Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure

Background

Increased ventricular arrhythmia density and reduced heart rate variability are associated with risk of death in patients with heart failure. Cholinesterase inhibition with pyridostigmine bromide increases heart rate variability in normal subjects, but its effect on patients with heart failure is unknown. In this study, we tested the hypothesis that short-term administration of pyridostigmine bromide, a cholinesterase inhibitor, reduces ventricular arrhythmia density and increases heart rate variability in patients with congestive heart failure.

Methods

Patients with heart failure and in sinus rhythm participated in a double-blind, cross-over protocol, randomized for placebo and pyridostigmine (30 mg orally 3 times daily for 2 days). Twenty-four hour electrocardiographic recordings were performed for arrhythmia analysis and for the measurement of time domain indices of heart rate variability. Patients were separated into 2 groups, according to their ventricular arrhythmia density. The arrhythmia group (n = 11) included patients with >10 ventricular premature beats (VPBs) per hour (VPBs/h), and the heart rate variability group (n = 12) included patients with a number of VPBs in 24 hours not exceeding 1% of the total number of R-R intervals.

Results

For the arrhythmia group, pyridostigmine resulted in a 65% reduction of ventricular ectopic activity (placebo 266 ± 56 VPBs/h vs pyridostigmine 173 ± 49 VPBs/h, P = .03). For the heart rate variability group, pyridostigmine administration increased mean R-R interval (placebo 733 ± 22 ms vs pyridostigmine 790 ± 33 ms, P = .01), and in the time domain indices of heart rate variability root-mean-square of successive differences (placebo 21 ± 2 ms vs pyridostigmine 27 ± 3 ms, P = .01) and percentage of pairs of adjacent R-R intervals differing by >50 ms (placebo 3% ± 1% vs pyridostigmine 6% ± 2%, P = .03).

Conclusion

In patients with heart failure, pyridostigmine reduced ventricular arrhythmia density and increased heart rate variability, most likely due to its cholinomimetic effect. Long-term trials with pyridostigmine in heart failure should be conducted.     

Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction

Objective

This study was undertaken to assess the relationship between acute hyperglycemia and left ventricular function after reperfusion therapy for acute myocardial infarction (AMI).

Methods

This study consisted of 529 patients with a first anterior wall AMI who underwent coronary angiography followed by coronary angioplasty or thrombolysis within 12 hours after the onset of chest pain. Plasma glucose was measured at the time of hospital admission. Acute hyperglycemia was defined as plasma glucose >10 mmol/L.

Results

Although acute hyperglycemia was associated with both lower acute left ventricular ejection fraction (LVEF) (46% ± 12% vs 48% ± 10%, P = .026) and lower predischarge LVEF (51% ± 15% vs 56% ± 15%, P = .001), the difference was more pronounced in the latter and the change in LVEF was significantly smaller in patients with acute hyperglycemia (4.8% ± 11.2% vs 8.0% ± 13.8%, P = .022). Multivariable analysis showed that there was a significant correlation between plasma glucose and impaired predischarge LVEF, even after adjustment of acute LVEF (r = −0.13, P = .005). Thirty-day mortality tended to be higher in patients with acute hyperglycemia than in patients without (7.1% vs 3.5%, P = .06). Multivariable analysis showed that plasma glucose (per 1 mmol/L increase) was an independent predictor of 30-day mortality after AMI (odds ratio 1.12, 95% CI 1.03-1.22, P = .009).

Conclusion

Acute hyperglycemia was independently associated with impaired left ventricular function and higher 30-day mortality after AMI. These results may provide a potential explanation for poor outcomes of patients with AMI and acute hyperglycemia.     

Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy

Background

Trimetazidine (TMZ) has been shown to partially inhibit free fatty acid oxidation by shifting substrate utilization from fatty acid to glucose. The aim of this study was to assess the effects of TMZ in patients with diabetes and ischemic cardiomyopathy.

Methods

Sixteen patients with diabetes and ischemic hypokinetic cardiomyopathy (all males) on conventional therapy were randomized to receive either placebo or TMZ (20 mg 3 times per day), each arm lasting 15 days, and then again to receive either placebo or TMZ for 2 additional 6-month periods, according to a double-blind, crossover design. At the end of each period, all patients underwent exercise testing, 2-dimensional echocardiography, and hyperinsulinemic/euglycemic clamp. Among the others, New York Heart Association class, ejection fraction, exercise time, fasting blood glucose, end-clamp M value (index of total body glucose disposal) and endothelin-1 levels were evaluated.

Results

Both in the short and long term (completed by 13 patients), on TMZ compared to placebo, ejection fraction (47 ± 7 vs 41 ± 9 and 45 ± 8 vs 36 ± 8%, P < .001 for both) and M value (4.0 ± 1.8 vs 3.3 ± 1.6, P = .003, and 3.5 ± 1.5 vs 2.7 ± 1.6 mg/kg body weight/min, P < .01) increased, while fasting blood glucose (121 ± 30 vs 136 ± 40, P = .02 and 125 ± 36 vs 140 ± 43, P = .19) and endothelin-1 (8.8 ± 3.8 vs 10.9 ± 3.8, P < .001 and 6.2 ± 2.4 vs 9.2 ± 4.3 pg/mL, P = .03) decreased. In the short term, 10 patients decreased 1 class on the NYHA scale during treatment with TMZ (P = .019 vs placebo). Eight patients decreased 1 NYHA class while on long-term TMZ treatment, while on placebo 1 patient increased 1 NYHA class and none improved (P = .018 vs placebo).

Conclusions

In a short series of patients with diabetes and ischemic cardiomyopathy, TMZ improved left ventricular function, symptoms, glucose metabolism, and endothelial function. Shifting energy substrate preference away from fatty acid metabolism and toward glucose metabolism by TMZ appears an effective adjunctive treatment in patients with diabetes with postischemic cardiomyopathy.     

Effects of Exenatide Combined with Lifestyle Modification in Patients with Type 2 Diabetes

Objective

To determine the effect of a lifestyle modification program plus exenatide versus lifestyle modification program plus placebo on weight loss in overweight or obese participants with type 2 diabetes treated with metformin and/or sulfonylurea.

Methods

In this 24-week, multicenter, randomized, double-blind, placebo-controlled study, 194 patients participated in a lifestyle modification program, consisting of goals of 600 kcal/day deficit and physical activity of at least 2.5 hours/week. Participants were randomized to 5 μg exenatide twice daily injection + lifestyle modification program (n = 96) or placebo + lifestyle modification program (n = 98), and after 4 weeks increased their exenatide dose to 10 μg twice daily or volume equivalent of placebo.

Results

Baseline characteristics: (mean ± standard deviation) age, 54.8 ± 9.5 years; weight, 95.5 ± 16.0 kg; hemoglobin A_1c, 7.6 ± 0.8%. At 24 weeks (least squares mean ± standard error), treatments showed similar decreases in caloric intake (−378 ± 58 vs −295 ± 58 kcal/day, exenatide + lifestyle modification program vs placebo + lifestyle modification program, P = .27) and increases in exercise-derived energy expenditure. Exenatide + lifestyle modification program showed greater change in weight (−6.16 ± 0.54 kg vs −3.97 ± 0.52 kg, P = .003), hemoglobin A_1c (−1.21 ± 0.09% vs −0.73 ± 0.09%, P <.0001), systolic (−9.44 ± 1.40 vs −1.97 ± 1.40 mm Hg, P <.001) and diastolic blood pressure (−2.22 ± 1.00 vs 0.47 ± 0.99 mm Hg, P = .04). Nausea was reported more for exenatide + lifestyle modification program than placebo + lifestyle modification program (44.8% vs 19.4%, respectively, P <.001), with no difference in withdrawal rates due to adverse events (4.2% vs 5.1%, respectively, P = 1.0) or rates of hypoglycemia.

Conclusions

When combined with lifestyle modification, exenatide treatment led to significant weight loss, improved glycemic control, and decreased blood pressure compared with lifestyle modification alone in overweight or obese participants with type 2 diabetes on metformin and/or sulfonylurea treatment.     

Beneficial effects of angiotensin-converting enzyme inhibitor and nitrate association on left ventricular remodeling in patients with large acute myocardial infarction: the Delapril Remodeling after Acute Myocardial Infarction (DRAMI) trial

Background

In the large-scale trial, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-3 (GISSI-3), patients receiving the combination of lisinopril and glyceryl trinitrate benefited most from experimental therapy. Therefore, a multicenter, randomized, double-blind study, Delapril Remodeling After Acute Myocardial Infarction (DRAMI), was designed to assess (1) the possible additive beneficial effect on left ventricular remodeling of nitrates when combined with an angiotensin-converting enzyme inhibitor (ACEI), and (2) the tolerability of a new ACEI, delapril, in respect to lisinopril in patients with large myocardial infarction (MI).

Methods

A total of 177 patients were randomized to receive delapril plus isosorbide-5-mononitrate (IS5MN) placebo, delapril plus IS5MN, lisinopril plus IS5MN placebo, or lisinopril plus IS5MN starting within the first 36 hours after the onset of symptoms and continuing for 3 months.

Results

More than 80% of the patients showed extensive ST-segment changes and 36.7% had signs or symptoms of heart failure during the first 36 hours. Over 3 months, IS5MN reduced, by 76%, the increase in LVEDV (17.4 ± 5.0 mL placebo vs 4.2 ± 4.4 mL IS5MN, P = .0439), reversed the increase in LVESV (7.5 ± 3.9 mL placebo vs −5.5 ± 2.9 mL IS5MN, P = .0052), and increased the recovery of LVEF (1.9% ± 1.3% placebo vs 6.7% ± 1.2% IS5MN, P = .0119). Overall, 3-month mortality was 10.2%; the most frequent clinical events were new episodes of severe heart failure (18.1%), persistent hypotension (10.7%), and post-MI angina (18.1%), with no differences between treatment groups.

Conclusions

Administration for 3 months of IS5MN combined with an ACEI, both started within 36 hours from the onset of symptoms, was safe and effective in reducing LV dilation and dysfunction after MI. The 2 ACEIs, delapril and lisinopril, appeared to be equally well tolerated.     

Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease,ischemic, and dilated cardiomyopathy

Background

Endothelial dysfunction has been described in patients with coronary artery disease (CAD) or chronic heart failure (CHF). Vitamin C administration leads to an improvement of endothelial function by reducing elevated levels of reactive oxygen species. It remains unclear, however, whether the degree of endothelial dysfunction caused by oxidative stress differs between CAD and CHF because of ischemic (ICM) or dilated cardiomyopathy (DCM).

Methods

In patients with CAD (n = 9; left ventricular ejection fraction [LVEF], 64% ± 3%), ICM (n = 9; LVEF, 25% ± 4%), DCM (n = 9; LVEF, 25% ± 3%), and healthy subjects (HS; n = 5; LVEF, 66% ± 5%) a change in internal radial artery diameter in response to acetylcholine (Ach; 15 and 30 μg/min) was measured with high-resolution ultrasound scanning during a co-infusion of normal saline or vitamin C (25 mg/min).

Results

Ach-mediated vasodilation was blunted in patients with CHF (DCM, 90 ± 20 μm; ICM, 86 ± 20 μm) and patients with CAD (336 ± 20 μm) as compared with HS (496 ± 43 μm; P <.05 vs patients with DCM, ICM, CAD). Vitamin C co-infusion increased Ach-mediated vasodilation by 180 ± 35 μm (to 270 ± 30 μm) in DCM (P <.05 vs CAD, HS) and by 294 ± 40 μm (to 380 ± 20 μm) in ICM (P <.05 vs DCM, CAD, HS). In patients with CAD, vitamin C increased Ach-mediated vasodilation by 146 ± 35 μm to normal values, whereas vascular diameter remained unchanged in HS (14 ± 20 μm; P = not significant).

Conclusions

Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.     

L-arginine supplementation does not inhibit neointimal formation after coronary stenting in human beings: an intravascular ultrasound study

Background

In-stent restenosis results from neointimal tissue proliferation. L-arginine supplementation improves endothelial function and reduces neointimal formation after arterial injury in animals. The aim of the study was to assess the influence of L-arginine administration on neointimal proliferation after coronary stenting in human beings.

Methods

We performed a prospective, randomized, double-blinded, placebo-controlled study in 60 men without diabetes. L-arginine/placebo was administered intravenously 12 hours before percutaneous coronary intervention (200 mg/kg for 240 minutes), during the procedure (200 mg/kg for 240 minutes), and intracoronarily immediately before stent implantation (500 mg for 10 minutes), and it was followed by oral treatment for next 2 weeks (6.0 g/d). By quantitative coronary angiography, late lumen loss, and intravascular ultrasound, neointimal volume and percent neointimal volume were calculated after 7 months of follow-up to assess neointimal formation.

Results

There were no differences in baseline clinical or angiographic characteristics between the two groups. Intravenous infusion of L-arginine increased plasma L-arginine concentrations 6-fold compared with placebo (661 ± 264 vs 107 ± 71 mmol/L, P < .001). During the 2-week period of oral treatment with L-arginine there was a sustained, significant increase of plasma L-arginine level (150 ± 50 vs 100 ± 17, P < .001, 135 ± 42 vs 89 ± 27, P < .001, respectively, on days 7 and 14 in the L-arginine group vs placebo). However, at 7-month follow-up, there was no difference in neointimal formation measured both by quantitative coronary angiography and intravascular ultrasound between the study groups.

Conclusions

Chronic systemic L-arginine administration has no effect on neointimal formation after coronary stenting in human beings.     

Effects of carvedilol therapy on restrictive diastolic filling pattern in chronic heart failure

Background

Carvedilol therapy during congestive heart failure demonstrated a good efficacy in mortality rate reduction and in improvement of left ventricular (LV) systolic performance. However, currently there is not any finding about the drug's effect on diastolic filling. The aim of this study was to evaluate the effects of β-blocker treatment on LV diastolic function with an eco-pulsed Doppler ultrasound scanning examination at transmitral level in a group of patients who were affected by heart failure with a restrictive filling pattern.

Methods

We studied 27 patients with idiopathic or ischemic dilated cardiomyopathy with LV severe systolic disfunction (ejection fraction <35%). Fourteen patients were randomized to receive carvedilol treatment (carvedilol group), and 13 patients continued to receive standard therapy with angiotensin-converting enzyme inhibitors, diuretics, and vasodilators (placebo group). All patients underwent an echo-Doppler ultrasound scanning examination at the beginning of the study and after 4 and 12 months of treatment.

Results

In the carvedilol group, we found a progressive improvement of Doppler ultrasound scanning parameters after 4 months, with a significant increase of A wave (P <.005), deceleration time (DT; P <.02) and isovolumetric relaxation time (IVRT; P <.02). These improvements were confirmed after 1 year of follow-up, whereas patients in the placebo group did not shown any significant modifications. After 1 year, the differences in these groups were more significant for A wave (39 ± 4 cm/sec carvedilol group vs 30 ± 4 cm/sec placebo group; P <.0001), for E/A ratio (1.8 ± 0.2 carvedilol group vs 2.6 ± 0.5 placebo group; P <.0002), for DT 1(40 ± 16 msec carvedilol group vs 112 ± 13 msec placebo group; P <.001), and for IVRT (74 ± 8 msec carvedilol group vs 57 ± 7 mesc placebo group; P <.0002). These changes seem to happen before systolic and morphological modifications.

Conclusion

Our results show that carvedilol therapy is a means of modifying parameters of diastolic filling favorably in patients with heart failure. These effects seem to be independent of those of systolic function. The improvement of systolic performance occurs after 1 year of treatment. The restrictive filling pattern, related to an unfavorable prognosis, changes toward pseudonormal or altered relaxation pattern during carvedilol therapy. Further investigations with a greater sample size will be necessary to confirm our findings.     

Epicardial ablation of right pulmonary artery ganglionated plexi for the prevention of atrial fibrillation originating in the pulmonary veins

Problem Presented

A novel study of catheter ablation of the right pulmonary artery ganglionated plexi (RPA GP) to reduce atrial fibrillation (AF) originating in the pulmonary veins (PVs) is presented.

Studies Undertaken

In 20 dogs, atrial effective refractory periods (AERPs), PVERP, and the dispersion of AERP (dAERP) were measured at baseline during RPA GP stimulation and after ablation. Programmed stimulation and burst stimulation protocols were performed at 4 distal PVs to measure the percentage of AF induced before and after ablation.

Results

Stimulation of the RPA GP shortened AERP (116 ± 16 vs 130 ± 10 milliseconds, P < .01) and PVERP (122 ± 14 vs 136 ± 12 milliseconds, P < .01), and increased dAERP (31 ± 6 vs 23 ± 6 milliseconds, P < .01). However, the above indices revealed an adverse change after excision (AERP, 138 ± 7 vs 130 ± 10 milliseconds; PVERP, 146 ± 18 vs 136 ± 12 milliseconds; and dAERP, 19 ± 5 vs 23 ± 6 milliseconds; P < .05). Furthermore, the percentage of AF induced from PVs was significantly reduced with vagosympathetic stimulation (40% vs 90%, P < .01).

Conclusions

Ablation of the RPA GP changes the electrophysiologic properties of both the atria and the PVs and decreases AF inducibility arising from the PVs.     

A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial

Background

Atrial fibrillation (AF) frequently occurs after cardiac surgical procedures, and β-blockers, sotalol, and amiodarone may reduce the frequency of AF after open heart surgery. This pilot trial was designed to test whether each of the active oral drug regimens is superior to placebo for prevention of postoperative AF and whether there are differences in favor of 1 of the preventive strategies.

Methods and results

We conducted a randomized, double-blinded, placebo-controlled trial in which patients undergoing cardiac surgery in the absence of heart failure and without significant left ventricular dysfunction (n = 253; average age, 65 ± 11 years) received oral amiodarone plus metoprolol (n = 63), metoprolol alone (n = 62), sotalol (n = 63), or placebo (n = 65). Patients receiving combination therapy (amiodarone plus metoprolol) and those receiving sotalol had a significantly lower frequency of AF (30.2% and 31.7%; absolute difference, 23.6% and 22.1%; odds ratios [OR], 0.37 [95% CI, 0.18 to 0.77, P < .01 vs placebo] and 0.40 [0.19 to 0.82, P = .01 vs placebo]) compared with patients receiving placebo (53.8%). Treatment with metoprolol was associated with a 13.5% absolute reduction of AF (P = .16; OR, 0.58 [0.29 to 1.17]. Treatment effects did not differ significantly between active drug groups. Adverse events including cerebrovascular accident, postoperative ventricular tachycardia, nausea, and dyspepsia, in hospital death, postoperative infections, and hypotension, were similar among the groups. Bradycardia necessitating dose reduction or drug withdrawal occurred in 3.1% (placebo), 3.2% (combined amiodarone and metoprolol; P = .65 vs placebo), 12.7% (sotalol; P < .05 vs placebo), and 16.1% (metoprolol; P < .05 vs placebo). Patients in the placebo group had a nonsignificantly longer length of hospital stay as compared with the active treatment groups (13.1 ± 8.9 days vs 11.3 ± 7; P = .10), with no significant difference between the active treatment groups.

Conclusions

Oral active prophylaxis with either sotalol or amiodarone plus metoprolol may reduce the rate of AF after cardiac surgery in a population at high risk for postoperative AF. Treatment with metoprolol alone resulted in a trend to a lower risk for postoperative AF.     

Effects of multivitamins and low-dose folic acid supplements on flow-mediated vasodilation and plasma homocysteine levels in older adults

Background

Hyperhomocysteinemia is associated with aging, endothelial dysfunction, and increased risk of coronary heart disease in older adults; however, the effects of homocysteine-lowering therapy on vascular reactivity in older persons are unknown. The objective of this study was to determine the effects of multivitamins (MV) and folic acid (FA) supplements on flow-mediated vasodilation (FMD) in older adults.

Methods

Individuals ≥70 years old with homocysteine levels ≥10 μmol/L were recruited for this 40-week, prospective, single-blinded study. All subjects were treated sequentially, with each of the following daily therapies for 10 weeks: (1) placebo, (2) MV (400 μg FA, 6 mg vitamin B₆, 25 μg vitamin B₁₂), (3) placebo, then (4) MV + FA (total FA, 1400 μg). FMD, folate intake, and laboratory values were measured at each visit. Investigators were blinded to subject treatment phase when measuring vessel diameters and calculating FMD.

Results

Twenty subjects (mean ± SEM age, 78.0 ± 1.2 [range, 70 to 88] years, 9 women) completed the MV and 17 completed the MV + FA interventions. FMD was impaired at baseline (2.0% ± 1.2%). During the 40-week study, homocysteine levels decreased by 1.4 ± 0.9 μmol/L (p_trend = 0.034) from a baseline of 12.8 ± 0.6 μmol/L; however, FMD did not change significantly (p_trend = 0.874). FMD did not improve after therapy with MV alone (3.0% ± 0.9% [week 10] vs 2.4% ± 1.1% [week 20], P = .716) or with MV + FA (2.6% ± 0.9% [week 30] vs 1.9% ± 0.7% [week 40], P = .484).

Conclusions

At doses commonly prescribed in clinical practice, MV and FA supplements did not improve FMD in older adults with hyperhomocysteinemia.     

Electrocardiographic findings in cardiogenic shock, risk prediction, and the effects of emergency revascularization: results from the SHOCK trial

Objectives

To evaluate electrocardiographic (ECG) parameters as predictors of 1-year mortality in patients developing cardiogenic shock after acute myocardial infarction (AMI), and to document associations between these ECG parameters and the survival benefit of emergency revascularization versus initial medical stabilization.

Background

Emergency revascularization reduces the risk of mortality in patients developing cardiogenic shock after AMI. The prognostic value of ECG parameters in such patients is unclear, and it is uncertain whether emergency revascularization reduces the mortality risk denoted by ECG parameters.

Methods

In a prospective substudy of 198 SHOCK (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) trial patients, ECGs recorded within 12 hours of shock were interpreted by personnel blinded to the patients' treatment assignment and outcome.

Results

The baseline heart rate was higher in non-survivors than in survivors (106 ± 20 versus 95 ± 24 beats/minute, P = .001). There was a significant association between the QRS duration and 1-year mortality in medically stabilized patients (115 ± 28 ms in non-survivors versus 99 ± 23 ms in survivors, P = .012), but not in emergently revascularized patients (110 ± 31 versus 116 ± 27 ms respectively, P = .343). The interaction between the QRS duration, mortality and treatment assignment was significant (P = .009). Among patients with inferior AMI, a greater sum of ST depression was associated with higher 1-year mortality in medically stabilized patients (P = .029), but not in emergently revascularized patients (P = .613, treatment interaction P = .025). On multivariate analysis, the independent mortality predictors were increasing age, elevated pulmonary capillary wedge pressure, heart rate, sum of ST depression in medically stabilized patients, and interaction (P = .016) between a prolonged QRS duration and treatment assignment. The adjusted hazard ratio for 1-year mortality per 20 ms increase in the QRS duration was 1.19 (95% CI 0.98-1.46) in medically stabilized patients and 0.81 (95% CI 0.63-1.03) in emergently revascularized patients.

Conclusion

ECG parameters identified patients with cardiogenic shock who were at high risk. Emergency revascularization eliminated the incremental mortality risk associated with cardiogenic shock in patients with a prolonged QRS duration, or inferior AMI accompanied by precordial ST depression. Prospective assessments of the magnitude of the treatment effect based on ECG parameters are required.     

Impact of short-term intermittent intravenous dobutamine therapy on endothelial function in patients with severe chronic heart failure

Background

Intermittent intravenous dobutamine therapy is used to treat patients with decompensated end-stage chronic heart failure (CHF), in whom the vascular endothelium is usually impaired. Although it has been suggested that modification or reversal of endothelial dysfunction may be of significant therapeutic benefit, the impact of short-term intermittent intravenous dobutamine therapy on flow-mediated dilation (FMD) in patients with severe decompensated end-stage chronic CHF has not been assessed.

Methods

We prospectively assessed the impact of intermittent intravenous low-dose dobutamine therapy on endothelium-dependent brachial artery FMD and endothelium-independent nitroglycerin (NTG)-mediated vasodilation using high resolution ultrasound scanning in 20 consecutive male patients with severe CHF and ischemic cardiomyopathy (New York Heart Association functional class IV), at baseline and after 4 months, and compared them to 20 age- and sex-matched control subjects. The cardiac index (CI), stroke index (SI), and systemic vascular resistance (SVR) were assessed non-invasively with a thoracic electrical bioimpedance device before and after intravenous dobutamine therapy.

Results

Intermittent intravenous dobutamine therapy resulted in significant improvement in post-intervention FMD compared with baseline (7.7% ± 2.4% vs 1.1% ± 2.6%; P = .001), a finding not evident in control subjects (1.3% ± 2.6% vs 1.2% ± 2.1%; P = .78). There was no significant effect of dobutamine treatment compared with control subjects on NTG-induced vasodilation (7.6% ± 5.5% vs 7.5% ± 8.8%, P = .979). Short-term dobutamine therapy also significantly improved SVR (1797 ± 926 dyne sec/cm⁵ vs 2172 ± 1133 dyne sec/cm⁵, P = .05), CI (2. 4± 0.6 L/min/m² vs 1.9 ± 0.6 L/min/m², P = .01), and SI (33.5 ± 11.7 mL/m² vs 27.2 ± 12.4 mL/m², P = .02).

Conclusions

Short-term intermittent intravenous low-dose dobutamine therapy significantly improved vascular endothelial function, perhaps demonstrating an additional mechanism for improved SVR, CI, and SI in patients with severe CHF.     

Impact of early, late, and no ST-segment resolution measured by continuous ST Holter monitoring on left ventricular ejection fraction and infarct size as determined by cardiovascular magnetic resonance imaging

Background

The goal of this study is to determine the predictive value of ST-segment resolution (STR) early after percutaneous coronary intervention (PCI), late STR, and no STR for left ventricular ejection fraction (LVEF) and infarct size (IS) by cardiovascular magnetic resonance (CMR) at follow-up in patients with ST-segment elevation myocardial infarction.

Methods

The analysis included 199 patients who were enrolled in the PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation trial and in whom both continuous ST Holter and CMR at follow-up were available. Patients were stratified into 3 groups: (1) early complete (≥70%) STR measured immediately after last contrast injection (n = 113); (2) late complete STR (n = 52), defined as complete STR from 30 to 240 minutes after PCI; and (3) no complete STR after 240 minutes (n = 34).

Results

Patients with early STR had more preserved LVEF and smaller IS compared to patients with late STR or no STR (LVEF: early STR, 54% ± 8%; late STR, 46% ± 13%; no STR, 43% ± 11%; and IS: 3.9 ± 3.3 g/m²; 8.0 ± 6.9 g/m²; 12.0 ± 6.0 g/m²; respectively; all P < .0001). Early STR was independently predictive for LVEF (β = 8.5; P = .0005) and IS (β = −7.0; P < .0001). Late STR was not predictive for LVEF (β = 1.6; P = .51) but predictive for IS (β = −3.5; P = .003).

Conclusions

Patients with early complete STR after primary PCI have better preserved LVEF and smaller IS. Patients with late complete STR do not have better preserved LVEF but do have smaller IS. ST-segment resolution is a strong, independent predictor of LVEF and IS as assessed by CMR.     

Clinical usefulness and prognostic value of elevated cardiac troponin I levels in acute pulmonary embolism

Background

Right ventricular myocardial ischemia and injury contribute to right ventricular dysfunction and failure during acute pulmonary embolism. The objective of this study was to evaluate the clinical usefulness of cardiac troponin I (cTnI) in the assessment of right ventricular involvement and short-term prognosis in acute pulmonary embolism

Methods

Thirty-eight patients with acute pulmonary embolism were included in the study. Clinical characteristics, right ventricular involvement, and clinical outcome were compared in patients with elevated levels of serum cTnI versus patients with normal levels of serum cTnI.

Results

Among the study population (n = 38 patients), 18 patients (47%) had elevated cTnI levels (mean ± SD 1.6 ± 0.7 ng/mL, range 0.7-3.7 ng/mL, median, 1.4 ng/mL), and comprised the cTnI-positive group. In the other 20 patients, the serum cTnI levels were normal (≤0.4 ng/mL), and they comprised the cTnI-negative group. In the cTnI-positive group (n = 18 patients), 12 patients (67%) had right ventricular dilatation/hypokinesia, compared with 3 patients (15%) in the cTnI-negative group (n = 20 patients, P = .004). Right ventricular systolic pressure was significantly higher in the cTnI-positive group (51 ± 8 mm Hg vs 40 ± 9 mm Hg, P = .002). Cardiogenic shock developed in a significantly higher number of patients with elevated serum cTnI levels (33% vs 5%, P = .01). In patients with elevated cTnI levels, the odds ratio for development of cardiogenic shock was 8.8 (95% CI 2.5-21).

Conclusions

Patients with acute pulmonary embolism with elevated serum cTnI levels are at a higher risk for the development of right ventricular dysfunction and cardiogenic shock. Serum cTnI has a role in risk stratification and short-term prognostication in patients with acute pulmonary embolism.     

Relationship of ventricular longitudinal function to contractile reserve in patients with mitral regurgitation

Background

Latent left ventricular (LV) dysfunction in patients with valvular or myocardial disease may be identified by loss of contractile reserve (CR) at exercise echocardiography. Contraction in the LV longitudinal axis may be more sensitive than radial contraction to minor disturbances of LV function. We sought to determine whether tissue Doppler measurement of longitudinal function could be used to identify CR.

Methods

Exercise echocardiography was performed in 86 patients (20 women, age 53 ± 18 years), 72 with asymptomatic or minimally symptomatic mitral regurgitation, and 14 normal controls. Pulsed-wave tissue Doppler imaging (DTI) was used to measure maximum annular systolic velocity at rest and stress. Inducible ischemia was excluded by analysis of wall motion by an experienced observer. CR was defined by ≥5% improvement of stress compared with rest ejection fraction (EF). Exercise capacity was assessed from expired gas analysis.

Results

CR was present in 34 patients with mitral regurgitation (47%); peak EF in patients with and without CR was 74% ± 11% versus 54% ± 15% (P < .0001). CR could not be predicted by resting EF, volumes or sphericity, and DTI measurement of base-apex function was the only resting echocardiographic parameter to distinguish between patients with and without CR (10 ± 2 vs 8 ± 2 cm/s, P < .03). This parameter showed greater differences after stress (14 ± 4 vs 11 ± 3 cm/s, P < .001). Patients with CR showed lower peak DTI than controls, as well as lower exercise capacity and EF response to exercise. In a multiple linear regression model, rest DTI (P = .03) was an independent correlate of contractile reserve. The other correlates were age (P < .0001), resting (P < .0001) and peak end-systolic volume (P = .01), and resting (P < .0001) and peak end-diastolic volume (P < .0001); the model r² was 0.93 (P < .001).

Conclusion

In the absence of regional LV dysfunction, measurement of longitudinal axis function by DTI may be a marker of CR.     

Grade 3 ischemia on admission electrocardiogram and chest pain duration predict failure of ST-segment resolution after primary percutaneous coronary intervention for acute myocardial infarction

Objectives

ST resolution (STR) is a surrogate marker of myocardial tissue reperfusion and a predictor of outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI). Terminal QRS distortion (grade 3 ischemia) has been shown to predict failure of STR after thrombolysis for STEMI, but the ability of grade 3 ischemia to predict STR with pPCI is unclear.

Methods

We retrospectively analyzed 155 patients who underwent pPCI and compared grade 2 ischemia (ST elevation without terminal QRS distortion; n = 89) to grade 3 ischemia (n = 66) on admission for baseline characteristics, in-hospital course, and STR immediately after pPCI and at 18 to 24 hours.

Results

Patients with grade 3 ischemia were older (60 ± 12 vs 56 ± 11 years; P = .018), had more anterior STEMI (42% vs 17%; P = .0004), and were less often smokers (41% vs 90%; P = .004). The grade 3 ischemic group had significantly less complete STR (35% vs 75% [P < .00001] immediately after pPCI and 33% vs 79% [P < .00001] 18-24 hours after pPCI), a longer hospital stay (6.4 ± 4.1 vs 4.9 ± 1.9 days; P = .008), and higher peak CKMB (292 ± 231 vs 195 ± 176 ng/mL; P = .0005). Duration of symptoms before pPCI (odds ratio [OR], 0.838; 95% confidence interval [CI], 0.724-0.969; P = .017) and grade 3 ischemia (OR, 0.181; 95% CI, 0.068-0.480; P < .001) were negative predictors of complete STR, whereas nonanterior STEMI (OR, 5.95; 95% CI, 2.154-16.436; P < .001) and initial sum of ST elevation (OR, 3.132; 95% CI, 1.140-8.605; P = .027) were positive predictors.

Conclusion

Grade 3 ischemia on presentation of STEMI and duration of chest pain are strong independent predictors of failure to achieve complete STR after pPCI.     

Rehabilitation: Periodic somatosensory stimulation increases arterial baroreflex sensitivity in chronic heart failure patients

Background

One of the beneficial effects of exercise training in chronic heart failure (CHF) is an improvement in baroreflex sensitivity (BRS), a prognostic index in CHF. In our hypothesis-generating study we propose that at least part of this effect is mediated by neural afferent information, and more specifically, by exercise-induced somatosensory nerve traffic.

Objective

To compare the effects of periodic electrical somatosensory stimulation on BRS in patients with CHF with the effects of exercise training and with usual care.

Methods

We compared in stable CHF patients the effect of transcutaneous electrical nerve stimulation (TENS, N = 23, LVEF 30 ± 9%) with the effects of bicycle exercise training (EXTR, N = 20, LVEF 32 ± 7%). To mimic exercise-associated somatosensory ergoreceptor stimulation, we applied periodic (2/s, marching pace) burst TENS to both feet. TENS and EXTR sessions were held during two successive days.

Results

BRS, measured prior to the first intervention session and one day after the second intervention session, increased by 28% from 3.07 ± 2.06 to 4.24 ± 2.61 ms/mm Hg in the TENS group, but did not change in the EXTR group (baseline: 3.37 ± 2.53 ms/mm Hg; effect: 3.26 ± 2.54 ms/mm Hg) (P(TENS vs EXTR) = 0.02). Heart rate and systolic blood pressure did not change in either group.

Conclusions

We demonstrated that periodic somatosensory input alone is sufficient and efficient in increasing BRS in CHF patients. This concept constitutes a basis for studies towards more effective exercise training regimens in the diseased/impaired, in whom training aimed at BRS improvement should possibly focus more on the somatosensory aspect.     

Is systolic blood pressure recovery after exercise a predictor of mortality?

Background

An attenuated systolic blood pressure recovery after exercise has been associated with the severity of atherosclerotic heart disease.

Methods

For 6 years, we observed 12,379 patients who underwent symptom-limited exercise testing. We excluded patients receiving antihypertensive medication and patients with valvular disease, emphysema, end-stage renal disease, heart failure, left ventricular systolic dysfunction, and atrial fibrillation. Blood pressure recovery ratio was defined as the ratio of systolic blood pressure at 3 minutes into recovery to systolic blood pressure at peak exercise; this has been shown to correlate with angiographic severity of coronary disease.

Results

The blood pressure recovery ratios ranged from 0.36 to 1.62, with values for increasing quartiles of 0.72 ± 0.05, 0.82 ± 0.02, 0.88 ± 0.02, and 0.99 ± 0.07. During follow-up, there were 430 deaths (3%). Five-year Kaplan Meier survival rates were 0.975, 0.974, 0.969, and 0.966 in quartiles 1 to 4, respectively. Compared with patients in the lowest quartile of blood pressure recovery ratio, patients in the highest quartile were at somewhat increased risk (hazard ratio, 1.71; 95% CI, 1.31-2.24; P <.001). However, after adjusting for age, sex, body mass index, resting heart rate and blood pressure, peak systolic blood pressure, heart rate recovery, exercise chronotropic response, cardiac history, and standard risk factors, this association was no longer present (adjusted hazard ratio, 1.05; 95% CI, 0.8-1.38; P = .74).

Conclusions

In this low-risk population, abnormal systolic blood pressure recovery after exercise was not independently predictive of mortality after correcting for differences in baseline and exercise characteristics.     

Acute angiotensin II receptor blockade improves insulin-induced microvascular function in hypertensive individuals

Objective

An effect of insulin that is crucial for stimulating glucose uptake is its ability to increase the number of perfused capillaries, and thereby enhance its own delivery, and that of glucose, to muscle cells. To unravel possible mechanisms involved in the insulin-sensitizing effects of angiotensin II receptor blockers (ARBs) in hypertensive individuals we investigated the effect of single-dose ARB administration on insulin-mediated microvascular perfusion in hypertensive individuals.

Methods

We examined the effects of ARB administration on hyperinsulinemia-associated capillary density by measuring baseline skin capillary density, capillary density during reactive hyperemia (hyperemic capillary recruitment), and capillary density during venous congestion in 17 hypertensive individuals in the basal state, during a hyperinsulinemic euglycemic clamp, and during a hyperinsulinemic clamp with acute ARB administration (600 mg irbesartan), acute calcium channel blockade (CCB; 10 mg felodipine ER), as a control for the reduction in blood pressure, or placebo. In addition, insulin sensitivity and blood pressure were measured.

Results

Compared to the basal state, hyperinsulinemia increased baseline capillary density (57.3 ± 6.8 vs. 60.3 ± 7.9 n/mm², P < 0.01), but not hyperemic capillary recruitment. ARB and CCB treatment induced similar blood pressure reductions. Compared to placebo, ARB, but not CCB, increased hyperinsulinemia-associated baseline capillary density (+ 2.3 ± 3.4 (P = 0.02) and − 0.4 ± 4.4 n/mm², respectively). Hyperinsulinemia-associated hyperemic capillary recruitment was not altered by either treatment. Compared to placebo, neither ARB nor CCB treatment enhanced insulin sensitivity.

Conclusions

Acute ARB administration increases insulin-induced microvascular perfusion in mildly hypertensive individuals; this beneficial effect on microvascular perfusion was however not associated with increased insulin-mediated glucose uptake.