The effect of sodium-glucose co-transporter 2 inhibitors on outcomes after cardiac resynchronization therapy.

AIMS: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium-glucose co-transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. METHODS AND RESULTS: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy-four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non-ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end-diastolic inner-dimension (LVIDd) and diastolic function (E/A and e/e'). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). CONCLUSIONS: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.

Cardiac resynchronization using fusion pacing during exercise.

INTRODUCTION: Fusion pacing requires correct timing of left ventricular pacing to right ventricular activation, although it is unclear whether this is maintained when atrioventricular (AV) conduction changes during exercise. We used cardiopulmonary exercise testing (CPET) to compare cardiac resynchronization therapy (CRT) using fusion pacing or fixed AV delays (AVD). METHODS: Patients 6 months post-CRT implant with PR intervals < 250 ms performed two CPET tests, using either the SyncAV™ algorithm or fixed AVD of 120 ms in a double-blinded, randomized, crossover study. All other programming was optimized to produce the narrowest QRS duration (QRSd) possible. RESULTS: Twenty patients (11 male, age 71 [65-77] years) were recruited. Fixed AVD and fusion programming resulted in similar narrowing of QRSd from intrinsic rhythm at rest (p = .85). Overall, there was no difference in peak oxygen consumption (V̇O2 PEAK , p = .19), oxygen consumption at anaerobic threshold (VT1, p = .42), or in the time to reach either V̇O2 PEAK (p = .81) or VT1 (p = .39). The BORG rating of perceived exertion was similar between groups. CPET performance was also analyzed comparing whichever programming gave the narrowest QRSd at rest (119 [96-136] vs. 134 [119-142] ms, p < .01). QRSd during exercise (p = .03), peak O2 pulse (mL/beat, a surrogate of stroke volume, p = .03), and cardiac efficiency (watts/mL/kg/min, p = .04) were significantly improved. CONCLUSION: Fusion pacing is maintained during exercise without impairing exercise capacity compared with fixed AVD. However, using whichever algorithm gives the narrowest QRSd at rest is associated with a narrower QRSd during exercise, higher peak stroke volume, and improved cardiac efficiency.

Exercise capacity following SARS-CoV-2 infection is related to changes in cardiovascular and lung function in military personnel.

BACKGROUND: Since the COVID-19 pandemic, post-COVID syndrome (persistent symptoms/complications lasting >12 weeks) continues to pose medical and economic challenges. In military personnel, where optimal fitness is crucial, prolonged limitations affecting their ability to perform duties has occupational and psychological implications, impacting deployability and retention. Research investigating post-COVID syndrome exercise capacity and cardiopulmonary effects in military personnel is limited. METHODS: UK military personnel were recruited from the Defence Medical Services COVID-19 Recovery Service. Participants were separated into healthy controls without prior SARS-CoV-2 infection (group one), and participants with prolonged symptoms (>12 weeks) after mild-moderate (community-treated) and severe (hospitalised) COVID-19 illness (group 2 and 3, respectively). Participants underwent cardiac magnetic resonance imaging (CMR) and spectroscopy, echocardiography, pulmonary function testing and cardiopulmonary exercise testing (CPET). RESULTS: 113 participants were recruited. When compared in ordered groups (one to three), CPET showed stepwise decreases in peak work, work at VT1 and VO2 max (all p < 0.01). There were stepwise decreases in FVC (p = 0.002), FEV1 (p = 0.005), TLC (p = 0.002), VA (p < 0.001), and DLCO (p < 0.002), and a stepwise increase in A-a gradient (p < 0.001). CMR showed stepwise decreases in LV/RV volumes, stroke volumes and LV mass (LVEDVi/RVEDVi p < 0.001; LVSV p = 0.003; RVSV p = 0.001; LV mass index p = 0.049). CONCLUSION: In an active military population, post-COVID syndrome is linked to subclinical changes in maximal exercise capacity. Alongside disease specific changes, many of these findings share the phenotype of deconditioning following prolonged illness or bedrest. Partitioning of the relative contribution of pathological changes from COVID-19 and deconditioning is challenging in post-COVID syndrome recovery.

Non-invasive left ventricular pressure-volume loops from cardiovascular magnetic resonance imaging and brachial blood pressure: validation using pressure catheter measurements.

Aims: Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. A non-invasive method for the computation of PV loops from magnetic resonance imaging and brachial cuff blood pressure has recently been proposed. Here we evaluated the fidelity of the non-invasive PV algorithm against invasive LV pressures in humans. Methods and results: Four heart failure patients with EF < 35% and LV dyssynchrony underwent cardiovascular magnetic resonance (CMR) imaging and subsequent LV catheterization with sequential administration of two different intravenous metabolic substrate infusions (insulin/dextrose and lipid emulsion), producing eight datasets at different haemodynamic states. Pressure-volume loops were computed from CMR volumes combined with (i) a time-varying elastance function scaled to brachial blood pressure and temporally stretched to match volume data, or (ii) invasive pressures averaged from 19 to 30 sampled beats. Method comparison was conducted using linear regression and Bland-Altman analysis. Non-invasively derived PV loop parameters demonstrated high correlation and low bias when compared to invasive data for stroke work (R2 = 0.96, P < 0.0001, bias 4.6%), potential energy (R2 = 0.83, P = 0.001, bias 1.5%), end-systolic pressure-volume relationship (R2 = 0.89, P = 0.0004, bias 5.8%), ventricular efficiency (R2 = 0.98, P < 0.0001, bias 0.8%), arterial elastance (R2 = 0.88, P = 0.0006, bias -8.0%), mean external power (R2 = 0.92, P = 0.0002, bias 4.4%), and energy per ejected volume (R2 = 0.89, P = 0.0001, bias 3.7%). Variations in estimated end-diastolic pressure did not significantly affect results (P > 0.05 for all). Intraobserver analysis after one year demonstrated 0.9-3.4% bias for LV volumetry and 0.2-5.4% for PV loop-derived parameters. Conclusion: Pressure-volume loops can be precisely and accurately computed from CMR imaging and brachial cuff blood pressure in humans.

Retained Metabolic Flexibility of the Failing Human Heart.

BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.

Detection and alterations of acetylcarnitine (AC) in human liver by 1 H MRS at 3T after supplementation with l-carnitine.

PURPOSE: Acetylcarnitine can be assessed in vivo using proton MRS (1 H-MRS) with long TEs and this has been previously applied successfully in muscle. The aim of this study was to evaluate a 1 H-MRS technique for liver acetylcarnitine quantification in healthy humans before and after l-carnitine supplementation. METHOD: Baseline acetylcarnitine levels were quantified using a STEAM sequence with prolonged TE in 15 healthy adults. Using STEAM with four different TEs was evaluated in phantoms. To assess reproducibility of the measurements, five of the participants had repeated 1 H-MRS without receiving l-carnitine supplementation. To determine if liver acetylcarnitine could be changed after l-carnitine supplementation, acetylcarnitine was quantified 2 h after intravenous l-carnitine supplementation (50 mg/kg body weight) in the other 10 participants. Hepatic lipids were also quantified from the 1 H-MRS spectra. RESULTS: There was good separation between the acetylcarnitine and fat in the phantoms using TE = 100 ms. Hepatic acetylcarnitine levels were reproducible (coefficient of reproducibility = 0.049%) and there was a significant (p < 0.001) increase in the relative abundance after a single supplementation of l-carnitine. Hepatic allylic, methyl, and methylene peaks were not altered by l-carnitine supplementation in healthy volunteers. CONCLUSION: Our results demonstrate that our 1 H-MRS technique could be used to measure acetylcarnitine in the liver and detect changes following intravenous supplementation in healthy adults despite the presence of lipids. Our techniques should be explored further in the study of fatty liver disease, where acetylcarnitine is suggested to be altered due to hepatic inflexibilities.

What Have We Learned in the Last 20 Years About CRT Non-Responders?

Although cardiac resynchronization therapy (CRT) has become well established in the treatment of heart failure, the management of patients who do not respond after CRT remains a key challenge. This review will summarize what we have learned about non-responders over the last 20 years and discuss methods for optimizing response, including the introduction of novel therapies.

Myocardial Energy Response to Glyceryl Trinitrate: Physiology Revisited.

Objective: Although intravenous nitrates are commonly used in clinical medicine, they have been shown to increase myocardial oxygen consumption and inhibit complex IV of the electron transport chain. As such we sought to measure whether myocardial energetics were impaired during glyceryl trinitrate (GTN) infusion. Methods: 10 healthy volunteers underwent cardiac magnetic resonance imaging to assess cardiac function and 31phosphorus magnetic resonance spectroscopy to measure Phosphocreatine/ATP (PCr/ATP) ratio and creatine kinase forward rate constant (CK kf ) before and during an intravenous infusion of GTN. Results: During GTN infusion, mean arterial pressure (78 ± 7 vs. 65 ± 6 mmHg, p < 0.001), left ventricular (LV) stroke work (7,708 ± 2,782 vs. 6,071 ± 2,660 ml mmHg, p < 0.001), and rate pressure product (7,214 ± 1,051 vs. 6,929 ± 976 mmHg bpm, p = 0.06) all fell. LV ejection fraction increased (61 ± 3 vs. 66 ± 4%, p < 0.001), with cardiac output remaining constant (6.2 ± 1.5 vs. 6.5 ± 1.4 l/min, p = 0.37). Myocardial PCr/ATP fell during GTN infusion (2.17 ± 0.2 vs. 1.99 ± 0.22, p = 0.03) with an increase in both CK kf (0.16 ± 0.07 vs. 0.25 ± 0.1 s-1, p = 0.006) and CK flux (1.8 ± 0.8 vs. 2.6 ± 1.1 µmol/g/s, p = 0.03). Conclusion: During GTN infusion, despite reduced LV stroke work and maintained cardiac output, there was a 44% increase in myocardial ATP delivery through CK. As PCr/ATP fell, this increase in ATP demand coincided with GTN-induced impairment of mitochondrial oxidative phosphorylation. Overall, this suggests that while GTN reduces cardiac work, it does so at the expense of increasing ATP demand beyond the capacity to increase ATP production.

Pneumopericardium and Pneumomediastinum After Implantation of a Cardiac Resynchronization Pacemaker.

A patient with previous coronary artery bypass grafting developed an iatrogenic pneumothorax, along with pneumopericardium and pneumomediastinum, after elective implantation of a cardiac resynchronization therapy pacemaker. There was no evidence of lead perforation, and the patient remained well and was successfully managed conservatively. We hypothesize that air tracked from the pneumothorax via microscopic pleuropericardial fistulae. (Level of Difficulty: Intermediate.).

The Tryton® dedicated bifurcation stent: Five-year clinical outcomes.

AIMS: We report the first 5 year clinical follow-up data for the Tryton® bifurcation stent. METHODS AND RESULTS: Clinical outcomes at five years were collected from 8 centres. Non-hierarchical Major Adverse Cardiovascular Events (MACE) and Major Adverse Cerebrovascular and Cardiovascular Events (MACCE) were collected. Diabetic and non-diabetic populations were compared, along with small (≤2.5 mm) vs large (>2.5 mm) side branch size. 173 patients with a follow up rate of 98% at 5 years were analysed. Non-hierarchical MACE was low at 9.8%, consisting of cardiac death of 1.2% (n = 2) and MI of 1.7% (n = 3). Target lesion revascularization (TLR) rate was 6.9% (n = 12). Non-hierarchical MACCE was also low, with major bleeding in 2.3% (n = 4) and strokes in 1.7% (n = 3) of patients. There was only 1 case (0.6%) of stent thrombosis that was definite and occurred very late (782 days). All-cause mortality was low, with 8.7% combined cardiac and non-cardiac death (n = 15). Diabetic patients had significantly higher event rates, but there was no difference in events with lesion stratification by side branch size. CONCLUSIONS: The Tryton® Side-Branch Stent has a non-hierarchical MACE of 9.8% and MACCE of 13.9% at 5 years. The TLR was 6.9% with only 1 case of stent thrombosis recorded.

Mitral Valve Diverticulum Presenting with Severe Mitral Stenosis: Case Report.

The case is presented of a non-infectious anterior mitral valve leaflet diverticulum, which appeared as symptomatic mitral stenosis. Unlike previous reports, there was no histological myxomatous degeneration of the valve. To the authors' knowledge, this is the first time a mitral valve diverticulum resulting in severe mitral stenosis has been reported in the literature.