Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise.

BACKGROUND: The mechanisms governing exercise-induced angina and its alleviation by the most commonly used antianginal drug, nitroglycerin, are incompletely understood. The purpose of this study was to develop a method by which the effects of antianginal drugs could be evaluated invasively during physiological exercise to gain further understanding of the clinical impact of angina and nitroglycerin. METHODS: Forty patients (mean age, 65.2±7.6 years) with exertional angina and coronary artery disease underwent cardiac catheterization via radial access and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual nitroglycerin was administered to half the patients, and all patients continued to exercise for 2 minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity and central aortic pressure were recorded with sensor wires. RESULTS: Patients continued to exercise after nitroglycerin administration with less ST-segment depression (P=0.003) and therefore myocardial ischemia. Significant reductions in afterload (aortic pressure, P=0.030) and myocardial oxygen demand were seen (tension-time index, P=0.024; rate-pressure product, P=0.046), as well as an increase in myocardial oxygen supply (Buckberg index, P=0.017). Exercise reduced peripheral arterial wave reflection (P<0.05), which was not further augmented by the administration of nitroglycerin (P=0.648). The observed increases in coronary pressure gradient, stenosis resistance, and flow velocity did not reach statistical significance; however, the diastolic velocity-pressure gradient relation was consistent with a significant increase in relative stenosis severity (k coefficient, P<0.0001), in keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilatation of normal segments, with trends toward reversal with nitroglycerin. CONCLUSIONS: The catheterization laboratory protocol provides a model to study myocardial ischemia and the actions of novel and established antianginal drugs. Administration of nitroglycerin causes changes in the systemic and coronary circulation that combine to reduce myocardial oxygen demand and to increase supply, thereby attenuating exercise-induced ischemia. Designing antianginal therapies that exploit these mechanisms may provide new therapeutic strategies.

Age is not a bar to PCI: Insights from the long-term outcomes from off-site PCI in a real-world setting.

OBJECTIVES: We sought to analyze the percutaneous coronary intervention (PCI) outcomes of very elderly patients (V. Eld. group, age >80 years) and compare their outcomes to a less elderly cohort (Eld. group, age 75-80 years) traditionally reported in the literature. BACKGROUND: Limited data exist on peri-procedural and long-term outcomes following PCI in the V. Eld. (age >80 years), with under-representation of this cohort in randomized controlled trials. These patients present with advanced complex coronary disease and multiple comorbidities. METHODS: All 580 consecutive patients aged ≥75 years (age 80 ± 4.9 years, 57.4% males) undergoing PCI between April 2006 and November 2011 were included. A total of 624 consecutive lesions were identified and analyzed. All V. Eld. patients (n = 253) were subsequently selected, and their outcomes compared to Eld. patients (n = 327). Mean follow-up was 30.8 ± 2.7 months with 98% clinical follow-up achieved. RESULTS: All comparative data are expressed as (V. Eld. vs Eld.) unless otherwise specified. All-cause mortality was significantly higher in the V. Eld. group (11.9% vs 6.1%), although this did not translate into a significant difference in cardiac mortality (6.3% vs 3.7%) or major adverse cardiac and cerebrovascular events (16.2% vs 12.5%). The composite incidence of myocardial infarction (MI), stroke, definite/probable stent thrombosis, and TIMI major bleed was 4.7%, 1.4% 1.9%, and 6.4%, respectively with no significant difference between both cohorts. CONCLUSIONS: This study demonstrates an acceptable occurrence of MI, death, repeat intervention, and stent thrombosis in a high-risk group of V. Eld. patients with de novo lesions. Age alone in the absence of other non-cardiac factors should not prohibit a patient from access to PCI.

Current Concepts in the Pathogenesis of Takotsubo Syndrome.

Takotsubo syndrome is typically characterized by acute reversible impairment of apical and mid -left ventricular systolic function. The pathophysiology is complex and remains to be completely understood. A catecholamine surge appears to be a central feature. Patients with prior history of psychiatric disorders have a predisposition. The putative role of a switch in b-adrenoceptor signalling resulting in negative inotropy remains uncertain. Downregulation of noncritical cellular functions may offer some protection in preventing irreversible cellular necrosis. Microvascular function is a common occurrence in these patients.

Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study.

BACKGROUND: Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo. METHODS AND DESIGN: The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3. DISCUSSION: The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study. TRIAL REGISTRATION: National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001.

Percutaneous paravalvular leak closure for symptomatic aortic regurgitation after CoreValve transcatheter aortic valve implantation.

OBJECTIVES: We present a case series of five patients in whom percutaneous paravalvular leak closure with the AVP4 device has been undertaken for symptomatic aortic regurgitation after CoreValve TAVI. BACKGROUND: Significant post-procedure aortic regurgitation (AR) is often difficult to assess, and is an important predictor of adverse outcome following TAVI. Paravalvular leak closure is an established procedure for surgical aortic prostheses, and has been undertaken for Edwards TAVIs, but has not been described for closure of CoreValve paravalvular leaks. METHODS AND RESULTS: Five patients were treated (mean age 81 ± 4 years) with residual grade 3-4 AR following placement of a single CoreValve (n = 2), double CoreValve (n = 2) or CoreValve within a bioprosthetic AVR (n = 1). The mean time post TAVI implantation was 308 ± 269 days. All patients were symptomatic with persistent NYHA Grade III dyspnoea. 6 devices were deployed successfully, with mean procedure time of 109 ± 23 min. There were no procedural complications and all patients were discharged home by Day 2. Residual AR after treatment was grade 0 (n = 2), grade 1 (n = 1), grade 2 (n = 1) and grade 3 (n = 1). Symptomatic improvement was noted in all 4 patients who have been reviewed in clinic since. CONCLUSIONS: This small series demonstrates the feasibility of paravalvular leak closure with the CoreValve TAVI, despite the adverse aortic lattice. The AVP4 device is ideally suited to this situation as it will pass through a 0.038' lumen and can therefore be delivered down standard diagnostic catheters.

A rare presentation of acute myocarditis as a manifestation of adult-onset Still's disease: a case report.

Background: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory condition characterized by a classical triad of symptoms that include prolonged fever, polyarthritis, and a characteristic salmon-pink skin rash. It can affect a variety of organ systems resulting in many different clinical presentations and is usually a diagnosis of exclusion. Myocarditis complicated by cardiogenic shock is a rare and life-threatening manifestation of AOSD, typically affecting younger patients. There is a limited experience and evidence in how best to manage this challenging patient cohort. Case summary: A previously fit and well 22-year-old male presented with fever, arthralgia, and general malaise. On clinical examination, he was pyrexial and hypotensive, requiring vasopressor support for presumed septic shock. Subsequent transthoracic echocardiography and cardiac MRI findings were in keeping with fulminant myocarditis. Further septic and auto-immune screens were negative although he responded well to high-dose intravenous corticosteroids. Attempts to wean immunosuppression were unsuccessful, and his ferritin was markedly elevated (20 233 µg/L). A diagnosis of AOSD was suspected after exclusion of other possible causes. The successful addition of tocilizumab (an interleukin-6 receptor antagonist) therapy allowed for gradual de-escalation of steroid therapy and disease remission, with on-going remission at 18 months on maintenance therapy. Discussion: This case highlights the importance of considering AOSD as a rare cause for myocarditis, especially when fever is present, or disease is severe. Failure to improve with first-line therapy involving high-dose corticosteroids, or inability to wean that therapy, should prompt consideration for escalation of therapy, with tocilizumab seemingly an effective treatment option.

Fully automatable, reproducible, noninvasive simple plethysmographic optimization: proof of concept and potential for implantability.

BACKGROUND: Hemodynamic optimization of cardiac resynchronization therapy (CRT) can be achieved reproducibly and--with bulky, nonimplantable equipment--noninvasively. We explored whether a simple photoplethysmogram signal might be used instead. METHOD: Twenty patients (age 65 ± 12) with CRT underwent automatic atrioventricular (AV) delay optimization, using a multiple-transitions protocol, at two atrially paced heart rates: just above sinus rate ("slow ApVp," 77 ± 11 beats per minute [bpm]) and 100 bpm ("fast ApVp"). We then retested to assess short-term reproducibility. RESULTS: All 80 optimizations identified an optimum (correctly oriented parabola). At 100 bpm, the simple photoplethysmogram had wider scatter between repeat optimizations than did Finometer: standard deviation of difference (SDD) 22 ms versus 14 ms, respectively, P = 0.028. The simple photoplethysmogram improved in reproducibility when slope (instead of peak) of its signal was used for optimization, becoming as reproducible as Finometer (SDD 14 ms vs 14 ms, P = 0.50). At slow heart rate, reproducibility of simple photoplethysmogram-based optimization worsened from 14 to 22 ms (P = 0.028), and Finometer-based optimization from 14 to 26 ms (P = 0.005). Increasing the number of replicates averaged improved reproducibility. For example, SDD of simple photoplethysmogram optimization (using peak) fell from 62 ms with two replicates to 22 ms with eight replicates (P < 0.0001). At 100 bpm, the eight-replicate protocol takes ∼12 minutes. CONCLUSIONS: A 12-minute protocol of simple photoplethysmographic AV optimization can be processed fully automatically. Blinded test-retest reproducibility of the optimum AV is good and improves with more replicates. If benefits to some patients are not to be neutralized by harm to others, endpoint studies should first test check narrowness of "within-patient error bars."

Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS): a double-blind randomised placebo-controlled crossover trial.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) activation may improve myocardial performance in the context of ischaemia, independent of glycaemic control, in individuals with and without type 2 diabetes mellitus. METHODS: The LIONESS trial was a single-centre randomised double-blind placebo-controlled crossover study to determine whether prolonged GLP-1R activation could improve exercise haemodynamics in chronic stable angina patients. Eligibility criteria comprised angiographic evidence of obstructive coronary artery disease (CAD) and an abnormal baseline exercise tolerance test (ETT) demonstrating > 0.1 mV of planar or downsloping ST-segment depression (STD). Those randomised to active agent started with a 1-week run-in phase of 0.6 mg liraglutide daily, an established injectable GLP-1R agonist, followed by 1 week of 1.2 mg liraglutide, after which patients performed a week 2 ETT. Patients then self-administered 1.8 mg liraglutide for a week before completing a week 3 ETT. The placebo arm received visually and temporally matched daily saline injections. Participants then crossed over to a 3-week course of saline injections interspersed with a week 5 ETT and week 6 ETT and vice versa. Co-primary endpoints were rate pressure product (RPP) at 0.1 mV STD and magnitude of STD at peak exercise. RESULTS: Twenty-two patients (21 without diabetes) were randomised. There was no significant difference between saline versus liraglutide in the co-primary endpoints of RPP achieved at 0.1 mV STD (saline vs. liraglutide 1.2 mg p = 0.097; saline vs. liraglutide 1.8 mg p = 0.48) or the degree of STD at peak exercise (saline vs. liraglutide 1.2 mg p = 0.68; saline vs. liraglutide 1.8 mg p = 0.57). Liraglutide did not cause symptomatic hypoglycaemia, renal dysfunction, acute pancreatitis or provoke early withdrawal from the trial. Liraglutide significantly reduced weight (baseline 88.75 ± 16.5 kg vs. after liraglutide 87.78 ± 16.9 kg; p = 0.0008) and improved the lipid profile (mean total cholesterol: at baseline 3.97 ± 0.88 vs. after liraglutide 3.56 ± 0.71 mmol/L; p < 0.0001). CONCLUSION: Liraglutide did not enhance exercise tolerance or haemodynamics compared with saline placebo during serial treadmill testing in patients with established obstructive CAD. It did, however, significantly reduce weight and improve the lipid profile. Trial Registration ClinicalTrials.gov Identifier NCT02315001. Retrospectively registered on 11th December 2014.