The carbon monoxide prodrug oCOm-21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

Musculoskeletal chest pain prevalence in emergency department presentations: A retrospective case notes review.

OBJECTIVE: Musculoskeletal (MSK) causes of chest pain are considered common in emergency care, yet management is limited, reported outcomes are poor and prevalence data in New Zealand are lacking. The present study aims to estimate the prevalence of MSK chest pain in New Zealand EDs and describe the characteristics of MSK chest pain cases. METHODS: A retrospective chart review was conducted based on de-identified clinical notes extracted from four hospitals within the South Island of New Zealand from 3 months spanning 1 March to 31 May 2021. Individual cases were categorised to the single best-fitting cause of chest pain using systems-based categorisation, based primarily on the doctors' documented final impression. RESULTS: A total of 1344 cases were categorised in the present study. MSK chest pain had a prevalence of 15% (range 11-31%) of chest pain presentations across all study sites. This represented the second most common system responsible for chest pain, after the cardiovascular system. The mean age of MSK chest pain cases was 46.9 (standard deviation [SD] 19.1) years, compared to 55.5 (SD 19.7) years in all cases. Age and gender-specific data, data from rural hospitals and MSK sub-type data are presented. CONCLUSIONS: These data provide a conservative estimate of MSK chest pain prevalence in EDs within the South Island of New Zealand. The findings highlight MSK chest pain as common in emergency care, providing a basis and justification for further research to improve management and outcomes for people with MSK chest pain.

No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies.

BACKGROUND: Most approaches to the creation of an interatrial shunt require placement of a permanent implant to maintain patency. OBJECTIVES: The goal of this study was to investigate the safety and efficacy of a no-implant interatrial shunt for patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF). METHODS: This was a multicenter, uncontrolled study of patients with HFpEF/HFmrEF and NYHA functional class ≥II, ejection fraction >40%, and pulmonary capillary wedge pressure (PCWP) during supine exercise ≥25 mm Hg with PCWP-to-right atrial gradient ≥5 mm Hg. Follow-up was through 6 months with imaging to assess shunt durability. RESULTS: A total of 28 patients were enrolled: mean age was 68 ± 9 years, and 68% were female. Baseline resting and peak exercise PCWP were 19 ± 7 mm Hg and 40 ± 11 mm Hg, respectively. All procedures displayed technical success with confirmation of left-to-right flow (shunt diameter 7.1 ± 0.9 mm). At 1 month, peak exercise PCWP decreased 5.4 ± 9.6 mm Hg (P = 0.011) with no change in right atrial pressure. There were no serious device or procedure-related adverse events through 6 months. Mean 6-minute walk distance increased 101 ± 71 meters (P < 0.001); Kansas City Cardiomyopathy Questionnaire Overall Summary Score increased 26 ± 19 points (P < 0.001); N-terminal pro-B-type natriuretic peptide decreased 372 ± 857 pg/mL (P = 0.018); and shunt patency was confirmed with unchanged diameter. CONCLUSIONS: In these feasibility studies of a no-implant interatrial shunt, HFpEF/HFmrEF shunts exhibited stability with favorable safety and early efficacy signals. The results show promise toward this new approach for treating patients with HFpEF/HFmrEF and an appropriate hemodynamic profile. (Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-1]; NCT04583527; Evaluation of the Safety and Effectiveness of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-2]; NCT04838353).

Sarco/endoplasmic reticulum calcium ATPase activity is unchanged despite increased myofilament calcium sensitivity in Zucker type 2 diabetic fatty rat heart.

Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PLB ratio were lower in the diabetic left ventricular tissues. However, the maximum SERCA Ca2+ uptake rate was not different between the diabetic and non-diabetic myocardium. Our data suggest that impaired contractility in the diabetic heart is not caused by SERCA Ca2+ mishandling. This study highlights the important role of the cardiac myofilament and provides new insight on the pathophysiology of diabetic heart dysfunction.

Treadmill running increases the calcium sensitivity of myofilaments in diabetic rats.

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 ß-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 pCa50, was measured in Zucker diabetic fatty (ZDF), nondiabetic (nDM), and diabetic (DM) rat hearts after 8 wk of either a sedentary (SED) or progressive treadmill running (TR) intervention. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Specific phospho-sites on cTnI and O-GlcNAcylation were quantified by immunoblot and total protein phosphorylation by fluorescent gel staining (ProQ Diamond). The novel finding in this study was that training increased pCa50 in both DM and nDM cardiomyocytes (P = 0.009). Phosphorylation of cTnI amino acid residues Ser23/24, a crucial protein kinase A site, and Threonine (Thr)144 was lower in DM hearts, but there was no effect of training on site-specific phosphorylation. In addition, total phosphorylation and O-GlcNAcylation levels were not different between SED and TR groups. These findings suggest that regular exercise may benefit the diabetic heart by specifically targeting myofilament contractile function.NEW & NOTEWORTHY We examined the effects of training on the myofilament calcium in diabetic rat hearts. After 8 wk of treadmill running, both nondiabetic and diabetic cardiomyocytes had increased myofilament calcium sensitivity compared with their sedentary counterparts, but there was no effect of training on the phosphorylation or O-GlcNAcylation status of myofilament proteins measured in this study. These data highlight one potential mechanism capable of reversing, in part, reduced cardiac reserve in the diabetic heart.

Effectiveness of Physical Activity and Exercise on Ambulatory Blood Pressure in Adults with Resistant Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: Resistant hypertension (RHT) is a phenotype of hypertension that is challenging to manage by medications alone. While high grade evidence supports physical activity (PA) and exercise to reduce blood pressure (BP) in hypertension, it is unclear whether these are also effective for RHT. AIMS: To determine the quality of evidence for the effectiveness of PA and exercise and the change of magnitude of 24-hour ambulatory BP (24hABP) in adults with RHT. METHODS: Scopus, MEDLINE, CINHAL, Web of Science, Embase and SPORTDiscus databases were searched. Cochrane risk of bias tools, Review Manager and Grading of the Recommendation Assessment, Development and Evaluation were used to assess the methodological quality, the clinical heterogeneity and quality of the evidence. RESULTS: Four studies comprising 178 individuals in total were included. A meta-analysis with random effects showed decreased 24hABP. The experimental group demonstrated grater mean differences for 24hABP following the PA and exercise programmes (systolic - 9.88 mmHg, 95% CI: - 17.62, - 2.14, I2 = 72%, p = 0.01; diastolic - 6.24 mmHg, 95% CI: - 12.65, 0.17, I2 = 93%,p = 0.06); and aerobic exercise (systolic - 12.06 mmHg, 95% CI: - 21.14, - 2.96, I2 = 77%, p = 0.009, diastolic - 8.19 mmHg, 95% CI: - 14.83, - 1.55, I2 = 92% ,p = 0.02). In the included studies, indirectness and publication bias were 'moderate' while inconsistency and imprecision were rated as 'low'. Thus, the overall quality of the evidence was considered to be 'low'. CONCLUSIONS: Low certainty evidence suggests that PA and aerobic exercise added to usual care may be more effective in 24hABP reduction in RHT than usual care alone. REGISTRATION: PROSPERO-2019 CRD42019147284 (21.11.2019).

Increased myofilament calcium sensitivity is associated with decreased cardiac troponin I phosphorylation in the diabetic rat heart.

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.

The prevalence of individuals at high risk of true resistant hypertension and obstructive sleep apnoea in a New Zealand cohort.

AIMS: To determine the prevalence of individuals at high risk of true resistant hypertension (tRHT) in Dunedin-based adults <60 years diagnosed with hypertension and pharmacologically managed with three or more antihypertensive medications (ie, apparent resistant hypertension (aRHT)); to describe characteristics of those with aRHT; and to investigate the association between tRHT and obstructive sleep apnoea in the group. METHODS: Participants with aRHT were recruited and data collected using standardised equipment and methodology. Characteristics were reported using descriptive statistics. The proportion (with 95% confidence intervals) of individuals at high risk of tRHT in individuals with aRHT was calculated. RESULTS: Twenty-five aRHT individuals participated (17 males; group mean age 51.8±8.9 years; body mass index 33.6±6.2 kg/m2). Measures (mean ±SD) for neck circumferences for males were 41.9±4.9cm, females 37.3±3.1cm; waist circumferences for males were 108.4±15.2cm, females 105.2±17.3cm. Group systolic and diastolic 24h ambulatory blood pressure (mmHg) were 148.9±20.5 (95% CI: 140.4 to 157.4), 88.2±14.6 (95% CI: 82.2 to 94.2); office blood pressure were 140.8±18.3 (95% CI: 133.2 to 148.3), 83.5±12.1 (95% CI: 78.5 to 88.5). The prevalence of individuals at high risk of tRHT was 88% (95% CI: 69% to 98%); proportion of obstructive sleep apnoea (OSA) risk among tRHT group was 86% (95% CI 65% to 97%). CONCLUSIONS: The prevalence of individuals at high risk of both tRHT and OSA risk was large in Dunedin-based adults diagnosed with aRHT. Anthropometric assessments indicated high abdominal and visceral adiposity. Group mean blood pressure values exceeded New Zealand's hypertension diagnostic value, suggesting uncontrolled RHT.

Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic hypertensive rat.

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.

Changes to management of a non-pandemic illness during the COVID-19 pandemic: case study of invasive management of acute coronary syndrome.

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.

Carvedilol and metoprolol are both able to preserve myocardial function in type 2 diabetes.

PURPOSE: Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as ß-blockers. ß-blocker efficacy is heterogenous, with second generation ß-blocker metoprolol selectively inhibiting ß1 -AR, while third generation ß-blocker carvedilol has α1 -AR inhibition, antioxidant, and anti-apoptotic actions alongside nonselective ß-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 ß-blockers. Both ß-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.

Myocardial global longitudinal strain: An early indicator of cardiac interstitial fibrosis modified by spironolactone, in a unique hypertensive rat model.

OBJECTIVES: Is global longitudinal strain (GLS) a more accurate non-invasive measure of histological myocardial fibrosis than left ventricular ejection fraction (LVEF) in a hypertensive rodent model. BACKGROUND: Hypertension results in left ventricular hypertrophy and cardiac dysfunction. Speckle-tracking echocardiography has emerged as a robust technique to evaluate cardiac function in humans compared with standard echocardiography. However, its use in animal studies is less clearly defined. METHODS: Cyp1a1Ren2 transgenic rats were randomly assigned to three groups; normotensive, untreated hypertensive or hypertensive with daily administration of spironolactone (human equivalent dose of 50 mg/day). Cardiac function and interstitial fibrosis development were monitored for three months. RESULTS: The lower limit of normal LVEF was calculated to be 75%. After three months hypertensive animals (196±21 mmHg systolic blood pressure (SBP)) showed increased cardiac fibrosis (8.8±3.2% compared with 2.4±0.7% % in normals), reduced LVEF (from 81±2% to 67±7%) and impaired myocardial GLS (from -17±2% to -11±2) (all p<0.001). Myocardial GLS demonstrated a stronger correlation with cardiac interstitial fibrosis (r2 = 0.58, p<0.0001) than LVEF (r2 = 0.37, p<0.006). Spironolactone significantly blunted SBP elevation (184±15, p<0.01), slowed the progression of cardiac fibrosis (4.9±1.4%, p<0.001), reduced the decline in LVEF (72±4%, p<0.05) and the degree of impaired myocardial GLS (-13±1%, p<0.01) compared to hypertensive animals. CONCLUSIONS: This study has demonstrated that, myocardial GLS is a more accurate non-invasive measure of histological myocardial fibrosis compared to standard echocardiography, in an animal model of both treated and untreated hypertension. Spironolactone blunted the progression of cardiac fibrosis and deterioration of myocardial GLS.

HIIT Improves Left Ventricular Exercise Response in Adults with Type 2 Diabetes.

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. PURPOSE: 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. METHODS: 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. RESULTS: HIIT increased V˙O2peak by approximately 15% (P < 0.002) 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 P < 0.01). 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 P > 0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P < 0.04), 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 P > 0.05). CONCLUSIONS: 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.

Breeding Characteristics and Dose-dependent Blood Pressure Responses of Transgenic Cyp1a1-Ren2 Rats.

Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic male Cyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet, without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude (I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite being transgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependent hypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d), we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) in the diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ± 19 mm Hg after 3 mo, with no adverse phenotypic features observed. In conclusion, Cyp1a1-Ren2 rats are a useful animal model to investigate hypertension-induced end-organ damage and potential new therapeutic targets to manage hypertension.

Ghrelin Preserves Ischemia-Induced Vasodilation of Male Rat Coronary Vessels Following ß-Adrenergic Receptor Blockade.

Acute myocardial infarction (MI) triggers an adverse increase in cardiac sympathetic nerve activity (SNA). Whereas ß-adrenergic receptor (ß-AR) blockers are routinely used for the management of MI, they may also counter ß-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 ß-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, ß-AR blockade did not alter the ischemia-induced vasodilation, yet in saline-treated rats, ß-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 ß-AR blockade treatment for preserving coronary blood flow and cardiac performance in patients who suffer an acute MI.

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection-A Proof-of-Concept Study.

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 MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 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.

Impaired ventricular filling limits cardiac reserve during submaximal exercise in people with type 2 diabetes.

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.

Safety and performance of the second generation EnligHTN™ Renal Denervation System in patients with drug-resistant, uncontrolled hypertension.

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.