Pre-Treatment With Glucagon-Like Peptide-1 Protects Against Ischemic Left Ventricular Dysfunction and Stunning Without a Detected Difference in Myocardial Substrate Utilization

AbstractObjectivesThis study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention.BackgroundGLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear.MethodsTwenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low-pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients.ResultsBO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dTmax, –4.3 vs. –19.0%, p = 0.02; delta stroke volume, –7.8 vs. –26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups.ConclusionsPre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023

Stunning and Right Ventricular Dysfunction Is Induced by Coronary Balloon Occlusion and Rapid Pacing in Humans: Insights From Right Ventricular Conductance Catheter Studies

BACKGROUND: We sought to determine whether right ventricular stunning could be detected after supply (during coronary balloon occlusion [BO]) and supply/demand ischemia (induced by rapid pacing [RP] during transcatheter aortic valve replacement) in humans. METHODS AND RESULTS: Ten subjects with single-vessel right coronary artery disease undergoing percutaneous coronary intervention with normal ventricular function were studied in the BO group. Ten subjects undergoing transfemoral transcatheter aortic valve replacement were studied in the RP group. In both, a conductance catheter was placed into the right ventricle, and pressure volume loops were recorded at baseline and for intervals over 15 minutes after a low-pressure BO for 1 minute or a cumulative duration of RP for up to 1 minute. Ischemia-induced diastolic dysfunction was seen 1 minute after RP (end-diastolic pressure [mm Hg]: 8.1±4.2 versus 12.1±4.1, P<0.001) and BO (end-diastolic pressure [mm Hg]: 8.1±4.0 versus 8.7±4.0, P=0.03). Impairment of systolic and diastolic function after BO remained at 15-minutes recovery (ejection fraction [%]: 55.7±9.0 versus 47.8±6.3, P<0.01; end-diastolic pressure [mm Hg]: 8.1±4.0 versus 9.2±3.9, P<0.01). Persistent diastolic dysfunction was also evident in the RP group at 15-minutes recovery (end-diastolic pressure [mm Hg]: 8.1±4.1 versus 9.9±4.4, P=0.03) and there was also sustained impairment of load-independent indices of systolic function at 15 minutes after RP (end-systolic elastance and ventriculo-arterial coupling [mm Hg/mL]: 1.25±0.31 versus 0.85±0.43, P<0.01). CONCLUSIONS: RP and right coronary artery balloon occlusion both cause ischemic right ventricular dysfunction with stunning observed later during the procedure. This may have intraoperative implications in patients without right ventricular functional reserve

Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies.

BACKGROUND: Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. METHODS: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. RESULTS: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). CONCLUSIONS: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022

Ventriculo-arterial coupling detects occult RV dysfunction in chronic thromboembolic pulmonary vascular disease.

Chronic thromboembolic disease (CTED) is suboptimally defined by a mean pulmonary artery pressure (mPAP)  0.68 and Ees/Ea < 0.68 subgroups demonstrated constant RV stroke work but lower stroke volume (87.7 ± 22.1 vs. 60.1 ± 16.3 mL respectively, P = 0.006) and higher end-systolic pressure (36.7 ± 11.6 vs. 68.1 ± 16.7 mmHg respectively, P < 0.001). Lower Ees/Ea in CTED also correlated with reduced exercise ventilatory efficiency. Low Ees/Ea aligns with features of RV maladaptation in CTED both at rest and on exercise. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction

Optimising RV-PA ventriculoarterial-coupling to improve RV diastolic function in patients with cardiopulmonary disorders

In recent years, an increasing body of evidence has emerged postulating that right ventricular (RV) - pulmonary artery (PA) ventriculoarterial coupling may offer insight into the transition from RV adaptation to RV maladaptation in different cardiopulmonary disorders and heart failure. RV-PA ventriculoarterial coupling is a matching between RV contractility (Ees – End-Systolic Elastance) and afterload (Ea – Effective Arterial Elastance). While ventriculoarterial coupling has been extensively described in the LV and used to determine optimal conditions for the efficient transfer to blood from the ventricle into the aorta, it remains unclear whether this relationship can be translated to the thinner walled RV that pumps at lower pressures against a more compliant pulmonary vascular system. Therefore, the pressure-volume (PV)-loop studies in this thesis were undertaken to assess whether ventriculoarterial uncoupling due to pressure overload or sub-optimal contractility contributed to further RV diastolic dysfunction. An in-vivo porcine model of RV-PA ventriculoarterial coupling was developed to define optimal conditions. This animal model was used to provide insights into two clinical patient groups that have RV dysfunction due to: i) long-term RV pressure overload in patients with a clinical diagnosis of chronic thromboembolic disease (CTED) / pulmonary hypertension (CTEPH); and ii) aortic valve stenosis transmitted by ventricular interdependence and septal wall reconfiguration in patients treated with transcatheter aortic valve implantation (TAVI). The animal model determined an ventriculoarterial coupling ratio at maximal stroke work (Ees/Eamax sw = 0.68±0.23) threshold, below which cardiac output and RV stroke work fell. In the first clinical study this threshold was used to reclassify 25% of a cohort of patients with CTED or CTEPH. Two patients with CTED were identified with an EesEa below 0.68 suggesting occult RV dysfunction whilst three patients with CTEPH demonstrated Ees/Ea≥0.68 suggesting residual RV energetic reserve. In the second clinical study ventricular interdependence phenomena caused septal reconfiguration and increased RV volumes after valve deployment, due to the reduction in LV afterload. However, the rapid pacing (RP) protocol used to stabilise the aortic valve during deployment also caused RP-induced ischemia and stunning. This resulted in the reduction of Ees and led to Ees/Ea uncoupling and further diastolic dysfunction. This work has demonstrated that: Low Ees/Ea aligns with features of RV maladaptation in CTED. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction in patients with otherwise normal pulmonary hemodynamics; and a reduction in Ees following TAVI correlates with increased RV diastolic dysfunction, due to RP-induced ischemia and stunning

RV diastolic dysfunction: time to re-evaluate its importance in heart failure

Right ventricular (RV) diastolic dysfunction was first reported as an indicator for the assessment of ventricular dysfunction in heart failure a little over two decades ago. However, the underlying mechanisms and precise role of RV diastolic dysfunction in heart failure remain poorly described. Complexities in the structure and function of the RV make the detailed assessment of the contractile performance challenging when compared to its left ventricular (LV) counterpart. LV dysfunction is known to directly affect patient outcome in heart failure. As such, the focus has therefore been on LV function. Nevertheless, a strategy for the diagnosis and assessment of RV diastolic dysfunction has not been established. Here, we review the different causal mechanisms underlying RV diastolic dysfunction, summarising the current assessment techniques used in a clinical environment. Finally, we explore the role of load-independent indices of RV contractility, derived from the conductance technique, to fully interrogate the RV and expand our knowledge and understanding of RV diastolic dysfunction. Accurate assessment of RV contractility may yield further important prognostic information that will benefit patients with diastolic heart failure

Overnight Ambulatory Urodynamics Change Patient Management Strategies and Improve Symptomatic Outcomes

ObjectivesTo determine the diagnostic value of overnight ambulatory urodynamics (aUDS) and to assess if a urodynamic diagnosis of detrusor overactivity (DO) or nocturnal enuresis resulted in a change in patient management and an improvement in their urinary symptoms. MethodsA retrospective review of 25 consecutive patients (28% male) with a median age of 38 years (range 18 to 86) having overnight aUDS for bothersome urinary symptoms of primarily nocturia and/or nocturnal enuresis following non-diagnostic conventional urodynamics between November 1998 and August 2018. Urinary symptoms were assessed before overnight aUDS and again after urological treatment following any changes in urodynamics diagnosis and treatment. Six patients were excluded as follow-up data were not available. ResultsTwenty-four patients (96%) presented with nocturia and 20 (80%) presented with nocturnal enuresis. DO was demonstrated in 19 (76%) patients (mean pressure 69.1±53.3 cmH2O). UUI was demonstrated in 16 (80%) out of the 20 patients who complained of nocturnal enuresis. Of the 19 patients with follow-up data, following overnight aUDS a change in urodynamic diagnosis was made in 15 patients (79%); 16 patients (84%) also had their clinical diagnosis and subsequent management changed; and 15 patients (79%) reported an improvement in their urinary symptoms following these changes in diagnosis and treatment. There was a significant improvement in ICIQ-OAB (120±44 versus 32±53, P < 0.0001) scores following the changes to clinical management post-overnight aUDS. ConclusionIn our study cohort, change in primary diagnosis following overnight aUDS led to a significant change in treatment care pathway and resulted in significant improvement in urinary symptoms at follow-up