Publications by authors named "David M Kaye"

251 Publications

Renal ACE2 (Angiotensin-Converting Enzyme 2) Expression Is Modulated by Dietary Fiber Intake, Gut Microbiota, and Their Metabolites.

Hypertension 2021 Apr 19:HYPERTENSIONAHA12117039. Epub 2021 Apr 19.

Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, Melbourne, Australia. (R.R.M., E.D., M.N., H.A.J., F.Z.M.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17039DOI Listing
April 2021

Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart.

Pharmaceuticals (Basel) 2021 Mar 15;14(3). Epub 2021 Mar 15.

Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung disease. We investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro by performing a radioisotopic assay for [H]-proline incorporation as a proxy for collagen synthesis. Exploratory studies in human cardiac fibroblasts treated with tilorone (10 µM) showed a significant reduction in transforming growth factor-β induced collagen synthesis compared to untreated fibroblasts. To determine if this finding could be recapitulated in vivo, mice with established pathological remodelling due to four weeks of transverse aortic constriction (TAC) were administered tilorone (50 mg/kg, i.p) or saline every third day for eight weeks. Treatment with tilorone was associated with attenuation of fibrosis (assessed by Masson's trichrome stain), a favourable cardiac gene expression profile and no further deterioration of cardiac systolic function determined by echocardiography compared to saline treated TAC mice. These data demonstrate that tilorone has anti-fibrotic actions in human cardiac fibroblasts and the adult mouse heart, and represents a potential novel therapy to treat fibrosis associated with heart failure.
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http://dx.doi.org/10.3390/ph14030263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998193PMC
March 2021

Oral Milrinone for the Treatment of Chronic Severe Right Ventricular Failure in Left Ventricular Assist Device Patients.

Circ Heart Fail 2021 Apr 19;14(4):e007286. Epub 2021 Mar 19.

Division of Cardiology, Columbia University Irving Medical Center, New York, NY (N.U., D.B., G.S.).

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007286DOI Listing
April 2021

High intraluminal pressure promotes vascular inflammation via caveolin-1.

Sci Rep 2021 Mar 15;11(1):5894. Epub 2021 Mar 15.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.
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http://dx.doi.org/10.1038/s41598-021-85476-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960707PMC
March 2021

Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: Lumi-Solve.

Cardiovasc Eng Technol 2021 Mar 11. Epub 2021 Mar 11.

Eastern Health Clinical School, Monash University, Box Hill, Australia.

Purpose: Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class.

Methods: In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model.

Results: Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3.

Conclusions: Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies.
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http://dx.doi.org/10.1007/s13239-021-00525-yDOI Listing
March 2021

Determinants and consequences of heart rate and stroke volume response to exercise in patients with heart failure and preserved ejection fraction.

Eur J Heart Fail 2021 Mar 8. Epub 2021 Mar 8.

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

Aims: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses.

Methods And Results: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m , healthy participants: +24 ± 12 mL/m , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF.

Conclusion: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.
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http://dx.doi.org/10.1002/ejhf.2146DOI Listing
March 2021

A prospective STudy using invAsive haemodynamic measurements foLLowing catheter ablation for AF and early HFpEF: STALL AF-HFpEF.

Eur J Heart Fail 2021 Feb 9. Epub 2021 Feb 9.

Baker Heart & Diabetes Institute, Melbourne, Australia.

Aims: The impact of atrial fibrillation (AF) ablation in early heart failure with preserved ejection fraction (HFpEF) is unknown. Our aim was to determine the impact of AF ablation on symptoms and exercise haemodynamic parameters of early HFpEF.

Methods And Results: Symptomatic AF patients referred for index AF ablation with ejection fraction ≥50% underwent baseline quality of life questionnaires, echocardiography, cardiac magnetic resonance imaging, exercise right heart catheterisation (exRHC), and brain natriuretic peptide (BNP) testing. HFpEF was defined by resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or peak exercise PCWP ≥25 mmHg. Patients with HFpEF were offered AF ablation and follow-up exRHC ≥6 months post-ablation. Of 54 patients undergoing baseline evaluation, 35 (65%) had HFpEF identified by exRHC. HFpEF patients were older (64 ± 10 vs. 54 ± 13 years, P < 0.01), and more frequently female (54% vs. 16%, P < 0.01), hypertensive (63% vs. 16%, P < 0.001), and suffering persistent AF (66% vs. 11%, P < 0.001), compared to those without HFpEF. Twenty HFpEF patients underwent AF ablation and follow-up exRHC 12 ± 6 months post-ablation. Nine (45%) patients no longer fulfilled exRHC criteria for HFpEF at follow-up. Patients remaining arrhythmia free (n = 9, 45%) showed significant improvements in peak exercise PCWP (29 ± 4 to 23 ± 2 mmHg, P < 0.01) and Minnesota Living with Heart Failure (MLHF) score (55 ± 30 to 22 ± 30, P < 0.01) while the remainder did not (PCWP 31 ± 5 to 30.0 ± 4 mmHg, P = NS; MLHF score 55 ± 23 to 25 ± 20, P = NS).

Conclusion: Heart failure with preserved ejection fraction frequently coexists in patients with symptomatic AF and preserved ejection fraction. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improves haemodynamic parameters, BNP and symptoms associated with HFpEF.
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http://dx.doi.org/10.1002/ejhf.2122DOI Listing
February 2021

Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure.

Sci Rep 2020 10 21;10(1):17919. Epub 2020 Oct 21.

Heart Failure Research Group, Baker Heart and Diabetes Institute, St Kilda Rd Central, PO Box 6492, Melbourne, VIC, 8008, Australia.

Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA amplicon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.
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http://dx.doi.org/10.1038/s41598-020-73614-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578080PMC
October 2020

Comparison of Circulatory Unloading Techniques for Venoarterial Extracorporeal Membrane Oxygenation.

ASAIO J 2020 Oct 14. Epub 2020 Oct 14.

From the Department of Mechanical and Aerospace Engineering, Monash University, Clayton, Victoria, Australia.

Left ventricular (LV) distention and pulmonary congestion are major complications inherent to venoarterial extracorporeal membrane oxygenation (ECMO). This study aimed to quantitatively compare the hemodynamic differences between common circulatory unloading methods for ECMO. Ten circulatory unloading techniques were evaluated on a mock circulatory loop simulating acute LV failure supported by ECMO. Simulated unloading techniques included: surgical and percutaneous pulmonary artery (PA) venting, surgical left atrial venting, surgical and percutaneous LV venting, atrial septal defect, partial support ventricular assist device, intraaortic balloon pump, and temporary VAD with inline oxygenator (tVAD). The most LV unloading occurred with the surgically placed LV vent and tVAD, which reduced LV end-diastolic volume from 295 to 167 ml and 82 ml, respectively. Meanwhile, the PA surgical vent was the most effective at reducing mean PA pressure from 21.0 to 10.6 mm Hg, and the tVAD was most effective at reducing left atrial pressure from 13.3 to 4.4 mm Hg. The major limitation of this study was the use of a mock circulatory loop, which simulated lower left atrial pressure than is typically seen clinically. This study identified clinically significant hemodynamic variability between the different circulatory unloading techniques evaluated. However, the applicability of these techniques will vary with different patient disease etiology. Further studies on ECMO unloading will help to quantify hemodynamic benefits and establish treatment guidelines.
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http://dx.doi.org/10.1097/MAT.0000000000001268DOI Listing
October 2020

Endothelial-specific overexpression of cationic amino acid transporter-1 prevents loss of kidney function in heart failure.

Clin Sci (Lond) 2020 10;134(20):2755-2769

Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.

Heart failure (HF) is associated with impaired L-arginine transport. In the present study, we tested the hypothesis that augmented L-arginine transport prevents the loss of kidney function in HF. Renal function was assessed in wildtype mice (WT), transgenic mice with HF (dilated cardiomyopathy, DCM) and double transgenic mice (double transgenic mice with DCM and CAT-1 overexpression, HFCAT-1) with HF and endothelial-specific overexpression of the predominant L-arginine transporter, cationic amino acid transporter-1 (CAT-1) (n=4-8/group). Cardiac function was assessed via echocardiography and left ventricular catheterisation. Renal function was assessed via quantification of albuminuria and creatinine clearance. Plasma nitrate and nitrite levels together with renal fibrosis and inflammatory markers were also quantified at study end. Albumin/creatinine ratio was two-fold greater in DCM mice than in WT mice (P=0.002), and tubulointerstitial and glomerular fibrosis were approximately eight- and three-fold greater, respectively, in DCM mice than in WT mice (P≤0.02). Critically, urinary albumin/creatinine ratio and tubulointerstitial and glomerular fibrosis were less in HFCAT-1 mice than in DCM mice (P<0.05). Renal CAT-1 expression and plasma nitrate and nitrite levels were less in DCM mice compared with WT (P≤0.03) but was greater in HFCAT-1 mice than in DCM mice (P≤0.009). Renal expression of IL-10 was less in DCM mice compared with WT (P<0.001) but was greater in HFCAT-1 mice compared with DCM mice (P=0.02). Our data provide direct evidence that augmented L-arginine transport prevents renal fibrosis, inflammation and loss of kidney function in HF.
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http://dx.doi.org/10.1042/CS20200087DOI Listing
October 2020

High-intensity interval training in patients with left ventricular assist devices: A pilot randomized controlled trial.

J Heart Lung Transplant 2020 12 20;39(12):1380-1388. Epub 2020 Aug 20.

School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia; Advanced Heart Failure and Cardiac Transplant Service, Fiona Stanley Hospital, Perth, Australia; Allied Health Department, Fiona Stanley Hospital, Perth, Australia. Electronic address:

Background: Left ventricular assist device (LVAD) implantation is an established treatment for patients with advanced heart failure. To date, studies evaluating the impact of aerobic training in patients with LVADs have focused on moderate-intensity exercise.

Methods: This pilot randomized controlled trial compared the effects of high-intensity interval training (HIIT) with those of moderate-intensity continuous training (MICT) on peak oxygen consumption (V̇O peak) in patients with LVADs. Secondary outcomes included 6-minute walk test distance, flow-mediated dilation, and anthropometry. Assessments were conducted at baseline and after 12 weeks of supervised training performed 3 times weekly. Participants were randomized to HIIT (4 sets of 4 minutes at 80%-90% V̇O reserve, alternating with 3 minutes at 50%-60% V̇O reserve) or MICT groups (28 minutes continuously at 50%-60% V̇O reserve). Within and between-group differences were analyzed using linear mixed models. Data are expressed as marginal means with 95% confidence intervals or as mean ± SD.

Results: A total of 21 participants were randomized (HIIT: age 57.7 ± 13.1 years; n = 11 and MICT: age 55.6 ± 14.2 years; n = 10) (mean ± SD). No major adverse events occurred in response to training in either group. HIIT significantly improved V̇O peak (15.6 [13.2-17.8] to 18.4 [16.0-20.8] ml/kg/min) (marginal mean [95% CI]) compared with MICT (16.2 [13.8-18.7] to 17.2 [14.6-19.7] ml/kg/min; p < 0.05 between groups). No significant group differences were detected in secondary outcomes.

Conclusion: In patients with LVADs, HIIT was well tolerated and increased aerobic capacity more than MICT. These preliminary findings support the prescription of high-intensity exercise in clinically stable patients with LVADs but warrant validation in a larger sample and across a broader range of physiologic and clinical outcomes.

Clinical Trial Registration: URL: https://www.anzctr.org.au, unique identifier: ACTRN12616001596493.
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http://dx.doi.org/10.1016/j.healun.2020.08.005DOI Listing
December 2020

Identification of physiologic treatment targets with favourable haemodynamic consequences in heart failure with preserved ejection fraction.

ESC Heart Fail 2020 Sep 9. Epub 2020 Sep 9.

Columbia University Medical School, New York, NY, USA.

Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by complex pathophysiology including an impaired diastolic reserve. We recently showed that milrinone favourably modifies filling pressures at rest and during exertion in HFpEF patients; however, the responsible mechanism is uncertain. The objective of this study was to develop a clearer understanding of the acutely modifiable physiologic parameters that may be targeted in HFpEF.

Methods And Results: We conducted computer modelling simulations based on invasive haemodynamic assessments, by right heart catheterization, in HFpEF patients at baseline and in response to milrinone. Our aim was to develop a detailed understanding of the physiologic mechanisms, which accounted for the observed actions. The resultant circulatory model of HFpEF encompassed the left ventricular (LV) end-systolic and end-diastolic pressure-volume relations, together with stressed blood volume, heart rate, and arterial mechanics. To support the modelled action of milrinone, we conducted complementary LV conductance catheter and echocardiography studies in sheep to evaluate LV end-systolic and end-diastolic pressure-volume relations. In HFpEF patients, the acute haemodynamic effects of intravenous milrinone (n = 10) administration compared with placebo (n = 10) included significant reductions in right atrial pressure (7 ± 1 to 3 ± 1 mmHg, P < 0.001) and pulmonary capillary wedge pressure (13 ± 1 to 8 ± 1 mmHg, P < 0.001), while cardiac index increased (2.77 ± 0.19 to 3.15 ± 0.14 L/min/m , P < 0.05), and mean arterial pressure remained unchanged (95 ± 2 to 93 ± 3 mmHg, P = not significant). Computer simulations showed that these haemodynamic effects were explained by a concomitant 31% reduction in stressed blood volume together with 44% increase in LV end-systolic elastance (LV E ). Individually, changes in these parameters were not sufficient to explain the haemodynamic effects of milrinone. In vivo studies conducted in sheep (n = 5) showed that milrinone reduced LV filling pressure (8.0 ± 0.8 to 2.7 ± 0.6 mmHg, P < 0.01) and increased LV E (0.96 ± 0.07 to 2.07 ± 0.49, P < 0.05), while no significant effect on LV stiffness was observed (0.038 ± 0.003 to 0.034 ± 0.008, P = not significant).

Conclusions: These data demonstrate that stressed blood volume in HFpEF represents a relevant physiologic target in HFpEF; however, concomitant modulation of other cardiovascular parameters including LV contractility may be required to achieve desirable haemodynamic effects.
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http://dx.doi.org/10.1002/ehf2.12908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754909PMC
September 2020

Impact of Interatrial Shunts on Invasive Hemodynamics and Exercise Tolerance in Patients With Heart Failure.

J Am Heart Assoc 2020 09 15;9(17):e016760. Epub 2020 Aug 15.

Cardiovascular Research Foundation New York NY USA.

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left-sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP-protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left-sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3- to 5-mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.
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http://dx.doi.org/10.1161/JAHA.120.016760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660772PMC
September 2020

Characterization of infected, explanted ventricular assist device drivelines: The role of biofilms and microgaps in the driveline tunnel.

J Heart Lung Transplant 2020 Jul 24. Epub 2020 Jul 24.

Infection and Immunity Theme, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, Victoria, Australia; Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address:

Background: Driveline infections remain a major complication of ventricular assist device (VAD) implantation. This study aimed to characterize in vivo microbial biofilms associated with driveline infections and host tissue integration of implanted drivelines.

Methods: A total of 9 infected and 13 uninfected drivelines were obtained from patients with VAD undergoing heart transplantation in Australia between 2016 and 2018. Each driveline was sectioned into 11 pieces of 1.5 cm in length, and each section was examined by scanning electron microscopy (SEM) and viable counts for microbial biofilms. Microorganisms were cultured and identified. Host tissue integration of clinical drivelines was assessed with micro-computed tomography (CT) and SEM. An in vitro interstitial biofilm assay was used to simulate biofilm migration in the driveline tunnel, and time-lapse microscopy was performed.

Results: Of the 9 explanted, infected drivelines, all had organisms isolated from varying depths along the velour section of the drivelines, and all were consistent with the swab culture results of the clinically infected exit site. SEM and micro-CT suggested insufficient tissue integration throughout the driveline velour, with microgaps observed. Clinical biofilms presented as microcolonies within the driveline tunnel, with human tissue as the sub-stratum, and were resistant to anti-microbial treatment. Biofilm migration mediated by a dispersal-seeding mechanism was observed.

Conclusions: This study of explanted infected drivelines showed extensive anti-microbial-resistant biofilms along the velour, associated with microgaps between the driveline and the surrounding tissue. These data support the enhancement of tissue integration into the velour as a potential preventive strategy against driveline infections by preventing biofilm migration that may use microgaps as mediators.
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http://dx.doi.org/10.1016/j.healun.2020.07.015DOI Listing
July 2020

Prehospital opioid dose and myocardial injury in patients with ST elevation myocardial infarction.

Open Heart 2020 07;7(2)

Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia

Objective: To characterise the relationship between opioid dose and myocardial infarct size in patients with ST elevation myocardial infarction (STEMI).

Methods: Patients given opioid treatment by emergency medical services with confirmed STEMI were included in this secondary, retrospective cohort analysis of the Air versus Oxygen in Myocardial Infarction (AVOID) study. Patients with cardiogenic shock were excluded. The primary endpoint was comparison of cardiac biomarkers as a measure of infarct size based on opioid dose (low ≤8.75 mg, intermediate 8.76-15 mg and high >15 mg of intravenous morphine equivalent dose).

Results: 422 patients were included in the analysis. There was a significantly higher proportion of patients with Thrombolysis in Myocardial Infarction (TIMI) 0 or 1 flow pre-percutaneous coronary intervention (PCI) (94% vs 81%, p=0.005) and greater use of thrombus aspiration catheters (59% vs 30%, p<0.001) in the high compared with low-dose opioid group. After adjustment for potential confounders, every 1 mg of intravenous morphine equivalent dose was associated with a 1.4% (95% CI 0.2%, 2.7%, p=0.028) increase in peak creatine kinase; however, this was no longer significant after adjustment for TIMI flow pre-PCI.

Conclusions: Our study suggests no benefit of higher opioid dose and a dose-dependent signal between opioid dose and increased myocardial infarct size. Prospective randomised controlled trials are required to establish causality given that this may also be explained by patients with a greater ischaemic burden requiring higher opioid doses due to more severe pain. Future research also needs to focus on strategies to mitigate the opioid-P2Y12 inhibitor interaction and non-opioid analgesia to treat ischaemic chest pain.
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http://dx.doi.org/10.1136/openhrt-2020-001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380835PMC
July 2020

Extended-Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction.

J Am Heart Assoc 2020 07 18;9(13):e015026. Epub 2020 Jun 18.

Department of Cardiology Alfred Hospital Melbourne Australia.

Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HFpEF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HFpEF. Methods and Results The MilHFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double-blind, placebo-controlled pilot study in 23 patients with symptomatic HFpEF. Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6-minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone-treated patients compared with placebo (+10±13 versus -3±15; =0.046). Six-minute walk distance also tended to improve in the treatment group compared with placebo (+22 [-8 to 49] versus -47 [-97 to 12]; =0.092). Heart rate (-1±5 versus -2±9 bpm; =0.9) and systolic blood pressure (-3±18 versus +1±12 mm Hg; =0.57) were unchanged. Early filling velocity/early mitral annular velocity (-0.3±3.0 versus -1.9±4.8; =0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HFpEF. Further longer-term studies are warranted to establish the role of this therapeutic approach in HFpEF. Registration URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616000619448.
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http://dx.doi.org/10.1161/JAHA.119.015026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670502PMC
July 2020

Device Based Approaches to the Prevention of Contrast-Induced Acute Kidney Injury.

Interv Cardiol Clin 2020 07 7;9(3):395-401. Epub 2020 May 7.

Department of Cardiology, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia; Department of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Melbourne, VIC 3168, Australia; Heart Failure Research Group, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. Electronic address:

Contrast-induced acute kidney injury is not uncommon after percutaneous coronary intervention, particularly in high-risk patients. Pharmacologic approaches have not demonstrated significant benefit, and numerous device-based approaches exist targeting a variety of pathways. In this review, we summarize the most recent interventions and the evidence behind them.
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http://dx.doi.org/10.1016/j.iccl.2020.02.005DOI Listing
July 2020

The Emerging Role of Gut Dysbiosis in Cardio-metabolic Risk Factors for Heart Failure.

Curr Hypertens Rep 2020 05 8;22(5):38. Epub 2020 May 8.

Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, 99 Commercial Road, Melbourne, Victoria, 3004, Australia.

Purpose Of Review: To summarize the recent evidence that supports a role for the gut microbiota, microbiota-derived metabolites, and dysbiosis on cardiovascular risk factors, and to discuss the neuro-cardio-metabolic mechanisms that link gut microbiota and heart failure.

Recent Findings: There is growing evidence that the gut microbiota communicates with and impacts the cardiovascular system, contributing to the development of heart failure once it becomes out of balance (i.e. gut dysbiosis). The exact mechanisms of how the gut microbiota influences cardiovascular outcomes are not fully understood, but immune dysregulation and disturbance of neuro-enteroendocrine hormones seem to be involved. The disturbances in the gut microbiota influence the progression of several risk factors for heart failure, including atherosclerosis, obesity, diabetes, kidney disease and hypertension. In turn, these conditions also act to regulate the gut microbiota through the deterioration of the integrity of the intestinal barrier and the release of neurotransmitters and gastrointestinal hormones. In normal and healthy physiological conditions, these interactions are homeostatic and tightly controlled. However, a combination of environmental exposures (e.g. antibiotics use and Western diet) and the host's intrinsic conditions (e.g. genetics and fluid status) can result in the breakdown of intestinal homeostasis and further progression of cardiovascular risk factors, which lead to the development of heart failure. Manipulation of the gut microbiota may have the potential to improve cardiovascular outcomes by ameliorating immune system dysregulation, enteroendocrine disruptions, and neurohormonal activation in patients with cardiovascular risk factors for heart failure.
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http://dx.doi.org/10.1007/s11906-020-01046-0DOI Listing
May 2020

Optimal Mechanical Unloading in Left Ventricular Assist Device Recipients Relates to Progressive Up-Titration in Pump Speed.

J Am Soc Echocardiogr 2020 05 12;33(5):583-593. Epub 2020 Mar 12.

Department of Cardiovascular Medicine, Alfred Hospital, Melbourne, Australia; Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia; Monash University, Melbourne, Australia. Electronic address:

Background: Left ventricular (LV) assist devices (LVADs) are known to elicit reverse remodeling by mechanically unloading the left ventricle. Current guidelines target a reduction in LV end-diastolic diameter (LVEDD) of 15% compared with pre-LVAD dimensions; however, there is significant heterogeneity in the degree of unloading achieved. We sought to investigate factors associated with mechanical unloading at 6 months of LVAD support.

Methods: Data were retrospectively collected for 75 LVAD recipients at five time points: pre-LVAD, within 14 days post-LVAD, and at 1, 3, and 6 months post-LVAD. The percentage change in LVEDD between the pre-LVAD and 6 months post-LVAD time points was termed ΔLVEDD. Optimal LV unloading was defined as ΔLVEDD of ≥15% at 6 months. Patients who achieved optimal unloading (group A, n = 30) were compared with patients who did not (group B, n = 45).

Results: At 6 months, optimally unloaded patients (group A) demonstrated higher fractional shortening (15% ± 10% vs 10% ± 7%, P = .007), lower rates of moderate or severe mitral regurgitation (10% vs 33%, P = .02), and lower pulmonary capillary wedge pressure (9 ± 4 vs 16 ± 7 mm Hg, P = .02). Right ventricular dysfunction was more prevalent at 6 months in poorly unloaded (group B) patients (73% vs 43%, P = .008). Between hospital discharge and 6 months, the percentage increase in pump speed (Δ revolutions per minute) was higher in group A patients (4.4% ± 3.7% vs 0.1% ± 2.6%, P < .001). In a multivariate analysis, Δ revolutions per minute and tricuspid annular systolic velocity (S') at 6 months were independently associated with 6-month ΔLVEDD.

Conclusions: Recipients of LVADs who undergo progressive pump speed up-titration during outpatient follow-up are more likely to sustain optimal LV unloading. Progressive LVAD-related right ventricular failure is prevalent in suboptimally unloaded patients.
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http://dx.doi.org/10.1016/j.echo.2020.01.002DOI Listing
May 2020

Long-Term Survival Following Transcatheter Mitral Valve Repair: Pooled Analysis of Prospective Trials with the Carillon Device.

Cardiovasc Revasc Med 2020 06 25;21(6):712-716. Epub 2020 Feb 25.

Poznan University of Medical Sciences, HCP Medical Center, Poznan, Poland.

Purpose: To report long-term survival and to identify potential determinants of survival among patients receiving treatment for functional mitral regurgitation (FMR) with the Carillon device.

Methods: This was a post hoc analysis in which we pooled prospectively collected data from three studies of the Carillon device with available long-term vital status data. Patient eligibility in these trials specified symptomatic congestive heart failure despite guideline-directed medical therapy, grade 2 to 4 FMR, left ventricular enlargement, and reduced ejection fraction. Echocardiographic parameters were available through the 12-month visit and vital status was available through 5 years. The association of patient characteristics and changes in echocardiographic parameters at 6 and 12 months with long-term survival was analyzed using Cox proportional hazards regression.

Results: A total of 74 patients (mean age 67 years, 72% male, 59% MR grade 3 or 4) were treated with the Carillon device. Over 1 year of follow-up, the New York Heart Association (NYHA) class decreased in 64% of patients, distance on the 6-minute walk test increased, and echocardiographic measures indicated significant decreases in MR grade and favorable left ventricular remodeling. The Kaplan-Meier survival rate was 83.6% at 1 year, 73.1% at 2 years, 67.9% at 3 years, and 56.2% at 4 and 5 years of follow-up. Primary determinants of long-term survival were a decrease in NYHA class, an increase in 6-minute walk test distance, and a decrease in regurgitant volume during the first year of follow-up.

Conclusions: Among patients with congestive heart failure and grade 2 to 4 FMR who were symptomatic despite guideline-directed medical therapy, transcatheter mitral valve repair with the Carillon device resulted in a favorable 5-year survival rate. The survival benefit was greatest among patients with improvement in clinical and hemodynamic parameters during the first year of follow-up.
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http://dx.doi.org/10.1016/j.carrev.2020.02.012DOI Listing
June 2020

Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease.

Circulation 2020 04 25;141(17):1393-1403. Epub 2020 Feb 25.

Heart Failure Research Group (D.M.K., W.A.S., H.A.J., D.H., B.G., A.F., F.Z.M.), Baker Heart and Diabetes Institute, Melbourne, Australia.

Background: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.

Methods: One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg·d). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.

Results: Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.

Conclusions: The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043081DOI Listing
April 2020

The effect of parity on exercise physiology in women with heart failure with preserved ejection fraction.

ESC Heart Fail 2020 02 20;7(1):213-222. Epub 2020 Jan 20.

Department of Cardiology, Alfred Hospital, Commercial Road, Melbourne, Victoria, 3004, Australia.

Aims: Women are overrepresented amongst patients with heart failure with preserved ejection fraction (HFpEF); however, the underpinning mechanism for this asymmetric distribution is unclear. Pregnancy represents a potential gender-specific risk factor for HFpEF. It leads to significant physiological adaption, and increasing parity has been associated with some cardiovascular risk. We sought to examine the relationship between prior parity with the rest and exercise haemodynamic and echocardiographic profile of women with HFpEF.

Methods And Results: Patients referred for assessment of exertional dyspnoea and confirmed to have a haemodynamic and clinical profile consistent with HFpEF were included. Detailed evaluation consisted of rest and exercise right heart catheterization and echocardiography. A socio-economic and obstetric history was also documented. Fifty-eight women were assessed and categorized as having either 0-2 births or ≥3 births, dividing the cohort equally. Women with ≥3 births achieved a lower symptom-limited workload than those with 0-2 births [38 (24-51) vs. 46 (31-68) W, P = 0.04]. Women with ≥3 births had a greater rise in pulmonary capillary wedge pressure indexed to workload with exercise [0.5 (0.3-0.8) vs. 0.3 (0.2-0.5) mmHg/W, P = 0.03], paralleled by a greater rise in right atrial pressure [10 (8-12) vs. 7 (3-11), P = 0.01]. Pulmonary vascular resistance was also higher in women with ≥3 births [1.9 (1.6-2.4) vs. 1.6 (1.4-1.9) mmHg/L/min rest, P = 0.046, and 1.9 (2.4-2.4) vs. 1.4 (1-1.8) mmHg/L/min exercise, P = 0.024]. Left ventricular ejection fraction was lower at rest [60 (57-61) vs. 63 (60-66), P = 0.008] and during exercise [65 (62-67) vs. 68 (66-70), P = 0.038] in women with higher parity.

Conclusions: Higher parity is associated with greater impairments in multiple physiologic parameters of HFpEF severity in women, including diastolic reserve, pulmonary vascular resistance, and systolic dysfunction.
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http://dx.doi.org/10.1002/ehf2.12557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083419PMC
February 2020

A Novel Epigenetic Drug-Eluting Balloon Angioplasty Device: Evaluation in a Large Animal Model of Neointimal Hyperplasia.

Cardiovasc Drugs Ther 2019 12;33(6):687-692

Eastern Health Clinical School, Monash University, Clayton, Australia.

Purpose: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH).

Methods: Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis.

Results: Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA.

Conclusions: Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.
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http://dx.doi.org/10.1007/s10557-019-06921-wDOI Listing
December 2019

Sex differences in heart failure.

Eur Heart J 2019 12;40(47):3859-3868c

University Medical Centre Groningen, Hanzeplein 1, GZ Groningen, The Netherlands.

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.
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http://dx.doi.org/10.1093/eurheartj/ehz835DOI Listing
December 2019

Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction.

J Am Coll Cardiol 2019 11;74(21):2539-2550

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion.

Objectives: The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs).

Methods: This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded.

Results: Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise.

Conclusions: Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234).
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http://dx.doi.org/10.1016/j.jacc.2019.08.1062DOI Listing
November 2019

Impaired l-arginine-nitric oxide pathway contributes to the pathogenesis of resistant hypertension.

Clin Sci (Lond) 2019 10;133(20):2061-2067

Heart failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia.

The precise mechanisms underlying resistant hypertension remain elusive. Reduced nitric oxide (NO) bioavailability is frequently documented in chronic kidney disease, obesity, diabetes and advanced age, all of which are risk factors for resistant hypertension. Sympathetic overactivity and chronic activation of the renin-angiotensin system are salient features of resistant hypertension. Interestingly, recent data indicate that renal sympathetic overactivity can reduce the expression of neuronal nitric oxide synthase in the paraventricular nucleus. Reduced NO levels in the paraventricular nucleus can increase sympathetic outflow and this can create a vicious cycle contributing to resistant hypertension. Angiotensin II can reduce l-arginine transport and hence NO production. Reduced NO levels may reduce the formation of angiotensin 1-7 dampening the cardio-protective effects of the renin-angiotensin system contributing to resistant hypertension. In addition, interleukin-6 (IL-6) is demonstrated to be independently associated with resistant hypertension, and IL-6 can reduce NO synthesis. Despite this, NO levels have not been quantified in resistant hypertension. Findings from a small proof of concept study indicate that NO donors can reduce blood pressure in patients with resistant hypertension but more studies are required to validate these preliminary findings. In the present paper, we put forward the hypothesis that reduced NO bioavailability contributes substantially to the development of resistant hypertension.
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http://dx.doi.org/10.1042/CS20190851DOI Listing
October 2019

Assessment of Predictors of Left Atrial Volume Response to a Transcatheter InterAtrial Shunt Device (from the REDUCE LAP-HF Trial).

Am J Cardiol 2019 12 26;124(12):1912-1917. Epub 2019 Sep 26.

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

In patients with heart failure and preserved or mildly reduced ejection fractions (EF ≥40%), implantation of an interatrial shunt device (IASD) resulted in heterogenous changes of the left atrial (LA) volume. Baseline characteristics that correlate with a favorable decrease in LA volume are unknown. We hypothesized that a larger ratio of left to right atrial volume at baseline would correlate strongly with LA volume decongestion following IASD implantation. Reduce Elevated LA Pressure in Patients With Heart Failure was a multicenter study of the safety and feasibility of IASD implantation. Sixty-four patients with EF ≥40% underwent device implantation along with baseline conventional echocardiograms, speckle tracking echocardiography, and resting and exercise hemodynamics. Higher LA compliance (-4.2%, p = 0.048) and right atrial reservoir strain (-0.8%, p = 0.005) were independently associated with a percent decrease in the systolic LA volume index from baseline to 6-months. In conclusion, greater LA volume reduction following IASD implantation is associated with higher baseline compliance of the left atrium and higher reservoir strain of the right atrium.
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http://dx.doi.org/10.1016/j.amjcard.2019.09.019DOI Listing
December 2019

Interatrial Shunt Device for Heart Failure With Preserved Ejection Fraction.

Front Cardiovasc Med 2019 18;6:143. Epub 2019 Sep 18.

Heart Failure Research Group, Department of Cardiology, Baker Heart and Diabetes Institute, Alfred Hospital, Melbourne, VIC, Australia.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the current burden of HF, and the prevalence is continuing to rise. In contrast to HF with reduced ejection fraction (HFrEF) there are no clinically effective evidence based therapies for HFpEF. The principal pathophysiologic disorder is an elevation of left atrial pressure, most notable during physical activity, which results from impaired left ventricular diastolic reserve, and increased left atrial stiffness. This review outlines the clinical development of a potential device based therapy for HFpEF, the interatrial shunt device (IASD).
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http://dx.doi.org/10.3389/fcvm.2019.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759808PMC
September 2019

The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation.

JACC Heart Fail 2019 11 11;7(11):945-955. Epub 2019 Sep 11.

CardioVascular Center Sankt Katherinen, Frankfurt, Germany; Anglia Ruskin University, Chelmsford, United Kingdom.

Objectives: This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling.

Background: Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis.

Methods: In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis.

Results: Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: -11.7 to -2.5] vs. an increase of 3.3 ml/beat [95% CI: -6.0 to 12.6], respectively; p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: -18.5 to -2.4] vs. an increase of 6.5 ml [95% CI: -5.1 to 18.2]; p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: -12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: -1.42 to 13.6]; p = 0.04).

Conclusions: The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR]; NCT02325830).
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http://dx.doi.org/10.1016/j.jchf.2019.06.011DOI Listing
November 2019