Neurohormonal Profile Research Articles

Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure.

Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read’s rebreathing method. The induction trial did not result in any adverse events and minimal SpO2 during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO2 during induced PB (r = −0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.

Comparison between cryoballoon and radiofrequency for atrial fibrillation ablation in patients with heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Radiofrequency (RF) and cryoballoon (CB) ablation are the most commonly performed methods for catheter ablation in patients with atrial fibrillation (AF). However, data regarding AF ablation in patients with reduced left ventricular ejection fraction (LVEF) is scarce. Purpose We aimed to compare the safety and efficacy of RF and CB AF ablation in heart failure (HF) patients with LVEF &amp;lt;50%. Methods HF patients whose LVEF &amp;lt; 50% were included in this retrospective study. Transthoracic echocardiography (TTE) was performed to evaluate LVEF by using Modified Simpson method before and after the procedure. Atrial tachyarrhythmia (ATa) recurrence was defined as detection of AF, atrial flutter, or atrial tachycardia (≥ 30 s) after a 3-month blanking period. Results Eighty-nine (n = 42 CB and n = 47 RF) HF patients were enrolled and baseline characteristics were listed in Table-1. There was no significant difference in AF recurrence rate between the groups [16 (38.1 %) in CB and 12 (25.5 %) in RF, respectively, P = 0.296] during the follow up of median 16.5 (10.25-24) and 11 (9-17) months (Figure-1). There was significant increase in LVEF (39.52 ± 7.77 vs. 46.30 ± 10.95, P &amp;lt; 0.001) and decrease in brain natriuretic peptide (BNP) [230 (10-1653.10) vs. 163 (10-1653.10), P = 0.003] levels after ablation. The changes in LVEF (P = 0.370) and BNP (P = 0.772) were similar between the CB and RF ablation groups. Conclusion Our findings demonstrated that AF ablation using either CB or RF was associated with an improvement in LVEF and neurohormonal profile in AF patients with reduced LVEF.

Long Term Impact of Epicardial Left Atrial Appendage Ligation on Systemic Hemostasis: LAA HOMEOSTASIS-2.

Background: Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. Objective: To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. Methods: In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. Results: In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. Conclusions: Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction.

Evaluation of the beneficial effect of metformin on clinical indicators of heart failure patients with coronary artery disease and impaired glucose tolerance within a 12-month follow-up

BackgroundTaking into account evident interrelation between chronic heart failure (CHF) and carbohydrate metabolism disorders (CMD), hyperglycemia correction should also mitigate adverse metabolic effects on the course of CHF, improving the quality of life (QOL) and prognosis. To date, there are several clinical observational and experimental studies on the cardioprotective properties of metformin. No randomized clinical trials currently available. PurposeSo, the aim of the study is to evaluate baseline and prospective data of ischemic etiology HF FC III (NYHA) patients with prediabetes. Methodsopen label randomized clinical trial in 76 CHF patients with prediabetes was performed. Inclusion criteria: ischemic CHF FC III (NYHA) without CMD and glucose-lowering drugs intake in anamnesis, not older than 65, receiving CHF and CAD basic therapy 3 months prior to inclusion. Exclusion criteria: acute coronary syndrome, acute CHF decompensation, thyroid dysfunction, CKD with eGFR less than 45 ml/min/1,74m2. Clinical examination with collection of complaints, medical history; systolic and diastolic blood pressure (DBP), heart rate (HR), anthropometric indicators (height, weight, BMI, waist circumference) were evaluated. HF FC was assessed by 6-minute walking test results, QOL – by MLHFQ. Laboratory data: fasting and postprandial glucose, HbA1C, lipid profile, creatinine with eGFR, daily proteinuria, serum lactate. Insulin, aldosterone, Nt-proBNP levels determined by ELISA. IR was assessed using HOMA-IR. LV EF was assessed using transthoracic echocardiography. All patients were on lifestyle modification (LSM) and randomized for 2 groups with (n=39) and without (n=37) metformin. Results. In comparison with baseline indicators in metformin group decreasing of BMI (p=0.000), DBP (p=0.005), HR (p=0.000), postprandial glycemia, HbA1C, insulin (IR), aldosterone and Nt-proBNP levels, as well as improvement of kidney function (serum creatinine, eGFR, daily proteinuria) and neurohormonal profile (aldosterone, Nt-proBNP) were revealed after 12 months (p=0.000 in all cases). Moreover, both indicators of QOL (MLHFQ points (p=0.001) and 6-minute walking test results (p=0.000)) and left ventricular ejection fraction were significantly better (p=0.000). In contrast, LSM was associated with significant increasing of fasting glucose and, what`s important, kidney function deterioration. No increasing of lactate was registered in two groups. ConclusionMetformin benefits in relation to CHF course become apparent and determine importance and necessity of further large, randomized placebo-controlled trials in HF patients. So, modern therapeutic approaches should be complex and span all pathophysiological links of CHF progression already at the prediabetes stage.

Neurohormonal Profiles of Assistance Dogs Compared to Pet Dogs: What Is the Impact of Different Lifestyles?

Simple SummaryDogs are currently involved in various roles in our society beyond companionship. The tasks humans assign to them impact their daily life and can sometimes create stressful situations, possibly jeopardizing their welfare. For example, assistance dogs need to manage their emotions in various challenging situations and environments. Thus, the capacity to cope with emotional stress is highly desirable in assistance dogs (~40% of assistance dogs fail to complete their education program). The emotional and stress responses are guided by brain processes involving neuromodulators. Neurohormonal profiling of these dogs can: (i) give cues about their emotional suitability to fulfill an assistance role; (ii) enhance their selection; and (iii) help to assess and improve their welfare state during the training course. We compared basal blood levels of three neuromodulators of interest between two populations, assistance vs. pet dogs. We found significantly different concentrations of oxytocin, a neuromodulator involved in social behavior. Levels of prolactin, a putative marker of chronic stress, were higher (although not statistically significant) and variable in assistance dogs. Dogs’ age also seemed to influence the various neuromodulators levels. These findings highlight the impact of different lifestyles undergone by dogs and the possibility to use neurohormonal profiling to monitor their effect on the dogs’ welfare and stress state.Assistance dogs must manage stress efficiently because they are involved in challenging tasks. Their welfare is currently a fundamental issue. This preliminary study aimed to compare assistance dogs (AD; n = 22) with pet dogs (PD; n = 24), using blood neuromodulator indicators to help find biomarkers that can improve the AD breeding, selection, training, and welfare monitoring. Both populations originated from different breeds, are of different ages, and had different lifestyles. Basal peripheral concentrations of prolactin (PRL), serotonin (5-HT), free (fOT) and total (tOT) oxytocin were measured by immunoassays. Multiple linear regressions were performed to assess the effect of activity, age, sex, and their interactions on these parameters. Correlations between neurohormonal levels were analyzed. No interactions were significant. fOT and tOT concentrations were significantly influenced by age (p < 0.0001 and p = 0.0002, respectively) and dogs’ activity (p = 0.0006 and p = 0.0277, respectively). A tendency was observed for age effect on PRL (p = 0.0625) and 5-HT (p = 0.0548), as well as for sex effect on tOT (p = 0.0588). PRL concentrations were heterogenous among AD. fOT and tOT were significantly but weakly correlated (Pearson’s r = 0.34; p = 0.04). Blood prolactin, serotonin, and oxytocin may represent biomarkers to assess workload and chronic stress-related responses in ADs and eventually improve their selection and training.

Effect of spironolactone and benazepril on furosemide-induced diuresis and renin-angiotensin-aldosterone system activation in normal dogs.

BackgroundDiuretic braking during furosemide continuous rate infusion (FCRI) curtails urine production.HypothesisRenin‐angiotensin‐aldosterone system (RAAS) activation mediates braking, and RAAS inhibition will increase urine production.AnimalsTen healthy purpose‐bred male dogs.MethodsDogs received placebo, benazepril, or benazepril and spironolactone PO for 3 days before a 5‐hour FCRI (0.66 mg/kg/h) in a 3‐way, randomized, blinded, cross‐over design. Body weight (BW), serum creatinine concentration (sCr), serum electrolyte concentrations, PCV, and total protein concentration were measured before PO medications, at hours 0 and 5 of FCRI, and at hour 24. During the FCRI, water intake, urine output, urine creatinine concentration, and urine electrolyte concentrations were measured hourly. Selected RAAS components were measured before and after FCRI. Variables were compared among time points and treatments.ResultsDiuretic braking and urine production were not different among treatments. Loss of BW, hemoconcentration, and decreased serum chloride concentration occurred during FCRI with incomplete recovery at hour 24 for all treatments. Although unchanged during FCRI, sCr increased and serum sodium concentration decreased at hour 24 for all treatments. Plasma aldosterone and angiotensin‐II concentrations increased significantly at hour 5 for all treatments, despite suppressed angiotensin‐converting enzyme activity during benazepril background treatment.ConclusionsThe neurohormonal profile during FCRI supports RAAS mediation of diuretic braking in this model. Background treatment with benazepril with or without spironolactone did not mitigate braking, but was well tolerated. Delayed changes in sCr and serum sodium concentration and incomplete recovery of hydration indicators caused by furosemide hold implications for clinical patients.

Insulin Resistance and Ischemic Etiology Heart Failure: Is There an Interrelationship in Clinical Practice?

Background. IR promotes the development of early atherosclerosis and may increase the risk of cardiovascular complications, which is of great importance in patients with CHF. Thus, the assessment of the relationship between IR and clinical indicators of CHF is relevant in the clinical aspect and needs more detailed research. Objective: To evaluate the relationship between IR and clinical parameters in hospitalized ischemic etiology CHF patients without concomitant CMD. Methods. The study included 174 hospitalized patients with a stable course of CHF FC III (NYHA) and CAD from 18 to 65 years old, without previously identified CMD. Anthropological, clinical, laboratory examination was carried out. The neurohormonal profile included insulin (IR by HOMA- IR), aldosterone, and Nt-proBNP levels. To study the relationship of IR with clinical parameters in CHF and CAD patients, a correlation analysis was performed. Results. A statistically significant relationship between IR and the following parameters was revealed: BMI (r = 0.186, p = 0.045), total FINDRISC score (r = 0.386, p = 0.000), SBP (r = 0.247, p = 0.007), DBP (r = 0.173, p = 0.063), HbA1c (r = 0.388, p = 0.000), insulin concentration (r = 0.833, p = 0.000). To identify independent predictors influencing IR, we carried out multivariate linear regression analysis with stepwise inclusion of indicators in the model, in which HOMA-IR was used as a dependent variable, and BMI, total FINDRISK scores, SBP, DBP, HbA1c levels were included as independent variables. It turned out that the independent factors associated with IR are: HbA1c (β = 0.144; p = 0.000) and the FINDRISK scale points (β = 0.064; p = 0.05). Conclusions. In patients with CHF and CAD, IR is interrelated with such indicators as BMI, FINDRISC total points, SBP, DBP, HbA1c. Independent predictors influencing IR are HbA1c and the FINDRISK total points.

Clinical and neurohormonal characteristics in African Americans with neurogenic orthostatic hypotension.

Neurogenic orthostatic hypotension (nOH) is the hallmark of neurodegenerative forms of autonomic failure, including pure autonomic failure, multiple system atrophy, and Parkinson's disease. Studies have shown autonomic physiological differences in Africans Americans (AA) such as lower heart rate variability, enhanced blood pressure reactivity, and blunted sympathetic neural response compared to non-Hispanic whites. However, the clinical characteristics and neurohormonal profile of autonomic failure in AA is unknown. A total of 65 patients with nOH participated in this study (9 AA and 56 non-Hispanic whites). Both groups were of similar age and comorbidity status, and they underwent standardized autonomic testing and assessment of neurohormonal levels and renin activity and aldosterone in supine and upright positions. There were no significant differences in baseline autonomic clinical characteristics between non-Hispanic whites and AA with nOH. Non-Hispanic whites demonstrated a significant increase in upright renin activity compared to AA (295 ± 88% vs. 13 ± 13%, respectively). AA showed a blunted increase in aldosterone compared to non-Hispanic whites (188 ± 27% vs. 59 ± 38%, respectively). These results indicated persistent suppression of the renin-angiotensin system in AA, particularly during upright posture. Our findings demonstrate that AA with nOH have similar clinical characteristics and hemodynamic autonomic profiles, but lower upright renin activity and aldosterone levels, compared to non-Hispanic whites. Renin suppression persists in AA with severe autonomic failure and can potentially contribute to postural changes and supine hypertension.

Anti-Hypertensive Medication in Geriatric Population with HFpEF

INTRODUCTION Heart failure with preserved ejection fraction (HFpEF) is a condition where the left ventricular function is ≥50%. This population has a high morbidity and mortality compared to its counter-part heart failure with reduced ejection fraction (HFrEF). However treatment in this group remain spares. Hypertension medications are widely used in practice for patients with heart failure with reduced ejection fraction, however its efficacy in HFpEF is still an ongoing research. METHOD Evidence based research from various different search engines such as Medline® , Cochrane ® , and Proquest® with inclusion of high quality evidence such as meta-analysis, systematic review, RCT, and cohort studies. The selected papers were screened for validity, importance and applicability to the case in question. RESULT The two different RCTs studies showed that ACE-I had no effects in HFpEF. Research by Kitzman et al. showed that ACE-I did not show any improvement of left ventricular mass, neuro-hormonal profile, and 6 minutes walking test. This was also confirmed by Zi et al., which in addition showed that ACE-I did not increase the quality of life in the geriatric subjects. CONCLUSION All in all, ACE-I as a type of anti-hypertensive medication does not benefit geriatric population of HFpEF

Neurohormonal and metabolic profile of heart failure in obese versus non-obese patients

Neurohormonal and metabolic profile of heart failure in obese versus non-obese patients

Effects of Heart Rate Reduction With Either Pyridostigmine or Ivabradine in Patients With Heart Failure: A Randomized, Double-Blind Study.

Heart rate (HR) reduction with ivabradine has been proved to reduce hospitalization and death from heart failure (HF). We sought to investigate whether pyridostigmine would effectively reduce HR in patients with chronic HF as compared with ivabradine. Twenty-one patients with HF who were in sinus rhythm with a resting HR over 70 bpm, despite optimal medical treatment, were included in a randomized, double-blind study comparing pyridostigmine versus ivabradine. The initial dose of ivabradine was 5 mg twice daily to reach a target HR between 50 and 60 bpm and could be titrated to a maximum of 7.5 mg twice daily. Pyridostigmine was used in a fixed dose of 30 mg 3 times daily. The baseline HR for ivabradine and pyridostigmine groups was 89.1 (13.5) and 80.1 (7.2) bpm, respectively (P = .083). After 6 months of treatment, HR was significantly reduced to 64.8 (8.3) bpm in the ivabradine group (P = .0014) and 63.6 (5.9) bpm in the pyridostigmine group (P = .0001). The N-terminal pro-B-type natriuretic peptide was reduced in the ivabradine group (median: 1308.4 [interquartile range: 731-1896] vs 755.8 [134.5-1014] pg/mL; P = .027) and in the pyridostigmine group (132.8 [89.9-829] vs 100.7 [38-360] pg/mL; P = .002). Inflammatory markers interleukin-1, interleukin-6, and tumor necrosis factor were reduced in both groups. Exercise capacity was improved in both groups, with increments in volume of oxygen utilization (O2; ivabradine: 13.1 vs 15.6, P = .048; pyridostigmine: 13.3 vs 16.7, P = .032). Heart rate recovery in the first minute postexercise was improved with pyridostigmine (11.8 [3.9] vs 18 [6.5]; P = .046), but not with ivabradine (13.3 [6.9] vs 14.1 [8.2]; P = .70). No differences in either group were observed in the myocardial scintigraphy with 123-iodine-metaiodobenzylguanidine. Both drugs significantly reduced HR, with improvements in exercise capacity and in neurohormonal and inflammatory profiles.

Blood Pressure and Renal Responses to Orthostatic Stress Before and After Radiofrequency Renal Denervation in Patients with Resistant Hypertension.

Background/AimsIn patients with resistant hypertension, renal denervation (RDN) studies have mainly focused their outcomes on blood pressure (BP). The aim of this study was to evaluate the long-term effect of RDN on neurohormonal profiles, renal hemodynamics and sodium excretion in a resting state and during stress induced by lower body negative pressure (LBNP).Materials and methodsThis was a single center prospective observational study. Norepinephrine, plasma renin activity (PRA), glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion were measured in unstimulated conditions (rest) and after one hour of LBNP at three different time points: before (M0), one (M1) and twelve months (M12) after RDN.ResultsThirteen patients with resistant hypertension were included. In the resting state, no differences were observed in norepinephrine, PRA, sodium excretion and mean BP levels after RDN. GFR (78 ± 32 ml/min at M0 vs 66 ± 26 ml/min at M12 (p = 0.012) and filtration fraction (22.6 ±5.4% at M0 vs 15.1 ±5.3% at M12 (p = 0.002)) both decreased after RDN. During LBNP, the magnitude of the mean BP increase was reduced from +6.8 ± 6.6 mm Hg at M0 to +2.3 ± 1.3 mm Hg at M12 (p = 0.005). The LBNP-induced increase in norepinephrine and decrease in GFR and sodium excretion observed before RDN were blunted after the procedure.ConclusionA decrease in GFR and filtration fraction was observed one year after RDN. In addition, our results suggest that RDN blunts not only the norepinephrine but also the mean BP, the GFR and the sodium excretion responses to an orthostatic stress one year after the intervention.Registry numberNCT01734096

Left Atrial Appendage Closure and Systemic Homeostasis: The LAA HOMEOSTASIS Study

BackgroundThe impact of left atrial appendage (LAA) exclusion, comparing an epicardial LAA or an endocardial LAA device, on systemic homeostasis remains unknown. ObjectivesThis study compared the effects of epicardial or endocardial LAA devices on the neurohormonal profiles of patients, emphasizing the roles of the renin-angiotensin-aldosterone system and the autonomic nervous system. MethodsThis is a prospective, single-center, observational study including 77 patients who underwent LAA closure by an epicardial (n = 38) or endocardial (n = 39) device. Key hormones involved in the adrenergic system (adrenaline, noradrenaline), renin-angiotensin-aldosterone system (aldosterone, renin), metabolic system (adiponectin, free fatty acids, insulin, β-hydroxybutyrate, and free glycerols), and natriuresis (atrial and B-type natriuretic peptides) were assessed immediately before the procedure, immediately after device deployment, at 24 h, and at 3 months follow-up. ResultsIn the epicardial LAA device group, when compared with baseline blood adrenaline, noradrenaline and aldosterone were significantly lower at 24 h and 3 months (p < 0.05). There was no significant change in levels post-endocardial LAA device implantation. After epicardial LAA device implantation, there were significant increases in adiponectin and insulin, with decreased free fatty acids at 3 months. There was no significant change in these levels post-endocardial LAA device. N-terminal pro-A-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide were significantly decreased in the acute phase after epicardial LAA device implantation, which subsequently normalized at 3 months. Post endocardial LAA device implantation, the levels increased immediately and normalized after 24 h. Systemic blood pressure was also significantly lower at all time points after epicardial LAA device implantation, which was not seen post-endocardial LAA device implantation. ConclusionsThere are substantial differences in hemodynamics and neurohormonal effects of LAA exclusion with epicardial and endocardial devices. Further studies are required to elucidate the underlying mechanism of these physiological changes.

ANALYSIS OF CHANGES IN THE SERUM LEVEL NT-proBNP AFTER ACE INHIBITORS THERAPY IN PATIENTS WITH HEART FAILURE

BNP secreted by left ventricle as response to wall stress in patient with heart failure. Elevated concentration of NT-pro-BNP correlate with severity of heart failure across all stages of the condition and left ventricle ejection fraction in patient. Several clinical trials have demonstrated that neurohormonal modulation on the RAAS decreases NT-proBNP level and results in favorable outcomes. One of the drug used for blocked RAAS system is ACE inhibitor, decrease of NT-proBNP level show response to therapy include therapy with ACE inhibitors. To analize changes in the levels serum NT-proBNP levels after ace inhibitor therapy in patients with heart failure and monitoring creatinine serum. This study was a observational, prospective, non-randomized trial involving patient age 21-75 years, with NYHA class II-III HF, using ACE inhibitor therapy plus other therapy maximum 3 months before study without ARB or beta blocker. We compared serum NT-pro-BNP and creatinin serum parameters before and after two months treatment with ACE inhibitor. This study conducted in cardiovascular ambulatory patient dr. Soetomo hospital Surabaya. Between August-November 2015, 13 patient (38-63 years, 6 woman, 7 men) include in this study. The mean baseline level of NT-proBNP is 2166.92±1236.73 pg/ml, and creatinin serum 1.023±0.601 mg/dL. The NT-pro-BNP were significantly decreased after two months of treatment with ACE inhibitors 1508.23±651 pg/mL (p=0.025), there were no significant differences creatinin serum between two groups 0.951±0.0365 mg/dL (p=0.111). The results demonstrated the benefits of ACE inhibitor on the neurohormonal profile in patients with HF. If necessary we could measure NT-proBNP level to support prognosis data and monitoring effectivity therapy especially ACE inhibitor which had antiremodelling effect towards patients with HF.

Heart Failure With Improved Ejection Fraction: Clinical Characteristics, Correlates of Recovery, and Survival: Results From the Valsartan Heart Failure Trial.

Heart failure with recovered or improved ejection fraction (HFiEF) has been proposed as a new category of HF. Whether HFiEF is clinically distinct from HF with persistently reduced ejection fraction remains to be validated. Of the 5010 subjects enrolled in the Valsartan Heart Failure Trial (Val-HeFT), 3519 had a baseline left ventricular EF of <35% and a follow-up echocardiographic assessment of EF at 12 months. Of these, 321 (9.1%) patients who had a 12-month EF of >40% constituted the subgroup with HFiEF. EF improved from 28.7±5.6% to 46.5±5.6% in the subgroup with HFiEF and remained reduced (25.2±6.2% and 27.5±7.1%) in the subgroup with HF with reduced ejection fraction. The group with HFiEF had a less severe hemodynamic, biomarker, and neurohormonal profile, and it was treated with a more intense HF medication regimen. Subjects who had higher blood pressure and those treated with a β-blocker or randomized to valsartan had greater odds of being in the HFiEF group, whereas those with an ischemic pathogenesis, a more dilated left ventricle, and a detectable hs-troponin had lower odds of an improvement in EF. Recovery of the EF to >40% was associated with a better survival compared with persistently reduced EF. Our data support HFiEF as a stratum of HF with reduced ejection fraction with a more favorable outcome, which occurs in a minority of patients with HF with reduced ejection fraction who have a lower prevalence of ischemic heart disease, a less severe hemodynamic, biomarker, and neurohormonal profile, and who are treated with a more intense HF medication regimen. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.

Long‐term L‐Triiodothyronine (T3) treatment in stable systolic heart failure patients: a randomised, double‐blind, cross‐over, placebo‐controlled intervention study

Chronic heart failure (HF) is characterized by reduced serum T3 levels and increased activity of the T3 degrading enzyme deiodinase D3. This may result in an intracellular composition of the cardiomyocyte mimicking that of hypothyroidism. Short-term T3-administration to systolic HF patients might be beneficial. Does long-term treatment with T3 have a beneficial effect on cardiac function and neurohormonal activation in chronic systolic HF patients with serum T3 levels below 1·6 nmol/l? A randomized, double-blind, cross-over, placebo-controlled intervention study with oral T3 treatment twice daily for 3 months. The T3 dose was uptitrated to a final dose avoiding reduced TSH levels. Left-ventricular ejection fraction (LVEF). Cardiac imaging was performed using multiple gated tomographic radionuclide ventriculography (MUGA-SPECT). Neurohormonal stimulation was evaluated by plasma measurements of natriuretic peptides, aldosterone, renin, noradrenalin and copeptin levels. The patients were monitored for potential cardiac arrhythmias at the start of each treatment period. Thirteen patients completed the protocol. Mean LVEF was 43%, range: 37-52 and serum T3 levels 1·4 nmol/l (0·9-1·6). The T3 dose was 20 μg per day (10-40). TSH levels did not change between groups, whereas serum T3 levels increased in the active arm. Cardiac function as measured by LVEF, end-diastolic and end-systolic volumes and cardiac output did not change during T3-treatment and neither did the neurohormonal profile. There were no side-effects in terms of cardiac arrhythmias and no change in resting heart rate. This study does not support the hypothesis that oral T3 treatment might be beneficial to patients with chronic, stable systolic HF with a modest degree of reduced LVEF and low-normal serum T3 concentrations. The study included both functional studies of heart contractility as well as measures of the neurohormonal activation.

Phosphoproteome mapping of cardiomyocyte mitochondria in a rat model of heart failure

Mitochondria are complex organelles essential to cardiomyocyte survival. Protein phosphorylation is emerging as a key regulator of mitochondrial function. In the study reported here, we analyzed subsarcolemmal (SSM) mitochondria harvested from rats who have received 4weeks of aldosterone/salt treatment to simulate the neurohormonal profile of human congestive heart failure. Our objective was to obtain an initial qualitative inventory of the phosphoproteins in this biologic system. SSM mitochondria were harvested, and the phosphoproteome was analyzed with a gel-free bioanalytical platform. Mitochondrial proteins were digested with trypsin, and the digests were enriched for phosphopeptides with immobilized metal ion affinity chromatography. The phosphopeptides were analyzed by ion trap liquid chromatography-tandem mass spectrometry, and the phosphoproteins identified via database searches. Based on MS/MS and MS(3) data, we characterized a set of 42 phosphopeptides that encompassed 39 phosphorylation sites. These peptides mapped to 26 proteins, for example, long-chain specific acyl-CoA dehydrogenase, Complex III subunit 6, and mitochondrial import receptor TOM70. Collectively, the characterized phosphoproteins belong to diverse functional modules, including bioenergetic pathways, protein import machinery, and calcium handling. The phosphoprotein panel discovered in this study provides a foundation for future differential phosphoproteome profiling toward an integrated understanding of the role of mitochondrial phosphorylation in heart failure.

Prognostic impact of discordant versus concordant left bundle branch block in heart failure patients undergoing cardiac resynchronization therapy

Purpose: Left bundle branch block (LBBB) is frequently observed in heart failure (HF) patients, and is recognized as both an adverse prognostic factor and a key-element for referring patients to cardiac resynchronization therapy (CRT). It has been previously defined as concordant (cLBBB) or discordant (dLBBB) when associated with a positive or negative T wave in leads I and V5-V6, respectively. Recently, dLBBB has been shown to be associated with a worse clinical, neurohormonal, and prognostic profile in systolic HF patients. Our aim was to evaluate the impact of CRT on the prognostic value of LBBB morphology in a population of systolic HF. Methods: A total of 406 consecutive systolic HF patients with LBBB (age 69±9 years, left ventricular ejection fraction, 26±6%), treated with CRT (CRT-P, n= 78; CRT-D, n= 328) from three Italian Centers underwent clinical, biohumoral, and echocardiographic characterization. All patients were then followed-up for cardiac events (median 31 months, range 1-137). Results: cLBBB was observed in 110 (27%) patients, dLBBB in 296 (73%). dLBBB was more frequent in patients with ischemic cardiomyopathy and associated with a shorter QRS duration and worse glomerular filtration rate (all p <0.05). No difference in pharmacological and device therapy was observed, except for a higher use of diuretics in dLBBB patients. At Kaplan-Meier analysis, dLBBB was associated with a worse prognosis for the composite end-point of sudden death and ICD shock (p<0.05), while no difference was observed in terms of either cardiac death or death due to HF progression. Conclusions: dLBBB, despite CRT, is associated with the occurrence of sudden death and implantable cardioverter defibrillator shock in systolic HF patients, identifying a subset with higher arrhythmic risk, needing an enhanced, targeted therapeutical effort.

Management of the unholy trinity diabetes-obesity-hypertension (diabesotension).

Diabetes, obesity and hypertension are common conditions and their concurrence is more common than would have been expected: 15% of the developed world suffer from the triad of "diabesotension". The pathophysiology involves characteristic neurohormonal profiles that collectively suggest the consideration of diabesotension as a distinct clinical entity. Diabesotensive patients have double the risk of suffering from the micro and macrovascular complications of each of the conditions alone. Therefore, it is critical to reduce their overall risk and provide them with special attention. Studies have shown that the number needed to treat in diabesotension is lower compared to non-obese. Appropriate treatment goals should be set. With regards to hypertension, recent clinical trials point to 130-135/80-85 mmHg. Lifestyle modifications are critical, therefore DASH and Mediterranean diet should be recommended along with a physical training program. Weight reduction strategies often fail and bariatric surgery should be considered. All antihypertensive drug-classes are adequate to treat uncomplicated diabesotension and it is not mandatory to include RAAS blockers as first-line therapy. However, as second line, for high risk patients and patients with nephropathy - a RAAS blocker is indicated. Combination therapy is almost always prescribed in the course of the disease. In the absence of compelling indications, a RAAS blocker with a calcium-channels blocker is preferred as it provides benefits beyond blood pressure control. Resistant hypertension is common, and secondary causes should be looked for, particularly sleep apnea. A novel procedure such as renal denervation is a promising option due to its antihypertensive and metabolic benefits. Copyright © 2012 John Wiley & Sons, Ltd.

Prognostic implications of renal dysfunction in patients hospitalized with heart failure: data from the last decade of clinical investigations

Numerous studies over the last decade have demonstrated that renal dysfunction and worsening renal function (WRF) are common in patients hospitalized for heart failure (HHF) and appear to be associated with poor in-hospital and post-discharge outcomes. Unfortunately, its etiology has not been completely understood, and its prediction during hospitalization remains challenging. The evaluation of renal impairment during hospitalization should take into consideration the underlying renal substrate (e.g., predisposing clinical comorbidities such as diabetes and hypertension), initiating mechanisms (e.g., in-hospital therapies such as diuretics), and amplifying factors (neurohormonal and hemodynamic profile changes). Various patterns of WRF may have different prognostic implications and may require different therapeutic approaches. WRF may be initially classified by duration (transient vs. persistent) and by etiology (elevated venous pressures vs. arterial underfilling). Other critical contributing factors during hospitalization include progressive left ventricular dysfunction, neurohormonal activation, and medications. Transient WRF as a result of aggressive therapy targeting congestion may not be associated with poor outcomes. Persistent WRF seen in patients with severe hemodynamic derangements may be associated with poor post-discharge prognosis. Future investigations must clarify the pathophysiological correlates of various patterns of WRF. To date, there is an unmet clinical need to achieve adequate control over congestion while preserving renal function in HHF patients. Thus, the aim of this review is to provide an in-depth and critical interpretation of the available data on the prognostic importance of RD and WRF during hospitalization in an effort to improve HF management.