRV before or during tilt or submaximal exercise testing. The HF component was significantly decreased during tilt compared with that in the supine position in both normal controls (5.85 ± 0.61 vs 5.08 ± 0.95 In(msec²), p = 0.005) and patients (5.58 ± 1.49 versus 4.74 ± 1.18 In(msec²), p = 0.003). There was again no significant change in the TF or LF components during tilt in either patients or controls. All frequency components were significantly decreased during submaximal exercise testing in both patients and controls. However, there was no significant difference in any of these tilt- and exercise-induced changes in HRV between normal controls and SCD survivors. In conclusion, passive head-up tilt and submaximal exercise induce a significant alteration of spectral HRV in survivors of SCD without significant structural heart disease similar to that in normal subjects. Short-term assessment of HRV before and during tilt and submaximal exercise does not help in identifying patients at high risk of SCD in this patient population.     

Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability

BackgroundTo examine the clinical effect of fluid restriction in patients admitted to the hospital with class IV heart failure (HF).Methods and ResultsThis is a single-blind randomized controlled study. Time to clinical stability was compared between the fluid restricted (FR: n = 34) and free fluid (FF: n = 33) groups respectively showing no significant difference (8.3 ± 6.3 days versus 7.0 ± 6.0 days, P = .17). There was no significant difference between groups in time to discontinuation of intravenous diuretic therapy (FR: 2.7 ± 4.5 days, FF: 3.2 ± 5.6 days, P = .70). Changes from baseline to achievement of clinical stability in serum urea (P = .23), serum creatinine (P = .14), BNP (P = .42), and sodium (P = .14) did not differ between the FF and FR groups. Baseline serum sodium levels did not predict the time to clinical stability (β = −0.11, 95% CI: −0.60, 0.23).ConclusionsFluid restriction is not an evidence-based therapy although it is occasionally applied in the management of HF. These results suggest that FR is not of any clinical benefit in patients with acute decompensated HF and this hypothesis should be tested in a larger randomized controlled study.     

Magnesium administration may improve heart rate variability in patients with heart failure

Background and aimIntracellular magnesium (icMg) depletion may coexist with normomagnesemia. Mg deficiency (serum and/or intracellular) and decreased heart rate variability (HRV) are common in heart failure (HF). Since both are predictors of poor prognosis, it was of interest to evaluate the effect of Mg supplementation on HRV in patients with HF.Methods and resultsWe investigated the effect of Mg administration on HRV in normomagnesemic patients with systolic HF. HRV, serum Mg and icMg were determined before and after 5-week 300 mg/day Mg citrate treatment in 16 patients (group 1). The control group included 16 Mg-non-treated HF patients (group 2). HRV was determined by a non-linear dynamics analysis, derived from the chaos theory, which calculates HRV–correlation dimension (HRV–CD). After 5 weeks, serum Mg (mmol/l) increased more significantly in group 1 (from 0.78 ± 0.04 to 0.89 ± 0.06, p < 0.001), than in group 2 (from 0.79 ± 0.07 to 0.84 ± 0.06, p = 0.042). IcMg and HRV–CD increased significantly only in group 1 (from 59 ± 7 to 66 ± 9 mmol/g cell protein, p = 0.025, and from 3.47 ± 0.42 to 3.94 ± 0.36, p < 0.001, respectively). In group 2, the differences in the respective parameters were 63 ± 12 to 66 ± 9 mmol/g cell protein (p = 0.7) and 3.59 ± 0.42 to 3.55 ± 0.4 (p = 0.8).ConclusionMg administration to normomagnesemic patients with systolic HF increases serum Mg, icMg and HRV–CD. Increasing of HRV by Mg supplementation may prove beneficial to HF patients.