Impact of α- Versus β-Blockers on Hypertensive Target Organ Damage: Results of a Double-Blind,Randomized, Controlled Clinical Trial

In hypertensive disease, the extent of target organ damage determines the prognosis. We conducted a 6-month, double-blind randomized study to compare the effects of an α₁-adrenoreceptor blocker (bunazosin) with those of a β₁-adrenoreceptor blocker (metoprolol) on early hypertensive target organ damage at a similar level of blood pressure reduction. The study consisted of 43 patients (29 men and 14 women) of varying ages (mean age 52 ± 9 years) with essential hypertension World Health Organization stage I–II. Both the α- and the β-blocker lowered blood pressure to a similar extent measured by 24-h blood pressure monitoring. The left ventricular mass was comparably reduced in both cohorts (α-blocker 284 ± 80 v 259 ± 67 g, P < .05, β-blocker 282 ± 74 v 254 ± 70 g, P < .05). Treatment with the α-blocker led to reduced total peripheral resistance (22.9 ± 8.0 v 19.9 ± 5.3 U, P < .05), whereas therapy with the β-blocker resulted in an elevated total peripheral resistance (25.5 ± 8.4 v 28.5 ± 9.3 U, P < .10; P < .05 for the difference in both groups). Renal plasma flow remained constant in the α-blocker treated group but decreased in the β-blocker treated group (508 ± 141 v 477 ± 134 mL/min/1.73 m², P < .05). Glomerular filtration rate as measured by inulin clearance tended to increase after treatment with the α-blocker (112 ± 20 v 115 ± 18 mL/min/1.73 m², P < .10) in accordance with a decrease of serum creatinine (1.00 ± 0.14 v 0.93 ± 0.12 mg/dL, P < .001). Plasma cholesterol and LDL cholesterol was lowered after treatment with the α-blocker (238 ± 48 v 312 ± 37 mg/dL; P < .001, and 153 ± 32 v 130 ± 25 mg/dL; P < .05) while remaining unchanged in group treated with the β-blocker. Left ventricular hypertrophy was similarily reduced with α- and with β-blockade at a comparable reduction of 24-h blood pressure. α-Blockers effected a more favorable renal and systemic hemodynamic profile than β-blockers, but only long-term prospective studies will answer the question whether these hemodynamic effects result into a better cardiovascular prognosis.     

Quantification of gluconeogenesis in cirrhosis: Response to glucagon

Background & Aims: Accelerated starvation and early recruitment of alternate fuels in cirrhosis have been attributed to reduced availability of hepatic glycogen. The aim of this study was to measure gluconeogenesis (as a marker of protein oxidation) in relation to total glucose production and glucagon-stimulated glycogenolysis. Methods: Glucose and urea production, gluconeogenesis, and glycogenolysis were calculated using stable isotope methods before and during glucagon infusion (3 ng · kg⁻¹ · min⁻¹) in 5 cirrhotic patients and 5 matched controls before and after glycogen repletion. Results: In the basal state, cirrhotic patients had a normal rate of glucose production, but the contribution of gluconeogenesis was increased (74.3% ± 4.1% vs. 55.6% ± 12.1%; P < 0.005). Glycogen repletion normalized the rate of gluconeogenesis. The glycemic response to glucagon (3 ng · kg⁻¹ · min⁻¹) was blunted in cirrhotic patients because of a lower rate of glycogenolysis (0.63 ± 0.23 vs. 1.22 ± 0.23 mg · kg⁻¹ · min⁻¹; P < 0.01) and was not affected by glycogen repletion. Despite increased gluconeogenesis, the simultaneously measured rate of urea synthesis was lower in cirrhotic patients (3.11 ± 1.02 vs. 5.0 ± 1.0 mg/kg; P < 0.05). Conclusions: These data show that in cirrhosis, glucose production is sustained by an increased rate of gluconeogenesis. The hepatic resistance to glucagon action is not caused by reduced glycogen stores.GASTROENTEROLOGY 1998;115:1530-1540     

Effects of Trimetazidine in Nonischemic Heart Failure: A Randomized Study

ObjectivesHeart failure (HF) is associated with changes in myocardial metabolism that lead to impairment of contractile function. Trimetazidine (TMZ) modulates cardiac energetic efficiency and improves outcomes in ischemic heart disease. We evaluated the effects of TMZ on left ventricular ejection fraction (LVEF), cardiac metabolism, exercise capacity, O₂ uptake, and quality of life in patients with nonischemic HF.Methods and ResultsSixty patients with stable nonischemic HF under optimal medical therapy were included in this randomized double-blind study. Patients were randomized to TMZ (35 mg orally twice a day) or placebo for 6 months. LVEF, 6-minute walk test (6MWT), maximum O₂ uptake in cardiopulmonary exercise test, different markers of metabolism, oxidative stress, and endothelial function, and quality of life were assessed at baseline and after TMZ treatment. Left ventricular peak glucose uptake was evaluated with the use of the maximum standardized uptake value (SUV) by 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET). Etiology was idiopathic in 85% and hypertensive in 15%. Both groups were similar in age, functional class, LVEF, and levels of N-terminal pro–B-type natriuretic peptide at baseline. After 6 months of TMZ treatment, no changes were observed in LVEF (31 ± 10% vs 34 ± 8%; P = .8), 6MWT (443 ± 25 m vs 506 ± 79 m; P = .03), maximum O₂ uptake (19.1 ± 5.0 mL kg⁻¹ min⁻¹ vs 23.0 ± 7.2 mL kg⁻¹ min⁻¹; P = .11), functional class (percentages of patients in functional classes I/II/III/IV 10/3753/0 vs 7/40/50/3; P = .14), or quality of life (32 ± 26 points vs 24 ± 18 points; P = .25) in TMZ versus placebo, respectively. In the subgroup of patients evaluated with ¹⁸FDG-PET, no significant differences were observed in SUV between both groups (7.0 ± 3.6 vs 8.2 ± 3.4 respectively; P = .47).ConclusionsIn patients with nonischemic HF, the addition of TMZ to optimal medical treatment does not result in significant changes of LVEF, exercise capacity, O₂ uptake, or quality of life.     

Feasibility of 68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT in Light-Chain Cardiac Amyloidosis

BackgroundSystemic amyloid light chain (AL) amyloidosis is the most common type of amyloidosis, leading to cardiomyocyte necrosis and interstitial fibrosis. Gallium-68-labeled fibroblast activation protein inhibitor 04 (⁶⁸Ga-FAPI-04) has recently been introduced for imaging fibroblast activation in cardiac diseases. To date, cardiac fibroblast and cardiac amyloidosis (CA) phenotype activities have not been mapped.ObjectivesThe aim of this study was to evaluate the feasibility of ⁶⁸Ga-FAPI-04 positron emission tomography (PET)/computed tomography (CT) in assessing AL CA.MethodsThirty consecutive patients (mean age: 59.1 ± 7.7 years; 20 men, 10 women) with biopsy-proven AL amyloidosis were enrolled prospectively (including 27 with AL CA and 3 without AL CA). All patients underwent ⁶⁸Ga-FAPI-04 PET/CT (107.4 ± 26.5 MBq). Global standardized uptake values and left ventricular (LV) molecular volume were calculated in correlation to echocardiography (n = 30), cardiac magnetic resonance (n = 18), and clinical biomarkers. Subsequently, the patients were categorized as having patchy (PET-patchy), extensive (PET-extensive), and negative (PET-negative) patterns.ResultsOf all patients, 80% (24 of 30) showed increased LV uptake (PET-patchy [n = 4] vs PET-extensive [n = 20]), whereas 6 patients did not show visible myocardial uptake. Standardized uptake value ratio and LV molecular volume were significantly higher in the PET-extensive than the PET-patchy group (2.79 mL ± 1.22 mL vs 1.53 mL ± 0.66 mL [P = 0.045] and 198.3 mL ± 59.97 mL vs 127.8 mL ± 25.82 [P = 0.005], respectively). Additionally, ⁶⁸Ga-FAPI-04 uptake was significantly correlated with clinical biomarkers (Mayo stage and N-terminal pro–brain natriuretic peptide), interventricular septal thickness, left ventricular ejection fraction (LVEF), LV end-systolic volume, extracellular volume, and LV global strain (P < 0.05).Conclusions⁶⁸Ga-FAPI-04 PET/CT is feasible in detecting myocardial fibroblast activation in patients with AL CA in correlation with myocardial remodeling. It might provide complementary information on cardiac molecular characterization and staging of disease.     

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.     

Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis

The current guidelines for acute myocardial infarction (AMI) recommended that β-blocker should be used in patients with decreased left ventricular (LV) systolic function for long-term period. However, the effect of β-blocker in AMI patients with preserved LV systolic function is uncertain. We sought to assess the long-term effect of β-blocker in AMI patients with preserved LV systolic function. During the follow-up period (1997–2011), total 3508 patients were performed percutaneous coronary intervention (PCI). Of these patients, 424 AMI patients with preserved LV systolic function [ejection fraction (EF) > 40 %] were analyzed. Median follow-up period was 4.7 years. Then, patients were divided into two groups (β-blocker group 197 patients and no-β-blocker group 227 patients). However, there are substantial differences in baseline characteristics between two groups. Therefore, we calculated propensity score to match the patients in β-blocker and no-β-blocker groups. After post-match patients (N = 206, 103 matched pair), β-blocker therapy significantly reduced cardiac death compared with no-β-blocker [hazard ratio (HR) 0.40, p = 0.04], whereas β-blocker therapy was not associated with major adverse cardiac events (MACE) and all-cause death. β-Blocker is an effective treatment for AMI patients who underwent PCI with preserved LV systolic function.     

T1 Measurements for Detection of Expansion of the Myocardial Extracellular Volume in Chronic Obstructive Pulmonary Disease

BackgroundWe aimed to assess whether chronic obstructive pulmonary disease (COPD) is associated with expansion of the myocardial extracellular volume (ECV) using T1 measurements.MethodsAdult COPD patients Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2 or higher and free of known cardiovascular disease were recruited. All study patients underwent measures of pulmonary function, 6-minute walk test, serum measures of inflammation, overnight polysomnography, and a contrast cardiac magnetic resonance study.ResultsEight patients with COPD were compared with 8 healthy control subjects. The mean predicted forced expiratory volume at 1 second of COPD subjects was 68%. Compared with control subjects, patients had normal left ventricular (LV) and right ventricular size, mass, and function. However, compared with control subjects, the LV remodelling index (median, 0.87; interquartile range [IQR], 0.71-1.14; vs median, 0.62; IQR, 0.60-0.77; P ¼ 0.03) and active left atrial emptying fraction was increased (median, 46; IQR, 41-49; vs median, 38; IQR, 33-43; P ¼ 0.005), and passive left atrial emptying fraction was reduced (median, 24; IQR, 20-30; vs median, 44; IQR, 31-51; P ¼ 0.007). The ECV was increased in patients with COPD (median, 0.32; IQR, 0.05; vs median, 0.27; IQR, 0.05; P = 0.001). The ECV showed a strong positive association with LV remodelling (r = 0.72; P = 0.04) and an inverse association with the 6-minute walk duration (r = −0.79; P = 0.02) and passive left atrial emptying fraction (r = −0.68; P = 0.003).ConclusionsExpansion of the ECV, suggestive of diffuse myocardial fibrosis, is present in COPD and is associated with LV remodelling, and reduced left atrial function and exercise capacity.     

Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production

BackgroundAltering the renin-angiotensin aldosterone system improve mortality in heart failure (HF) in part through an improvement in nitric oxide (NO)-mediated endothelial function. This study examined if spironolactone affects endothelial nitric oxide synthase (eNOS) and NO-mediated vasorelaxation in HF.Methods and ResultsRats with HF after coronary artery ligation were treated with spironolactone for 4 weeks. Rats with HF had a decrease (P < .05) in left ventricular (LV) systolic pressure (130 ± 7 versus 118 ± 6 mm Hg) and LV pressure with respect to time (9122 ± 876 versus 4500 ± 1971 mm Hg/second) with an increase in LV end-diastolic pressure (4 ± 2 versus 23 ± 8 mm Hg). Spironolactone did not affect hemodynamics but it improved (P < .05) endothelial-dependent vasorelaxation at more than 10⁻⁸ M acetylcholine that was abolished with N^G-monomethyl-L-arginine. The eNOS levels were decreased (P < .05) in the LV and the aorta; spironolactone restored LV and aortic eNOs levels to normal.ConclusionSpironolactone prevents the decrease in eNOS in the LV and aorta and improves NO-dependent vasorelaxation, suggesting that one potential mechanism of spironolactone is an improvement in vasoreactivity mediated though an increase in NO.     

Fibrinolytic function in diuretic-induced volume depletion

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 ± 0.21 v 0.34 ± 0.06 ng mL⁻¹ · h⁻¹ [P < .001]) and further increased after losartan (6.39 ± 1.16 ng mL⁻¹ · h⁻¹ [P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 ± 5.8 v 21.1 ± 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 ± 1.82 v 3.88 ± 0.79 IU/mL [P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 ± 3.6 ng/mL and 4.55 ± 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.     

Carvedilol improves left atrial and left ventricular function and reserve in dilated cardiomyopathy after 1 year of treatment

BackgroundThe aim of this study was to evaluate the effects of carvedilol therapy on left atrial (LA) function in patients with heart failure from nonischemic dilated cardiomyopathy.Methods and ResultsThirty-five patients (42.4 ± 13.5 years) in New York Heart Association functional Class II-III have been studied. A low-dose (20 μg·kg·min) echo-dobutamine study has been performed, before and 12 months after carvedilol therapy. Twelve months after carvedilol therapy, a significant improvement in LA and left ventricular (LV) function was observed. To investigate the beneficial effects of carvedilol, patients were separated into 2 groups according to the presence of pretreatment LV contractile reserve (CR) (ejection fraction [EF] increases >20% after dobutamine infusion): Group A consisted of 18 patients with CR and Group B of 17 patients without CR. After carvedilol treatment, both the LV and LA function were improved in group A (P < .01 for all). However, in group B, only the LA function was significantly improved (left atrial ejection volume increased from 10.4 ± 3 mL to 15.4 ± 6.7, P < .01 and LA ejection fraction from 19.6 ± 45.3% to 29.4 ± 12.5%, P < .01), whereas the LV contractile reserve has partially reappeared (EF from 29.9 ± 4.5% at baseline, increased after dobutamine infusion to 35.8 ± 6.8%, P < .0001).ConclusionsIn conclusion, carvedilol therapy is associated with improvement in both LV and LA functions in nonischemic dilated cardiomyopathy. In a subgroup of these patients, carvedilol may act differently on LV and LA function.     

Discrepancy between myocardial perfusion and fatty acid metabolism following acute myocardial infarction for evaluating the dysfunctional viable myocardium

ObjectiveFollowing acute myocardial infarction (AMI) the area of myocardial perfusion and metabolism mismatch is designated as dysfunctional viable myocardium. ¹²³I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) is clinically very useful for evaluating myocardial fatty acid metabolism, and ⁹⁹mTc-Tetrofosmin (TF) is a widely used tracer for myocardial perfusion. This study was designed to evaluate the degree of discrepancy between BMIPP and TF at the subacute state of AMI.MethodsFifty-two patients (aged 59 ± 10 years; mean 46 years) with AMI were enrolled, and all of them underwent percutaneous coronary intervention (PCI). Patients were classified according to ST-T change and PCI timing. ¹²³I-beta-methyl iodophenyl pentadecanoic acid and TF cardiac scintigraphy were performed on 7 ± 3.5 days of admission using a dual headed gamma camera. Perfusion and fatty acid metabolism defect were scored on a 17 segments model.ResultsThe mean BMIPP defect score on early and delayed images were 16.67 ± 10.19 and 16.25 ± 10.40, respectively. The mean TF defect score was 10 ± 7.69. Defect score of BMIPP was significantly higher than that of the TF (P < 0.0001; 95% CI 4.32–7.02), and there was a strong correlation between perfusion and metabolism defect score (r = 0.89, P < 0.00001). Forty-seven (90%) patients showed mismatched defect (BMIPP > TF), and 5 (10%) patients showed matched defect (BMIPP = TF). Mismatched defect score (MMDS) was significantly higher in patients with ST-segment elevation myocardial infarction (STEMI) than that of non-ST-segment elevation myocardial infarction (NSTEMI) (P < 0.041; 95% CI 0.11–5.19).ConclusionAt the subacute state of AMI, most of the patients showed perfusion-metabolism mismatch, which represents the dysfunctional viable myocardium, and patients with STEMI showed higher mismatch.     

Losartan improves heart rate variability and heart rate turbulence in heart failure due to ischemic cardiomyopathy

BackgroundHeart rate variability (HRV) and heart rate turbulence are known to be disturbed and associated with excess mortality in heart failure. The aim of this study was to investigate whether losartan, when added on top of β-blocker and angiotensin-converting enzyme inhibitor (ACEI) therapy, could improve these indices in patients with systolic heart failure.Methods and ResultsSeventy-seven patients (mean age 60.4 ± 8.0, 80.5% male) with ischemic cardiomyopathy (mean ejection fraction 34.5 ± 4.4%) and New York Heart Association Class II-III heart failure symptoms, already receiving a β-blocker and an ACEI, were randomly assigned to either open-label losartan (losartan group) or no additional drug (control group) in a 2:1 ratio and the patients were followed for 12 weeks. The HRV and heart rate turbulence indices were calculated from 24-hour Holter recordings both at the beginning and at the end of follow-up. The baseline clinical characteristics, HRV, and heart rate turbulence indices were similar in the 2 groups. At 12 weeks of follow-up, all HRV parameters except pNN50 increased (SDNN: 113.2 ± 34.2 versus 127.8 ± 24.1, P = .001; SDANN: 101.5 ± 31.7 versus 115.2 ± 22.0, P = .001; triangular index: 29.9 ± 11.1 versus 34.2 ± 7.9, P = .008; RMSSD: 29.1 ± 20.2 versus 34.3 ± 23.0, P = .009; NN50: 5015.3 ± 5554.9 versus 6446.7 ± 6101.1, P = .024; NN50: 5.65 ± 6.41 versus 7.24 ± 6.99, P = .089; SDNNi: 45.1 ± 13.3 versus 50.3 ± 14.5, P = .004), turbulence onset decreased (−0. 61 ± 1.70 versus −1.24 ± 1.31, P = .003) and turbulence slope increased (4.107 ± 3.881 versus 5.940 ± 4.281, P = .004) significantly in the losartan group as compared with controls.ConclusionsA 12-week-long losartan therapy significantly improved HRV and heart rate turbulence in patients with Class II-III heart failure and ischemic cardiomyopathy already on β-blockers and ACEI.     

Hypercholesterolemia exacerbates ventricular remodeling in the rat model of myocardial infarction

BackgroundDetrimental left ventricular (LV) remodeling is exacerbated in hypercholesterolemic patients with myocardial infarction; however, this could result from either larger infarcts or more extensive remodeling itself in this population. Therefore, we sought to investigate whether high cholesterol feeding exacerbates LV remodeling and heart failure in rats with myocardial infarction independently from its influence on infarct size.Methods and ResultsMyocardial infarction was induced by permanent ligation of left coronary artery in rats fed normal and high-cholesterol diet and the animals were followed for 8 weeks. Hypercholesterolemic rats were matched with normocholesterolemic animals for infarct size 24 hours after infarction and exhibited more pronounced LV dilation at 8 weeks after infarction (LV systolic/diastolic diameter 8.1 ± 0.2/10.2 ± 0.3 versus 6.7 ± 0.2/8.9 ± 0.2, respectively, measured by echocardiography, P < .05 each). Pressure-volume curves obtained in isolated Langendorff-perfused hearts revealed higher diastolic LV volumes (1677 ± 102 versus 1385 ± 46 μL/kg body weight, P < .05) and hemodynamic examination demonstrated higher LV end-diastolic pressure (21.8 ± 0.7 versus 18.7 ± 1.0 mm Hg, P < .05) in hypercholesterolemic rats compared with normocholesterolemic animals.ConclusionIn a rat model of myocardial infarction, LV remodeling and heart failure are more pronounced in rats fed high-cholesterol diet in comparison to animals fed normal chow. This effect is independent from effect of hypercholesterolemia on infarct size.     

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.     

Impact of ventricular dyssynchrony on postexercise accommodation of systolic myocardial motion in hypertensive patients with heart failure and a normal ejection fraction: a tissue-Doppler echocardiography study

BackgroundWe hypothesized left ventricular (LV) dyssynchrony would affect postexercise accommodation of regional myocardial motion in patients with heart failure and a normal ejection fraction (HFNEF).Methods and ResultsTissue-Doppler echocardiography was studied in 100 hypertensive patients with LV ejection fraction >50%. Among them, 70 HFNEF patients were classified into the systolic dyssynchrony (Dys: >65 ms difference of electromechanical delay between septal and lateral segments) (43 patients) and nondyssynchrony (Ndys: 27 patients) groups, and the other 30 patients were as the control (Ctrl). The systolic myocardial velocities (Sm) of 6-basal LV segments at baseline and after exercise were analyzed. When compared with the Ctrl group, the baseline lower mean Sm of 6 LV segments in the Ndys group could increase to a similar postexercise level as that in the Ctrl group, whereas that in the Dys group remained lower after exercise (7.8 ± 1.3 versus Ndys: 8.6 ± 1.5 and Ctrl: 8.9 ± 1.2 cm/s, P < .05, respectively). This is mainly due to a much higher percentage increase of lateral Sm after exercise in the Ndys group (Ndys: 49 versus Dys: 29%, P < .05).ConclusionsDyssynchrony-related regional myocardial contractile abnormality after exercise in HFNEF patients suggested the detrimental impact of electromechanical uncoupling on HF symptoms.     

Acute Effects of Intravenous Nesiritide on Cardiac Contractility in Heart Failure

BackgroundAlthough nesiritide is a potent vasodilator, studies using myocytes and isolated muscle strips have shown that recombinant B-type natriuretic peptide (BNP; nesiritide) decreases contractility. We sought to determine whether nesiritide decreases contractility in heart failure patients.Methods and ResultsTwenty-five heart failure patients underwent left heart catheterization (using a pressure-volume conductance catheter) and echocardiography at baseline and after a 2 mcg/kg bolus and 30-minute nesiritide infusion (0.01 mcg·kg·min). From invasive and noninvasive measurements, left ventricular (LV) systolic function indices were calculated, including ejection fraction, end-systolic elastance (E_es; single-beat invasive and noninvasive methods) and preload-recruitable stroke work (PRSW; noninvasive, single-beat method). The mean age was 60 ± 11 years, 48% were male, 56% had coronary disease, and 64% had hypertension. Although nesiritide did not change LV ejection fraction, it did decrease contractility on pressure-volume analysis. Noninvasive E_es decreased from 2.6 ± 1.6 to 2.0 ± 1.4 mm Hg/mL (P = .02). For those with reduced ejection fraction, E_es decreased by invasive (P = .006) and noninvasive (P = .02) methods. PRSW decreased from 76 ± 37 to 62 ± 28 g/cm² (P = .003). On tissue Doppler imaging, nesiritide reduced the systolic annular tissue velocity of the mitral annulus from 8.0 ± 1.9 to 6.9 ± 1.3 cm/s (P = .04).ConclusionsNesiritide infusion acutely decreases derived measures of contractility and systolic function in patients with chronic heart failure.     

Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis

BackgroundCalcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque.MethodsIn the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction.Findings101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p<0·01). NaF uptake displayed a progressive rise with valve severity (r²=0·540) with a more modest increase observed for FDG (r²=0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry (r²=0·79) and was a better predictor of disease progression at 1 year (r²=0·44, n=20) than was FDG (r²=0·02) or baseline calcium score (r²=0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02).InterpretationIn the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk.FundingBritish Heart Foundation.     

Polymorphisms of β-adrenoceptor and Natriuretic Peptide Receptor Genes Influence the Susceptibility to and the Severity of Idiopathic Dilated Cardiomyopathy in a Chinese Cohort

BackgroundThis study evaluated the potential effects of β-adrenoceptor (β-AR) and natriuretic peptide receptor (NPR) gene polymorphisms on the susceptibility to and the severity of idiopathic dilated cardiomyopathy (IDCM) in a Chinese cohort.Methods and ResultsTen polymorphisms in the coding regions of β1-AR, β2-AR, β3-AR, NPR1, and NPR2 were genotyped in 430 IDCM patients and 468 healthy subjects. Patients with IDCM were followed for 2 years. In multi-loci combined subtype analysis, the combined profile of β-AR and NPR was significantly different between IDCM patients and controls (P < .0001), mainly influenced by 2 loci β1-Ser49Gly and NPR2-C2077T, which were also associated with the severity of IDCM. In single-loci analysis, allele frequencies of β1-Gly49, NPR1-Glu939, and NPR2-T2077 were higher in patients with IDCM than in controls. Genotypes carrying NPR2-T2077 allele showed 1.94-fold independent risk for IDCM phenotype than C2077 homozygote (P < .001). Carriers of the NPR2-T2077 or β1-Gly49 variant had worse New York Heart Association functional class or echocardiographic results and elevated serum brain natriuretic peptide, experienced severe symptoms, and required intensive medications and frequent hospitalization for heart failure. Furthermore, synergistic interactions between NPR2-C2077T and β1-Ser49Gly were detected by multifactor-dimensionality reduction method.ConclusionsThis study suggests that NPR2-T2077 and β1-Gly49 polymorphisms may be genetically synergistic adverse factors for the susceptibility to or the severity of IDCM.     

Effect of Comorbidities and Medications on Left Ventricular Mass Regression After Bariatric Surgery

J Clin Hypertens (Greenwich). 2010;12:223–227. ^©2010 Wiley Periodicals, Inc. Hypertension, diabetes, and obesity frequently coexist and significantly contribute to cardiovascular morbidity and mortality. Weight loss in obese individuals has been associated with improved blood pressure control and regression in left ventricular (LV) hypertrophy. The authors investigated the impact of comorbidity and medication on clinical and echocardiographic parameters after weight loss in obese patients. Serial echocardiography and clinical data were collected in 62 patients before bariatric surgery and after 6 months or 10% weight loss. Obese patients with diabetes or hypertension had higher baseline LV mass (LVM) (334±73 g in hypertension and diabetes vs 252±97 g in hypertension and 219±75 g in disease-free patients, P=.003; P=.089for differences in LVM indexed by height), despite the lack of significant differences in body mass index or systolic blood pressure. There were no significant differences in baseline LVM or LVM index related to the medication used to treat hypertension. After weight loss, patients on β-blocker therapy experienced the most significant LV hypertrophy regression (−76.5±79.1 g with β-blockers, −17.8±43.7 g with diuretics, −4.5±46.6 g with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and −23.1±50.9 g in not treated patients, overall P=.538; β-blockers vs no therapy P<.005; P=.145 for differences in LVM index). Bariatric surgery, combined with a weight loss program, provide substantial weight and LVM reduction regardless of comorbidities or blood pressure changes. β-Blocker therapy appears to be associated with the greatest LVM regression after weight loss.     

What level of plasma homocyst(e)ine should be treated?: Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 μmol/L

High levels of plasma homocyst(e)ine (H[e]) are associated with increased vascular risk. Treatment is being contemplated, but the level at which patients should be treated is not known. We compared the response of carotid plaque to vitamin therapy in patients with H(e) above and below 14 μmol/L, a level commonly regarded as high enough to warrant treatment. Two-dimensional B-mode ultrasound measurement of carotid plaque was used to assess the response to vitamin therapy with folic acid 2.5 mg, pyridoxine 25 mg, and cyanocobalamin 250 μg daily, in 101 patients with vascular disease (51 with initial plasma levels above, and 50 below 14 μmol/L). Among patients with plasma H(e) >14 μmol/L, the rate of progression of plaque area was 0.21 ± 0.41 cm²/year before vitamin therapy, and −0.049 ± 0.24 cm²/year after vitamin therapy (P2 = .0001; paired t test). Among patients with levels <14 μmol/L, the rate of progression of plaque was 0.13 ± 0.24 cm²/year before vitamin therapy and −0.024 ± 0.29 cm²/year after vitamin therapy (P2 = .022, paired t test). The change in rate of progression was −0.15 ± .44 cm²/year below 14 μmol/L, and −0.265 ± 0.46 cm²/year above 14 μmol/L (P = 0.20). Vitamin therapy regresses carotid plaque in patients with H(e) levels both above and below 14 μmol/L. These observations support a causal relationship between homocyst(e)ine and atherosclerosis and, taken with epidemiologic evidence, suggest that in patients with vascular disease, the level to treat may be <9 μmol/L.