Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

INTRODUCTION: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. MATERIALS AND METHODS: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. RESULTS AND CONCLUSIONS: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

Health-related quality of life in older patients with acute coronary syndrome randomised to an invasive or conservative strategy. The After Eighty randomised controlled trial.

Objective: in the After Eighty study (ClinicalTrials.gov.number, NCT01255540), patients aged 80 years or more, with non-ST-elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UAP), were randomised to either an invasive or conservative management approach. We sought to compare the effects of these management strategies on health related quality of life (HRQOL) after 1 year. Methods: the After Eighty study was a prospective randomised controlled multicenter trial. In total, 457 patients aged 80 or over, with NSTEMI or UAP, were randomised to either an invasive strategy (n = 229, mean age: 84.7 years), involving early coronary angiography, with immediate evaluation for percutaneous coronary intervention, coronary artery bypass graft, optimal medical therapy, or to a conservative strategy (n = 228, mean age: 84.9 years). The Short Form 36 health survey (SF-36) was used to assess HRQOL at baseline, and at the 1-year follow-up. Results: baseline SF-36 completion was achieved for 208 and 216 patients in the invasive and conservative groups, respectively. A total of 137 in the invasive group and 136 patients in the conservative group completed the SF-36 form at follow-up. When comparing the changes from follow-up to baseline (delta) no significant changes in quality-of-life scores were observed between the two strategies in any of the domains, expect for a small but statistically significant difference in bodily pain. This difference in only one of the SF-36 subscales may not necessarily be clinically significant. Conclusion: from baseline to the 1 year follow-up, only minor differences in change of HRQOL as measured by SF-36 were seen by comparing an invasive and conservative strategy. ClinicalTrials.gov identifier: NCT01255540.

NT-proBNP predicts myocardial recovery after non-ST-elevation acute coronary syndrome.

OBJECTIVES: Our aim was to investigate the associations between B-type natriuretic peptide (NT-proBNP), troponin T (TnT) and C-reactive protein (CRP) and changes in left ventricular function and size after acute coronary syndrome. DESIGN: In 119 patients admitted for non-ST-elevation acute coronary syndrome, echocardiography and blood sampling were performed prior to coronary angiography. Echocardiography was repeated at follow-up after 8 ± 3 months. Left ventricular function was assessed by speckle tracking echocardiography. In 50 patients, infarct size was determined by magnetic resonance imaging. The associations between baseline levels of NT-proBNP, TnT and CRP and myocardial functional recovery, left ventricular intraventricular volumes and infarct size were determined by linear regression. RESULTS: All three biomarkers were associated with myocardial dysfunction at baseline. However, high levels of NT-proBNP were associated with better myocardial recovery, as measured by global longitudinal strain, even after adjusting for other factors potentially influencing myocardial recovery. CONCLUSION: Elevated levels of NT-proBNP at baseline are independently associated with improved myocardial performance 8 months after non-ST-elevation acute coronary syndrome.

Differential effects of metoprolol and atenolol to neuropeptide Y blockade in coronary artery disease.

OBJECTIVE: To explore possible differential effects between metoprolol and atenolol in patients with coronary artery disease. DESIGN: The study was randomized, double blind, two-way crossover with the Y1 antagonist AR-H040922 given as IV infusion for 2 h or placebo. Most patients were treated with metoprolol or atenolol. In a post hoc analysis we compared the hemodynamic response to exercise of the Y1 antagonist in patients on metoprolol (n = 16) and atenolol (n = 5), and assessed respiratory sinus arrhythmia (RSA), an indirect measurement of cardiac vagal activation, in the placebo phase in patients on metoprolol (n = 26) and on atenolol (n = 24). RESULTS: 1) The Y1 antagonist reduced the systolic blood pressure rise during and after exercise during atenolol, but not during metoprolol, while heart rate and maximal load were similar with the two beta-blockers and not affected by the Y1 antagonist. 2) At equal heart- and respiration-rate 7-8 min after exercise the RSA was significantly lower in atenolol than in metoprolol patients, while no difference was seen at rest before exercise. CONCLUSION: These findings from this hypothesis generating study indicate that peripheral effects of NPY contribute less to cardiovascular stress reactions in patients on metoprolol than in those on atenolol.

Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure.

We recently demonstrated that circulating MGP [matrix Gla (γ-carboxylated glutamate) protein] levels were associated with left ventricular dysfunction and increased mortality in patients with symptomatic aortic stenosis. We hypothesized that patients with chronic HF (heart failure) would have dysregulated MGP levels. We examined plasma dp-cMGP (non-phosphorylated carboxylated MGP) and dp-ucMGP (non-phosphorylated undercarboxylated MGP) in 179 patients with chronic HF and matched healthy controls as well as the relationship between MGP and cardiac dysfunction as assessed by echocardiographic measurements, inflammation [CRP (C-reactive protein)] and neurohormonal activation [NT-proBNP (N-terminal proB-type natriuretic peptide)] and the prognostic value of MGP levels in relation to mortality in these patients. We found markedly enhanced plasma dp-cMGP and, in particular, of dp-ucMGP in chronic HF with increasing levels with disease severity. Elevated MGP species were associated with ischaemic aetiology, increased CRP and NT-proBNP levels, as well as systolic and diastolic dysfunction. Finally, dp-ucMGP was associated with long-term heart transplant-free survival (n=48) in univariate, but not in multivariate, analysis. However, plasma dp-ucMGP was markedly higher in patients who died because of progression of HF (n=12) and gave prognostic information also in multivariate analysis. In conclusion, a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic HF.

Patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris randomised to an invasive versus conservative strategy: angiographic and procedural results from the After Eighty study.

OBJECTIVES: We aimed to report the angiographic and procedural results of the After Eighty study (ClinicalTrials.gov, NCT01255540), and to identify independent predictors of revascularisation. METHODS: Patients of ≥80 years old with non-ST-elevation myocardial infarction and unstable angina pectoris were randomised to an invasive or conservative strategy. Angiographic and procedural results were recorded. Univariate and multivariate analyses were performed to explore variables predicting revascularisation. RESULTS: Among 229 patients in the invasive group, 220 underwent immediate coronary angiography (90% performed via the radial artery). Of these patients, 48% had three-vessel disease or left main stenosis, 18% two-vessel disease, 16% one-vessel disease, 17% minor coronary vessel wall changes and two patients had normal coronary arteries. Six patients (3%) underwent coronary artery bypass graft. Percutaneous coronary intervention (PCI) was performed in 107 patients (49%), with 57% treated with bare metal stents, 37% drug-eluting stents and 6% balloon angioplasty. On average, 1.7 lesions were treated and 2 stents delivered per patient. Complications included 1 major PCI-related bleeding (successfully treated), 2 minor access site-related bleedings, 3 side branch occlusions during PCI and 11 periprocedural myocardial infarctions (considered end points). Sex, bundle branch block and smoking were independent predictors of revascularisation. CONCLUSIONS: PCI was performed in approximately half of the patients, similar to findings in younger populations. Procedural success was high, with few complications. TRIAL REGISTRATION NUMBER: NCT01255540.

Rosuvastatin alters the genetic composition of the human gut microbiome.

The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.

Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study.

BACKGROUND: Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD). METHODS AND RESULTS: Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-alpha, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage. CONCLUSIONS: Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

Focal impulse and rotor modulation as a stand-alone procedure for the treatment of paroxysmal atrial fibrillation: A within-patient controlled study with implanted cardiac monitoring.

BACKGROUND: Focal impulse and rotor modulation (FIRM) has been proposed as a novel approach for the treatment of atrial fibrillation (AF). OBJECTIVE: This study aimed to investigate the efficacy of FIRM as a stand-alone procedure for the treatment of paroxysmal AF. METHODS: A total of 27 patients with paroxysmal AF underwent sequential biatrial computational mapping. Sites with repetitive centrifugal or spiral reentry-like activity were considered to be AF-sustaining sources and targeted by irrigated radiofrequency (RF) ablation. All patients were seen in the outpatient clinic after 1, 3, and 6 months and thereafter every 6 months. Cardiac monitors were implanted 3 months before ablation in 17 patients (63%). RESULTS: Repetitive activity interpreted as sustained AF sources was found in all patients, with an average of 3.0 ± 1.1 sources located in the left atrium and 0.6 ± 0.6 sources in the right atrium. The majority of sources were rotors (95%). The total source-ablation radiofrequency time was 20.0 ± 9.0 minutes. At 15.2 ± 3.9 months of follow-up, the prespecified end point of <1% AF burden (outside a 3-month blanking period) was achieved in 2 of the 17 continuously monitored patients (12%). Of all the 27 patients who underwent FIRM, AF episodes of ≥30 minutes were recorded in 23 (85%), while AF episodes ≥60 minutes were recorded in 21 patients (78%). CONCLUSION: This study suggest that biatrial ablation of localized patient-specific sources alone, as detected by this method, is not sufficient to reduce paroxysmal AF burden in the majority of patients.

Effect of thalidomide in patients with chronic heart failure.

BACKGROUND: Congestive heart failure (CHF) is characterized by enhanced immune activation, which possibly plays a pathogenic role in this disorder. We therefore examined whether immunomodulation with thalidomide could improve cardiac performance in patients with CHF. METHODS: Nine patients with chronic symptomatic CHF and left ventricular ejection fraction (LVEF) <40%, who were receiving "optimal" conventional cardiovascular treatment, were given 200 mg thalidomide daily in an open design for a period of 6 weeks. Tumor necrosis factor (TNF)-alpha and LVEF were measured at baseline and on completion of the study. RESULTS: Two patients withdrew because of side effects. Sedation was common and required dose reduction in 6 of 7 patients completing the study. Plasma levels of TNF-alpha were elevated at baseline compared with levels in healthy control patients, but decreased significantly from 33.9 +/- 10.1 pg/mL to 19.3 +/- 6.1 pg/mL during therapy (P <.05). LVEF increased in all patients from 26% +/- 9% to 34% +/- 10% at the end of the observation period (P <.05). CONCLUSIONS: In this pilot study, therapy with thalidomide in patients with CHF resulted in decreased TNF-alpha levels and increased cardiac performance. Although few patients were included, our results suggest that thalidomide should be further investigated as an immunomodulating agent in CHF.

Intravenous immunoglobulin does not reduce left ventricular remodeling in patients with myocardial dysfunction during hospitalization after acute myocardial infarction.

BACKGROUND: Left ventricular (LV) remodeling takes place after acute myocardial infarction (MI), potentially leading to overt heart failure (HF). Enhanced inflammation may contribute to LV remodeling. Our hypothesis was that the immunomodulating effects of intravenous immunoglobulin (IVIg) would be beneficial in patients with impaired myocardial function after MI by reducing myocardial remodeling and improving myocardial function. METHODS: Sixty-two patients with acute MI treated by percutaneous coronary intervention, with depressed LV ejection fraction (LVEF) were randomized in a double-blinded fashion to IVIg as induction therapy and thereafter as monthly infusions or placebo for 26 weeks. The primary end point was changes in LVEF from baseline to 6 months as assessed by MRI. RESULTS: Our main findings were: (i) LVEF increased significantly from 38 ± 10 (mean ± SD) to 45 ± 13% after IVIg and from 42 ± 9 to 49 ± 12% after placebo with no difference between the groups. (ii) The scar area decreased significantly by 3% and 5% in the IVIg and placebo group, respectively, with no difference between the groups. (iii) During the induction therapy (baseline to day 5), IVIg induced both inflammatory (e.g., increase in tumor necrosis factor α and monocyte chemoattractant protein-1) and anti-inflammatory (e.g., increase in interleukin-10 and decrease in leukocyte counts) variables, but during maintenance therapy there were no differences in changes of inflammatory mediators between IVIg and placebo. CONCLUSIONS: IVIg therapy after ST elevation MI managed by primary PCI does not affect LV remodeling or function. This illustrates the challenges of therapeutic intervention directed against the cytokine network, to prevent post-MI remodeling.