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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

The cardiovascular benefits of regular exercise are unequivocal, yet patients with type 2 diabetes respond poorly to exercise due to a reduced cardiac reserve. The contractile response of diabetic cardiomyocytes to β-adrenergic stimulation is attenuated, which may result in altered myofilament calcium sensitivity and posttranslational modifications of cardiac troponin I (cTnI). Treadmill running increases myofilament calcium sensitivity in nondiabetic rats, and thus we hypothesized that endurance training would increase calcium sensitivity of diabetic cardiomyocytes and alter site-specific phosphorylation of cTnI. Calcium sensitivity, or pCa

Background: Thirteen percent of deaths worldwide are attributed to blood pressure above the normal range, or hypertension. Activation of the sympathetic nervous system plays a predominant role in b...

Background: Hypertension is highly prevalent globally but controlling hypertension with medication alone is challenging. Resistant hypertension, a special hypertension phenotype, is even more chall...

NEW FINDINGS What is the central question of this study? In Zucker Diabetic Fatty rats, does cardiomyocyte myofilament function change through the time course of diabetes and what are the mechanisms behind alterations in calcium sensitivity? What is the main finding and its importance? Zucker Diabetic Fatty rats had increased myofilament calcium sensitivity and reduced phosphorylation at cardiac troponin I without differential O-GlcNAcylation. ABSTRACT The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament calcium regulation of contraction is altered while also categorizing the levels of phosphorylation and O-GlcNAcylation in the myofilaments. Calcium sensitivity (pCa50 ) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12 weeks old) and after 8 weeks of uncontrolled hyperglycaemia (20 weeks old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+ ]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. pCa50 was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (P = 0.0001). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (P = 0.003 and P = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa50 is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats and suggests an important role for cTnI phosphorylation in the DM heart.

Aims The renin-angiotensin-aldosterone axis plays a key role in mediating cardiac and kidney injury. Mineralocorticoid receptor antagonism has beneficial effects on cardiac dysfunction, but effects are less well quantified in the cardiorenal syndrome. This study investigated cardiac and kidney pathophysiology following permanent surgical ligation to induce myocardial infarction (MI) in hypertensive animals with or without mineralocorticoid receptor antagonism. Methods Hypertension was induced in adult male Cyp1a1Ren2 rats. Hypertensive animals underwent MI surgery (n = 6), and were then treated daily with spironolactone for 28 days with serial systolic blood pressure measurements, echocardiograms and collection of urine and serum biochemical data. They were compared to hypertensive animals (n = 4), hypertensive animals treated with spironolactone (n = 4), and hypertensive plus MI without spironolactone (n = 6). Cardiac and kidney tissue was examined for histological and immunohistochemical analysis. Results MI superimposed on hypertension resulted in an increase in interstitial cardiac fibrosis (p Conclusion This model of progressive cardiorenal dysfunction more closely replicates the clinical setting. Mineralocorticoid receptor blockade at a clinically relevant dose, blunted progression of cardiac and kidney fibrosis with reduction in cardiac and kidney inflammatory myofibroblast and macrophage infiltration. Further studies are underway to investigate the combined actions of angiotensin blockade with mineralocorticoid receptor blockade.

Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole‐3‐carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis., In the setting of severe hypertension, spironolactone reduces kidney fibrosis independent of a hypotensive effect. Mineralocorticoid receptor antagonism reduces hypertensive‐mediated kidney fibrosis.

The coronavirus 2019 (COVID-19) pandemic requires significant changes to standard operating procedures for non-COVID-19 related illnesses. Balancing the benefit from standard evidence-based treatments with the risks posed by COVID-19 to patients, healthcare workers and to the population at large is difficult due to incomplete and rapidly changing information. In this article, we use management of acute coronary syndromes as a case study to show how these competing risks and benefits can be resolved, albeit incompletely. While the risks due to COVID-19 in patients with acute coronary syndromes is unclear, the benefits of standard management are well established in this condition. As an aid to decision making, we recommend systematic estimation of the risks and benefits for management of any condition where there is likely to be an increase in non-COVID-19 related mortality and morbidity due to changes in routine care.

Purpose Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β‐blockers. β‐blocker efficacy is heterogenous, with second generation β‐blocker metoprolol selectively inhibiting β1‐AR, while third generation β‐blocker carvedilol has α1‐AR inhibition, antioxidant, and anti‐apoptotic actions alongside nonselective β‐AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction. Methods Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol. Results Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β‐blockers. Both β‐blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function. Conclusions Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats., In this manuscript, we present data comparing the effects of carvedilol and metoprolol on in vivo and in vitro cardiac function in both diabetic and non‐diabetic human patients, as well as in a rat model of type 2 diabetes (Zucker Diabetic Fatty rats). Our data demonstrate that both carvedilol and metoprolol are able to improve the contractility of cardiac muscle from diabetic humans and rats, as well as preserving cardiac function in both models. Importantly, we saw no extra improvement in individuals or animals that received carvedilol over those who received metoprolol, suggesting that any improvement in health outcomes provided by carvedilol (as seen in the COMET study) are not derived from differences in the contractile function of the cardiac muscle.

Acute myocardial infarction (MI) triggers an adverse increase in cardiac sympathetic nerve activity (SNA). Whereas β-adrenergic receptor (β-AR) blockers are routinely used for the management of MI, they may also counter β-AR-mediated vasodilation of coronary vessels. We have reported that ghrelin prevents sympathetic activation following MI. Whether ghrelin modulates coronary vascular tone following MI, either through the modulation of SNA or directly as a vasoactive mediator, has never been addressed. We used synchrotron microangiography to image coronary perfusion and vessel internal diameter (ID) in anesthetized Sprague-Dawley rats, before and then again 30 minutes after induction of an MI (left coronary artery ligation). Rats were injected with either saline or ghrelin (150 µg/kg, subcutaneously), immediately following the MI or sham surgery. Coronary angiograms were also recorded following β-AR blockade (propranolol, 2 mg/kg, intravenously). Finally, wire myography was used to assess the effect of ghrelin on vascular tone in isolated human internal mammary arteries (IMAs). Acute MI enhanced coronary perfusion to nonischemicregions through dilation of small arterioles (ID 50 to 250 µm) and microvessel recruitment, irrespective of ghrelin treatment. In ghrelin-treated rats, β-AR blockade did not alter the ischemia-induced vasodilation, yet in saline-treated rats, β-AR blockade abolished the vasodilation of small arterioles. Finally, ghrelin caused a dose-dependent vasodilation of IMA rings (preconstricted with phenylephrine). In summary, this study highlights ghrelin as a promising adjunct therapy that can be used in combination with routine β-AR blockade treatment for preserving coronary blood flow and cardiac performance in patients who suffer an acute MI.

Background Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. Methods Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. Results People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. Conclusions People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes. Electronic supplementary material The online version of this article (10.1186/s12933-017-0644-1) contains supplementary material, which is available to authorized users.

Introduction Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. Methods Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. Results At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNA frequency (–12.2 bursts/min 1 , 95% CI [–13.6, –10.7]) and LV mass (–27 g/m 2 , 95% CI [–47, –8]) were reduced. Mean ambulatory BP (systolic: –24 mm Hg, 95% CI [–42, –5] and diastolic: –13 mm Hg, 95% CI [–22, –4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: –25 mm Hg, 95% CI [–45, –5] and diastolic: –13 mm Hg, 95% CI [–24, –1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. Discussion Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.

Background and aims Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and performance of the second generation EnligHTN™ Renal Denervation System. Methods This first-in-human, prospective, multi-center, non-randomized study included 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mmHg) with drug-resistant hypertension. The primary safety and performance objectives were to characterize, from baseline to 6 months post procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure. Results Renal artery denervation, using the second generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, 6, 12, 18 and 24 months by 19/7, 26/9, 25/7, 23/7, 25/8 and 27/9 mmHg, respectively ( p ≤ 0.0005). No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through 24 months of follow-up. Conclusions Renal sympathetic denervation using the second generation EnligHTN Renal Denervation System resulted in safe, rapid, and significant mean office blood pressure reduction that was sustained through 24 months. Future studies will need to address the utility of this system against an appropriate sham based comparator.

Graphical abstract, Highlights • This case demonstrates cough as an extremely rare but notable cause of TC. • Plausible mechanisms include catecholamine surge, impaired cardiac microvascular and metabolic function, and extreme haemodynamic stress during cough. • Cough should be considered as a potential aetiology in differential diagnosis of TC. • There could be severe as well as subclinical cases of cough induced TC that goes unidentified.

Type 2 diabetes is associated with reduced left ventricular reserve. It is unclear whether exercise training improves left ventricular function in people with type 2 diabetes.This study aimed to determine whether 3 months of high-intensity interval training (HIIT) improves left ventricular function during exercise in adults with type 2 diabetes.Participants performed a V˙O2peak test and received a DXA scan and total blood volume measurement at baseline. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular stroke volume (LVSV) were then measured at rest and during low- and moderate-intensity semirecumbent exercise in adults with type 2 diabetes before and after 3 months of HIIT (n = 11) or no training (control) (n = 5). The effects of HIIT were determined using repeated-measures ANOVA.HIIT increased V˙O2peak by approximately 15% (P0.002) but did not change body composition or total blood volume. LVESV decreased and LVEDV and LVSV increased from rest to moderate-intensity exercise in both groups at baseline (all P0.01). Three months of HIIT increased LVEDV (P = 0.008) and LVSV (P = 0.02) at all conditions, but there was no difference in controls (all P0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P0.04), but LVESV was unchanged in controls. Increased LVEDV explained 51% of the change in LVSV after HIIT intervention. Mitral inflow parameters and mitral annular velocities were unaffected by HIIT (all P0.05).HIIT training increased the LVSV response to exercise in adults with type 2 diabetes. These data suggest that HIIT can improve LV filling and emptying during exercise and reverse early cardiac consequences of type 2 diabetes.

The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. 'Subclinical' changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.

Background: Resistant hypertension, a special phenotype of hypertension, is associated with increased cardiovascular risk. Exercise and physical activity are recommended as non-pharmacological interventions to manage blood pressure in hypertension. Little is known about the effectiveness of exercise in resistant hypertension. A bidirectional relationship has been identified between resistant hypertension and obstructive sleep apnoea but the literature pertaining to the benefit of exercise for populations with both conditions, is minimal. This study aims to identify the effectiveness of exercise in reducing blood pressure in a cohort of adults with resistant hypertension and high risk of obstructive sleep apnoea.Methods: Dunedin based adults with resistant hypertension and high risk of obstructive sleep apnoea will be recruited from the community and health centres to participate in the study. Consenting volunteers (no. of fourteen) will participate in a 12-week exercise programme including aerobic and strength training. The primary outcome measure will be 24h ambulatory blood pressure while the secondary outcomes will be anthropometrics, activity parameters, sleep parameters, cardiac structure and function, and quality of life. The measurements at the end of the 12-week exercise programme will be compared with baseline to determine the effectiveness of exercise in reducing blood pressure in the cohort with resistant hypertension and risk of obstructive sleep apnoea.Conclusions: Exercise and physical activity are recommended to manage hypertension. Therefore, it is anticipated that the exercise programme will have a positive effect on the blood pressure of the participants. The findings have potential to change the direction of research in the area by filling the knowledge gaps.Trial Registration: The Ministry of Health, New Zealand (Ethics Ref: 18/CEN/257), Trial registry: ACTRN12618001881224p).

Background/objectives Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and efficacy of the next generation EnligHTN™ renal denervation system. Six-month primary endpoint data are presented here. Methods We conducted this first-in-human, prospective, multi-center, non-randomized study in 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mm Hg) with drug-resistant hypertension. The primary safety and efficacy objectives were to characterize, from baseline to 6 months post-procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure. Results Renal artery denervation, using the next generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, and 6 months by − 19/7, − 26/9 and − 25/7 mm Hg, respectively (P ≤ 0.0005). No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through. Conclusions Renal sympathetic denervation using the next generation EnligHTN renal denervation system resulted in safe, rapid, and significant mean office blood pressure reduction that was sustained through 6 months. Future studies will need to address the utility of this system against an appropriate placebo based comparator.

Background Previous studies have documented the prevalence of abdominal aortic aneurysm (AAA) during transthoracic echocardiography, but the effect of such screening on subsequent vascular interventions remains unclear. Aim This study aimed to determine the utility of opportunistic selective screening for AAA in a contemporary large series of patients having transthoracic echocardiography. Methods Subjects aged 50 years or older having transthoracic echocardiography had scanning of the infrarenal aorta in a consecutive series of 10 403 men and women. Results The study subjects had a mean age of 70.2 ± 10.7 years, and 54.1% were men. There was a 3.5% (95% confidence interval (CI) 3.2–3.9%) prevalence of AAA with a median diameter of 39 mm (interquartile range 32 mm–48 mm). In males ≥ 65 years the prevalence of newly diagnosed AAA was 6.2% (95% CI 5.5–7.0%). Of those with newly diagnosed AAA, 39.7% underwent AAA repair. Age and male gender were associated with AAA prevalence. After adjustment for age and gender, echocardiographic variables associated with AAA were left ventricular end diastolic dimension (odds ratio (OR) 1.02, 95%CI 1.01–1.04), interventricular septum thickness (OR 1.11, 95% CI 1.06–1.17), left ventricular posterior wall thickness (OR 1.09, 95% CI 1.03–1.15), left atrial diameter (OR 1.04, 95% CI 1.02–1.07) and aortic root diameter (OR 1.09, 95% CI 1.06–1.11). Conclusions This study revealed a high prevalence of newly diagnosed AAA in a group of older men having cardiac evaluation. There was a relationship of increasing age with AAA, and a significant proportion of newly diagnosed subjects were not suitable for AAA repair.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age‐matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty‐three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo‐plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced‐breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying‐to‐stand, and Valsalva maneuver. Baseline and paced‐breathing ECG were analyzed for HRV (frequency‐domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12‐lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P

Endovascular renal denervation (sympathectomy) is a novel procedure developed for the treatment of resistant hypertension. Evidence suggests that it reduces both afferent and efferent sympathetic nerve activity, which may offer clinical benefit over and above any blood pressure-lowering effect. Studies have shown objective improvements in left ventricular mass, ventricular function, central arterial stiffness, central haemodynamics, baroreflex sensitivity and arrhythmia frequency. Benefits have also been seen in insulin resistance, microalbuminuria and glomerular filtration rate. In chronic kidney disease, elevated sympathetic activity has been causally linked to disease progression and cardiovascular sequelae. Effecting a marked reduction in sympathetic hyperactivity may herald a significant step in the management of this and other conditions. In this in-depth review, the pathophysiology and clinical significance of the sympatholytic effects of endovascular renal denervation are discussed.

Objectives: Increased chronic postprocedural levels of active matrix metalloproteinase-9 (MMP-9) have been associated retrospectively with a history of in-stent restenosis (ISR). This study aimed to determine whether index or post-percutaneous coronary intervention (PCI) plasma levels of active MMP-9 are a predictor of subsequent clinical ISR, in a standard population of patients treated with bare metal coronary stents. Methods: Four hundred thirty-two patients were prospectively recruited and sampled at index and 3 and 6 months after PCI. Those who developed symptomatic angiographically confirmed ISR were compared to randomly selected, asymptomatic controls, stratified by index presentation in a nested case-control design. Plasma samples were analyzed for the active form of MMP-9. Results: In all, 35 patients (8.1%) developed ISR, and these were compared to 98 controls. The increase in active MMP-9 over 3 months was significantly greater in the ISR group (p = 0.030) and independent of the established risk factors. Index clinical presentation was not associated with acute changes in active MMP-9; however, patients with ST-elevation myocardial infarction had greater increases in active MMP-9 at 3 months. Conclusions: The change in active MMP-9 over 3 months after bare metal coronary stent placement appears to be independently associated with the development of ISR in a standard PCI population.

Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). Purpose: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to β-adrenergic stimulation. Methods: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and V˙O2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental β-adrenergic stimulation (dobutamine). Results: V˙O2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. Conclusions: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to β-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.

Background: A genetic variant at codon 200 (Pro200Leu) of the gene encoding for glutathione peroxidase 1 (GPx1), a selenium-dependent enzyme, is associated with lower enzyme activity; however, the evidence is limited to in vitro and observational studies. Objective: The objective was to determine whether the GPx1 Pro200Leu genetic variants modify the response of whole-blood glutathione peroxidase (GPx) activity to selenium supplementation in patients with coronary artery disease in New Zealand. Design: The results from 2 parallel-design, double-blind trials were combined. Participants were randomly assigned to receive a daily supplement of 100 μg Se as L-selenomethionine (n = 129) or placebo (n = 126) for 12 wk. Plasma selenium and whole-blood GPx activity were measured at baseline and at week 12. Participants were genotyped for the GPx1 Pro200Leu polymorphism. Results: Selenium supplementation increased whole-blood GPx activity by 5 (95% CI: 4, 7) U/g hemoglobin (P < 0.001); however, the magnitude of the increase did not differ by genotype (P = 0.165 for treatment-by-genotype interaction). In an exploratory analysis, a significant nutrient-gene interaction was apparent when baseline plasma selenium concentrations were included in the regression model (P = 0.006 for treatment-by-genotype x baseline selenium concentration interaction). Increases in GPx activity were 2-fold higher in Pro homozygotes than in participants carrying a Leu allele when baseline selenium concentrations were ≤1.15 μmol/L (P < 0.05). Conclusions: These results indicate that GPx1 Pro200Leu variants do not substantially modify the response of whole-blood GPx to selenium supplementation in individuals with relatively high plasma selenium concentrations. A nutrient-gene interaction was observed when the baseline selenium concentration was low, but this requires independent confirmation. This trial was registered at www.actr.org.au as ACTRN12605000412639 and ACTRN12606000197538.

Objectives: This study sought to evaluate the safety and feasibility of all operators at a single center changing from predominantly femoral to radial access for coronary percutaneous procedures. Background: The radial artery is currently regarded as a useful vascular access site for coronary angiography and percutaneous coronary intervention (PCI). The reduction in local vascular access complications is thought to be a major advantage of the radial route. Despite this, the technique is used less frequently possibly reflecting concerns by cardiologists about the feasibility of using radial access as a preferred option. Methods: A retrospective study of 1004 consecutive patients who underwent coronary angiography with or without PCI was analyzed. Procedure details and clinical outcomes were assessed according to the radial or femoral approaches. Results: The success rate for cardiac catheterization via the radial approach was 97.4% (815/837) and the femoral approach was 98.8% (165/167). The procedural failure rate for radial access was not different from the femoral route [2.6% vs. 1.2%; odds ratio (OR), 2.26; 95% confidence interval (CI), 0.53–9.71; P = 0.41]. Major access site complications occurred in 0.25% patients in the radial group compared with 4.8% patients in the femoral group [OR, 0.05 (95% CI, 0.01–0.23); P < 0.0001]. Conclusions: The radial approach has a high rate of success and is associated with fewer major local vascular access site complications than the femoral route. These results can be achieved early in the operator learning curve of low to medium volume operators. © 2011 Wiley Periodicals, Inc.

This study aimed to determine whether plasma levels of active matrix metalloproteinases (MMP) are predictors of in-stent restenosis (ISR) in New Zealand patients treated with bare-metal coronary stents.A group of 152 patients with a history of ISR were compared with 151 symptom free 1-year post-stenting patients (non-ISR). Demographic and angiographic characteristics were collected. Plasma samples were analyzed for the active forms of MMP-1, -2, -3 and -9 as well as tissue inhibitor of metalloproteinases (TIMP-1) using ELISA-based isoform sensitive assays.Both active MMP-9 and active MMP-3 were independently associated with history of ISR. Elevated levels of both active MMP-3 and -9 had an adjusted odds ratio of 11.8 (95% CI: 4-35, p0.0001) for association with ISR, with 37% of ISR patients having such levels versus 11% on non-ISR. The addition of both of the MMP biomarkers significantly increased the area under the curve (AUC) of a receiver operator characteristic (ROC) analysis incorporating the significant demographic and angiographic variables (AUC 0.85 versus 0.78, p0.005).Measures of plasma active MMP isoforms appear to be independently associated with ISR, and assessment of multiple MMP markers yields cumulative utility.

OBJECTIVE To Evaluate the clinical outcome of patients with acute coronary syndrome (ACS) in the Coronary Care Unit (CCU) over three decades in Dunedin, New Zealand. DESIGN Registry study. SETTING AND PATIENTS all consecutive patients (n = 3,013) with ACS admitted to the CCU from 1979 to 1981 (n = 966) and from 1989 to 1991 (n = 1470) were included prospectively. Data on ACS patients managed in the CCU in 2001-2002 (n = 577) were obtained via medical chart review. RESULTS There was a rising proportion of older (> or = 75 years of age) patients with ACS (3.8% in 1979-1981, 15.2% in 1989-1991 and 25.6% in 2001-2002, P < 0.0005). However, we observed a progressive reduction of in-hospital mortality for ACS (10.7, 7.3 and 5.0%, P < 0.005) and for ST-elevation myocardial infarction (STEMI) (18.4, 16.1 and 6.6%, P < 0.005). The progressive fall in mortality rate was also observed amongst older patients, both for ACS (27, 19.2 and 11.5%, P = 0.011) and for STEMI (34.8, 30.9 and 15.4%, P < 0.005). Of concern, only 10% of patients presented within 1 h of symptom onset and 50% within 5 h, and this has not changed over three decades. The variables associated with < 5 h from symptom onset to presentation were men [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.10-1.42, P = 0.001], a history of ischaemic heart disease (OR 1.25, 95% CI 1.09-1.43, P = 0.002) and STEMI (OR 1.41, 95% CI 1.18-1.67, P < 0.0001). Advanced age was not a predictor for late presentation. CONCLUSIONS Over the past three decades, more old patients were treated in the CCU. However, there was a decline in hospital mortality, particularly for STEMI. Further efforts are required to decrease the time to presentation.

Study objectives To evaluate the frequency of sleep-disordered breathing (SDB) in patients presenting with acute cardiovascular events. Design Repeat observational study. Setting Coronary care unit of a university hospital. Patients A total of 26 patients presenting with unstable angina, myocardial infarction, or left ventricular failure. Measurements Level 3 portable sleep study performed at the time of acute presentation (study 1; 26 patients) and again ≥ 6 weeks later (study 2; 18 patients). Results SDB (apnea-hypopnea index ≥ 15) was identified in 13 of 26 patients (50%) during study 1. One patient had central sleep apnea. Of the 18 who completed the two studies, SDB was confirmed in 10 of 18 patients (56%) during study 1 but in only 5 of 18 patients (28%) during study 2. All five of those patients had obstructive sleep apnea (OSA). Six patients were deemed to have false-positive results for SDB at follow-up, and one patient was deemed to have a false-negative result. Detailed analysis suggested that supine posture during study 1 may have contributed to the high false-positive rate, even though only three of six patients fulfilled the criteria for positional OSA. Conclusions SDB occurs commonly in patients presenting with an acute cardiovascular event. Consideration of the diagnosis of SDB is an important strategy for secondary prevention. However, our findings indicate that SDB abnormalities may be transient. Sleep studies to investigate SDB as a potential risk factor for cardiovascular morbidity should be carried out when the patient is clinically stable.

OBJECTIVES: We sought to demonstrate the safety and performance of the actinomycin D-coated Multilink-Tetra stent(Guidant Corp., Santa Clara, California) in the treatment of patients with single de novo native coronary lesions. BACKGROUND: Drug-eluting stents (DES) releasing sirolimus or paclitaxel dramatically reduce restenosis. The anti-proliferative drug, actinomycin D, which is highly effective in reducing neointimal proliferation in preclinical studies, was selected for clinical evaluation. METHODS: The multi-center, single-blind, three-arm ACTinomycin-eluting stent Improves Outcomes by reducing Neointimal hyperplasia (ACTION) trial randomized 360 patients to receive a DES (2.5 or 10 microg/cm(2) of actinomycin D) or metallic stent (MS). The primary end points were major adverse cardiac events (MACE) at 30 days, diameter stenosis by angiography, tissue effects, and neointimal volume by intravascular ultrasound (IVUS) at six months. When early monitoring revealed an increased rate of repeat revascularization, the protocol was amended to allow for additional follow-up for DES patients. Angiographic control of MS patients was no longer mandatory. RESULTS: The biased selection of DES patients undergoing IVUS follow-up invalidated the interpretation of the IVUS findings. The in-stent late lumen loss and that at the proximal and distal edges were higher in both DES groups than in the MS group and resulted in higher six-month and one-year MACE (34.8% and 43.1% vs. 13.5%), driven exclusively by target vessel revascularization without excess death or myocardial infarction. CONCLUSIONS: The results of the ACTION trial indicate that all anti-proliferative drugs will not uniformly show a drug class effect in the prevention of restenosis.

AIMS The aim of this IVUS substudy was to assess the efficacy of the Y-shaped Medtronic bifurcation-dedicated stent (BDS) for the treatment of de novo coronary bifurcated lesions. METHODS AND RESULTS In the BRANCH trial, post-procedure IVUS was performed in 45 patients. IVUS was available in both branches in 19 lesions and only the main branch (MB) in 26 lesions. IVUS analysis included four distinct locations: proximal MB, bifurcation site, distal MB, and side branch (SB). Lumen symmetry was calculated as minimum/maximum lumen diameters. The quantity of isolated stent struts across the SB ostium was used to assess inadequate strut apposition to the carina resulting in partial jailing of the SB orifice. A minimum stent area (MSA)

Diabetes reduces heart rate (HR) reserve during maximal exercise. We measured HR during a low- and high-dose (0.1 and 0.4 mg·kg-1) atropine bolus followed by incremental dobutamine infusions (5 - 40 μg·kg-1·min-1) up to 85% maximal HR to determine the roles of the parasympathetic and sympathetic nervous system in the diabetic HR response. Five 18 – 30 year old individuals with type 1 diabetes (T1D), but without cardiovascular disease or hypertension and four age-, sex- and training-matched non-diabetic subjects (CON) performed a VO2max test (with ECG) on a cycle ergometer. On a second day, parasympathetic control was determined by comparing the change in HR during atropine doses using ANOVA. Sympathetic responsiveness was compared using the slope of the change in HR (after high-dose atropine) across dobutamine infusion rates. VO2max and maximal HR during the exercise test were the same between groups (P > 0.05). Resting HR was greater in the T1D vs. CON (75 ± 4 vs. 62 ± 6 beats·min-1; P < 0.05). Heart rat...

OBJECTIVES The purpose of this study was to test the hypothesis that intake of used cooking fat is associated with impaired endothelial function. BACKGROUND Diets containing high levels of lipid oxidation products may accelerate atherogenesis, but the effect on endothelial function is unknown. METHODS Flow-mediated endothelium-dependent dilation and glyceryl trinitrate-induced endothelium-independent dilation of the brachial artery were investigated in 10 men. Subjects had arterial studies before and 4 h after three test meals: 1) a meal (fat 64.4 g) rich in cooking fat that had been used for deep frying in a fast food restaurant; 2) the same meal (fat 64.4 g) rich in unused cooking fat, and 3) a corresponding low fat meal (fat 18.4 g) without added fat. RESULTS Endothelium-dependent dilation decreased between fasting and postprandial studies after the used fat meal (5.9 ± 2.3% vs. 0.8 ± 2.2%, p = 0.0003), but there was no significant change after the unused fat meal (5.3 ± 2.1% vs. 6.0 ± 2.5%) or low fat meal (5.3 ± 2.3% vs. 5.4 ± 3.3%). There was no significant difference in endothelium-independent dilation after any of the meals. Plasma free fatty acid concentration did not change significantly during any of the meals. The level of postprandial hypertriglyceridemia was not associated with change in endothelial function. CONCLUSIONS Ingestion of a meal rich in fat previously used for deep frying in a commercial fast food restaurant resulted in impaired arterial endothelial function. These findings suggest that intake of degradation products of heated fat contribute to endothelial dysfunction.

Procedural and 6-mo clinical outcomes were evaluated in 34 consecutive patients who had stenting (

Objectives. This study sought to compare the clinical features and outcome of a first myocardial infarction with onset of symptoms during or within 30 min of exercise, at rest and in bed. Background. It is not known whether activity at onset influences outcome of acute myocardial infarction. Methods. Information collected using a standard questionnaire was used to relate activity at the onset of symptoms to in-hospital outcome in 2,468 consecutive patients admitted to a coronary care unit with a first myocardial infarction between 1975 and 1993. Results. Patients with exercise-related onset were more likely to be younger and male. Those with onset in bed were more likely to be older and have a history of stable or unstable angina. Compared with patients whose symptoms began at rest, those with exercise-related onset had a lower in-hospital mortality rate after adjusting for age, gender and year of admission (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.40 to 0.89), and patients with onset in bed had a higher mortality rate (OR 1.38, 95% CI 1.03 to 1.85). The incidence of cardiac failure requiring diuretic therapy was also lower for exercise-related onset (OR 0.83, 95% CI 0.67 to 1.04) and higher when onset was in bed (OR 1.36, 95% CI 1.11 to 1.66). Conclusions. There is an association between activity at onset and outcome of acute myocardial infarction. Differences in pathophysiology or in the population at risk could explain this observation. (J Am Coll Cardiol 1997;29:250–3)

New Zealand has a number of plants, both native and introduced, contact with which can lead to poisoning. The New Zealand National Poisons Centre (NZNPC) frequently receives enquiries regarding exposures to poisonous plants. Poisonous plants can cause harm following inadvertent ingestion, via skin contact, eye exposures or inhalation of sawdust or smoked plant matter.The purpose of this article is to determine the 15 most common poisonous plant enquiries to the NZNPC and provide a review of current literature, discussing the symptoms that might arise upon exposure to these poisonous plants and the recommended medical management of such poisonings.Call data from the NZNPC telephone collection databases regarding human plant exposures between 2003 and 2010 were analysed retrospectively. The most common plants causing human poisoning were selected as the basis for this review. An extensive literature review was also performed by systematically searching OVID MEDLINE, ISI Web of Science, Scopus and Google Scholar. Further information was obtained from book chapters, relevant news reports and web material.For the years 2003-2010 inclusive, a total of 256,969 enquiries were received by the NZNPC. Of these enquiries, 11,049 involved exposures to plants and fungi. The most common poisonous plant enquiries, in decreasing order of frequency, were: black nightshade (Solanum nigrum), arum lily (Zantedeschia aethiopica), kowhai (Sophora spp.), euphorbia (Euphorbia spp.), peace lily (Spathiphyllum spp.), agapanthus (Agapanthus spp.), stinking iris (Iris foetidissima), rhubarb (Rheum rhabarbarum), taro (Colocasia esculentum), oleander (Nerium oleander), daffodil (Narcissus spp.), hemlock (Conium maculatum), karaka (Corynocarpus laevigatus), foxglove (Digitalis purpurea) and ongaonga/New Zealand tree nettle (Urtica ferox). The combined total of enquiries for these 15 species was 2754 calls (representing approximately 25% of all enquiries regarding plant exposures). The signs and symptoms resulting from poisoning from these plants are discussed. Medical treatment recommendations are made.Poisoning following ingestion or other forms of exposures to plants in New Zealand is relatively common, particularly among children. However, serious adverse reactions are comparatively rare. Accurate plant identification and details on the type of exposure can be important in assessing the likely risks. Effective medical management of these poisonings can be achieved by following the principles outlined in this review.

This study aimed to investigate whether the endogenous active levels of MMP-9 or tissue inhibitor of metalloproteinases-1 (TIMP-1) were related to indices of diastolic dysfunction (DD) in the setting of contemporary treatment of coronary artery disease (CAD).We prospectively studied 116 patients with CAD and preserved left ventricular LV systolic function (ejection fraction ≥ 45%). All patients were free of heart failure symptoms at recruitment and underwent percutaneous intervention (PCI) of culprit lesions. Demographic and angiographic characteristics were collected. Plasma samples were analysed for the active form of MMP-9 and TIMP-1 using enzyme-linked immunosorbent assay-based isoform sensitive assays. Conventional and tissue Doppler-echocardiographic assessment of diastolic filling was undertaken with measurements of maximal early (E) and late (A) transmitral velocities in diastole, E/A ratio, E-wave deceleration time, isovolumic relaxation time, peak systolic (S), diastolic (D) and atrial reversal velocities of pulmonary venous flow, S/D fraction, time difference between A and duration of atrial reversal flow, early diastolic peak velocities of the lateral mitral annulus (E') and E/E'. Active MMP-9 level was higher in patients with more severe phases of DD (normal [n=22]: median 0.57 ng/ml; mild [n=19] 0.83 ng/ml; mild-moderate [n=41] 0.64 ng/ml; moderate or severe [n=34] 1.63 ng/ml; p0.0001 for trend). Three month post-PCI elevated levels of active MMP-9 had an adjusted odds ratio of 11.2 (2.3-56.0, p0.004) for association with moderate or severe DD.Elevated active MMP-9 level is associated with more severe DD in patients with CAD and preserved systolic function, which may indicate abnormal extracellular matrix metabolism in myocardial ischaemia.

Background New Zealand Māori have some of the highest rates of Group A streptococcal infection (GAS) in the world. GAS elevates titres of antistreptokinase (SK) neutralising antibodies and may induce resistance to SK. Methods Anti-SK titres were measured in 180 patients presenting with symptoms consistent with an acute coronary syndrome to three New Zealand rural hospitals, selected because they provide care for patients from communities with different socio-economic and ethnic mixes (Māori proportions varying between 6% and 67%). Findings Compared with the community with the lowest proportion of Māori, patients in the community with the highest proportion of Māori had mean anti-SK titres that were 2.8 times higher (p=0.05). They were 2.5 times more likely to have a high anti-SK titre (33% vs 13% p=0.035). Interpretation Alternatives to reperfusion with SK should be the first-choice therapy in hospitals serving communities with high rates of GAS such as some predominantly Māori and Pacific Island communities.