Coronary Artery Disease Is A Stronger Predictor of All-Cause Mortality Than Left Ventricular Ejection Fraction Among Patients With Newly Diagnosed Heart Failure: Insights From the WDHR.

BACKGROUND: In patients with newly diagnosed heart failure (HF) and left ventricular ejection fraction (LVEF) <50%, little is known whether LVEF per se or presence of coronary artery disease (CAD) provides independent prognostic information on all-cause mortality. METHODS AND RESULTS: Using the WDHR (Western Denmark Heart Registry), we identified 3620 patients with newly diagnosed HF and LVEF 10% to 49% referred for first-time coronary angiography as part of general workup of HF. Patients were stratified by LVEF (10%-35% versus 36%-49%) and presence of CAD. We estimated 10-year all-cause mortality risk and calculated hazard ratios adjusted for relevant comorbidities and risk factors (aHRs). CAD was present in 1592 (44%) patients. Lower LVEF was associated with a relative 15% increased 10-year mortality: 37% for LVEF 36% to 49% versus 42% for LVEF 10% to 35% (aHR, 1.15 [95% CI, 0.99-1.34]). This result did not change when stratified into those with CAD (52% versus 56%; aHR, 1.11 [95% CI, 0.91-1.35]) and those without CAD (27% versus 33%; aHR, 1.24 [95% CI, 0.97-1.57]). In comparison, presence and extent of CAD were associated with a relative 43% increased 10-year mortality (CAD versus no CAD, 55.0% versus 31.5%; aHR, 1.43 [95% CI, 1.25-1.64]). Compared with a matched general population, excess mortality risk was higher for patients with HF and CAD (54.7% versus 26.3%; aHR, 2.10 [95% CI, 1.85-2.39]) versus those with HF and no CAD (31.4% versus 17.2%; aHR, 1.76 [95% CI, 1.52-2.02]). CONCLUSIONS: Among newly diagnosed patients with HF and LVEF <50%, presence and extent of CAD are associated with substantial higher all-cause mortality risk than lower LVEF.

Inflammatory-mediated atrial cardiomyopathy diagnosed using multimodality imaging and successfully treated with prednisolone: a case report.

Background: Atrial fibrillation is a common cardiac arrhythmia and often develops secondary to structural cardiac changes. Both the occurrence of atrial fibrillation and/or structural changes of the heart may lead to development of atrial cardiomyopathy and heart failure (HF). However, isolated atrial cardiomyopathy caused by focal atrial thickening is a rare condition, previously only described in case reports as a result of different aetiologies all linked to inflammation. Case summary: A patient with inflammatory-mediated atrial cardiomyopathy causing atrial fibrillation and acute decompensated HF presented as isolated left atrial wall thickening on transoesophageal echocardiography. The diagnosis was confirmed using multimodality imaging with transthoracic and transoesophageal echocardiography, cardiac magnetic resonance imaging, positron emissions tomography/computer tomography scanning and intracardiac echocardiography-guided endomyocardial biopsy. Despite no specific histological aetiology, the observed atrial cardiomyopathy might be associated with type 1 diabetes mellitus. The patient in the present case was successfully treated with prednisolone. Discussion: Diabetes mellitus is an important risk factor for developing atrial fibrillation and diabetic cardiomyopathy, due to reduced levels of anti-inflammatory and increased levels of proinflammatory cytokines causing cardiac inflammatory structural remodelling. The regression of the atrial thickening might be due to prednisolone's anti-inflammatory effects and thereby ability to suppress atrial remodelling and reduce the occurrence of atrial fibrillation. However, the effect of prednisolone might only affect the non-manifested inflammatory-mediated atrial remodelling. Due to the rare occurrence of isolated atrial cardiomyopathy a multiple imaging approach during the diagnostic process and follow-ups are essential to determine the aetiology and effect of the treatment.

Antithrombotic treatment for chronic coronary syndrome: Evidence and future perspectives.

Background The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. Summary Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with e.g., concomitant atrial fibrillation or venous thromboembolism. Key messages This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

Impact of Coronary Artery Disease in Women With Newly Diagnosed Heart Failure and Reduced Ejection Fraction.

BACKGROUND: The representation of women in heart failure studies has been inadequate, resulting in a knowledge gap regarding the prognostic impact of coronary artery disease (CAD) on all-cause mortality in women with newly diagnosed heart failure and reduced ejection fraction (HFrEF). OBJECTIVES: This study aims to assess the prognostic impact of CAD in women with HFrEF. METHODS: Using the Western Denmark Heart Registry, the authors identified 891 women and 2,403 men referred for first-time coronary angiography because of HFrEF. The authors stratified for presence of CAD, estimated 10-year all-cause mortality, and calculated crude and adjusted HRs (aHRs) with 95% CIs. RESULTS: The 10-year mortality was 60% in women with CAD and 27% in women without CAD; for men, the corresponding numbers were 54% and 36%. When adjusted for comorbidities, women without CAD had a lower relative 10-year mortality than men without CAD (aHR: 0.73; 95% CI: 0.58-0.91), whereas women with CAD had similar relative mortality as men with CAD (aHR: 1.00; 95% CI: 0.81-1.24) (Pinteraction = 0.037). Assessed by the number of coronary vessels with significant stenosis, CAD extent was associated with mortality for both women (P < 0.01) and men (P < 0.01). However, compared to those without CAD, the aHR was higher for women with any degree of CAD (aHR ranging from 1.61 [95% CI: 1.09-2.38] for diffuse CAD to 2.01 [95% CI: 1.19-3.40] for 3-vessel disease) than for men with 3-vessel disease (aHR: 1.51; 95% CI: 1.19-1.91). CONCLUSIONS: In patients with newly diagnosed HFrEF, the presence and extent of CAD has significantly greater prognostic impact among women than among men.

[Chronic coronary syndrome].

In the 2019 European Society of Cardiology guidelines, chronic coronary syndrome (CCS) was introduced as a new term for stable coronary artery disease. Diagnosis, treatment and prevention of CCS have undergone major changes. In the diagnostic management of CCS, there is increased focus on non-invasive imaging modalities, including coronary CT angiography. Based on the risk of thrombosis and bleeding, choice and duration of antithrombotic treatment should be individualised, especially following coronary revascularisation.

Intra- and postoperative complications using LigaSure™ Small Jaw in patients undergoing thyroidectomy: a register-based study.

PURPOSE: LigaSure™ Small Jaw (LSJ) reduces operation duration and intraoperative blood loss in patients undergoing thyroidectomy. However, the evidence is sparse regarding postoperative complications and among relevant patients subgroups. In a large cohort of patients including relevant patient subgroups, we evaluated intra- and postoperative complications using LSJ. METHODS: Single-centre register-based study evaluating 3346 patients undergoing hemi- or total thyroidectomy. We compared differences in intra- and postoperative complications using LSJ compared to conventional technique. Multivariate analyses were conducted to adjust for potential confounders. RESULTS: Compared to the conventional technique, LSJ was associated with less postoperative drainage (OR 0.4, p = 0.02) and postoperative haemorrhage (OR 0.3, p = 0.02) among patients undergoing hemi- and total thyroidectomy with benign histology, respectively, but with increased risk of postoperative infection [3 (6.4%) vs. 0 (0.0%) patients, p = 0.04] among patients undergoing total thyroidectomy with malignant histology. LSJ was associated with reduced operation duration (- 12.2 min, p < 0.001, - 7.9 min, p < 0.001 and - 13.2 min, p = 0.002) and intraoperative blood loss (- 52.1 ml, p < 0.001, - 13.6 ml, p < 0.001 and - 12.9 ml, p = 0.02) compared to conventional technique among patients undergoing total and hemithyroidectomy with benign histology and hemithyroidectomy with malignant histology, respectively. CONCLUSION: LSJ was associated with a reduced risk of postoperative haemorrhage and less postoperative drainage but increased risk of postoperative infection depending on the type of thyroidectomy and histology of the thyroid gland. LSJ was associated with only a small reduction in operation duration and intraoperative blood loss. TRIAL REGISTRATION: The study was based on data prospectively registered in the Danish national database THYKIR.

Myocardial subcellular glycogen distribution and sarcoplasmic reticulum Ca2+ handling: effects of ischaemia, reperfusion and ischaemic preconditioning.

Ischaemic preconditioning (IPC) protects against myocardial ischaemia-reperfusion injury. The metabolic and ionic effects of IPC remain to be clarified in detail. We aimed to investigate the effect of IPC (2 times 5 min ischaemia) on the subcellular distribution of glycogen and Ca2+-uptake and leakiness by the sarcoplasmic reticulum (SR) in response to ischaemia-reperfusion in cardiomyocytes of isolated perfused rat hearts (Wistar rats, 335 ± 25 g). As estimated by quantitative transmission electron microscopy, the pre-ischaemic contribution [%, mean (95% CI)] of three sub-fractions of glycogen relative to total glycogen was 50 (39:61) as subsarcolemmal, 41 (31:50) as intermyofibrillar, and 9 (5:13) as intramyofibrillar glycogen. After 25 min of ischaemia, the relative contribution (%) of subsarcolemmal glycogen decreased to 39 (32:47) in control hearts (Con) and to 38 (31:45) in IPC. After 15 min reperfusion the contribution of subsarcolemmal glycogen was restored to pre-ischaemic levels in IPC hearts, but not in Con hearts. IPC increased the left ventricular developed pressure following ischaemia-reperfusion compared with Con. In saponin-skinned cardiomyocyte bundles, ischaemia reduced the SR Ca2+-uptake rate, with no effect of IPC. However, IPC reduced a SR Ca2+-leakage at pre-ischaemia, after ischaemia and during reperfusion. In conclusion, subsarcolemmal glycogen was preferentially utilised during sustained myocardial ischaemia. IPC improved left ventricular function reflecting reduced ischaemia-reperfusion injury, mediated a re-distribution of glycogen towards a preferential storage within the subsarcolemmal space during reperfusion, and lowered SR Ca2+-leakage. Under the present conditions, we found no temporal associations between alterations in glycogen localisation and SR Ca2+ kinetics.

[Arrhythmia-inducedheartfailure].

Tachycardia, atrial fibrillation and premature ventricular contractions can trigger a reversible cardiomyopathy, which can result in clinical heart failure. The diagnosis is retrospective and based on recovery of left ventricular ejection fraction following appropriate arrhythmia management. The arrhythmia can be fully or partly responsible for the reduced ejection fraction depending on coexisting structural heart disease. Early and aggressive treatment targeting the arrhythmia as described in this review, is important to prevent complications including persistent pathophysiological changes.

Optimizing heart failure treatment following cardiac resynchronization therapy.

BACKGROUND: Device therapy in addition to medical treatment improves prognosis in a subset of patients with heart failure and reduced ejection fraction. However, some patients remain symptomatic or their heart failure even progresses despite cardiac resynchronization therapy (CRT). The aim of the study was to evaluate the proportion of patients who could benefit from optimization of medical therapy using sacubitril/valsartan, ivabradine, or both following CRT implantation. METHODS: We conducted a post hoc analysis of a single-centre, patient and outcome-assessor blinded, randomized-controlled trial, in which patients scheduled for CRT were randomized to empiric (n = 93) or imaging-guided left-ventricular lead placement (n = 89). All patients underwent clinical evaluation and blood sampling at baseline and 6 months following CRT implantation. The proportion of patients meeting the indication for sacubitril/valsartan (irrespective of angiotensin-converting enzyme inhibitor or angiotensin 2 receptor blocker dosage) and/or ivabradine according to current guidelines was evaluated at baseline and after 6 months. RESULTS: Of 182 patients with an indication for CRT, 146 (80%) also had an indication for optimization of medical therapy at baseline by adding sacubitril/valsartan, ivabradine, or both. Of the 179 survivors at 6 months, 136 (76%) were still symptomatic after device implantation; of these, 51 (38%) patients had an indication for optimization of medical therapy: sacubitril/valsartan in 37 (27%), ivabradine in 7 (5%), and both drugs in 7 (5%) patients. Seven (18%) patients without indication at baseline developed an indication for medical optimization 6 months after CRT implantation. CONCLUSION: In the present study, 38% of those who remained symptomatic 6 months after CRT implantation were eligible for optimization of medical therapy with sacubitril/valsartan, ivabradine, or both. Patients with CRT may benefit from systematic follow-up including evaluation of medical treatment.

Effect of Blood Flow Restricted Resistance Exercise and Remote Ischemic Conditioning on Functional Capacity and Myocellular Adaptations in Patients With Heart Failure.

BACKGROUND: Patients with congestive heart failure (CHF) have impaired functional capacity and inferior quality of life. The clinical manifestations are associated with structural and functional impairments in skeletal muscle, emphasizing a need for feasible rehabilitation strategies beyond optimal anticongestive medical treatment. We investigated whether low-load blood flow restricted resistance exercise (BFRRE) or remote ischemic conditioning (RIC) could improve functional capacity and quality of life in patients with CHF and stimulate skeletal muscle myofibrillar and mitochondrial adaptations. METHODS: We randomized 36 patients with CHF to BFRRE, RIC, or nontreatment control. BFRRE and RIC were performed 3× per week for 6 weeks. Before and after intervention, muscle biopsies, tests of functional capacity, and quality of life assessments were performed. Deuterium oxide was administered throughout the intervention to measure cumulative RNA and subfraction protein synthesis. Changes in muscle fiber morphology and mitochondrial respiratory function were also assessed. RESULTS: BFRRE improved 6-minute walk test by 39.0 m (CI, 7.0-71.1, P=0.019) compared with control. BFRRE increased maximum isometric strength by 29.7 Nm (CI, 10.8-48.6, P=0.003) compared with control. BFRRE improved quality of life by 5.4 points (CI, -0.04 to 10.9; P=0.052) compared with control. BFRRE increased mitochondrial function by 19.1 pmol/s per milligram (CI, 7.3-30.8; P=0.002) compared with control. RIC did not produce similar changes. CONCLUSIONS: Our results demonstrate that BFRRE, but not RIC, improves functional capacity, quality of life, and muscle mitochondrial function. Our findings have clinical implications for rehabilitation of patients with CHF and provide new insights on the myopathy accompanying CHF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03380663.

Myocardial strain assessed by feature tracking cardiac magnetic resonance in patients with a variety of cardiovascular diseases - A comparison with echocardiography.

Myocardial deformation assessed by speckle tracking echocardiography (STE) is increasingly used for diagnosis, monitoring and prognosis in patients with clinical and pre-clinical cardiovascular diseases. Feature tracking cardiac magnetic resonance (FT-CMR) also allows myocardial deformation analysis. To clarify whether the two modalities can be used interchangeably, we compared myocardial deformation analysis by FT-CMR with STE in patients with a variety of cardiovascular diseases and healthy subjects. We included 40 patients and 10 healthy subjects undergoing cardiac magnetic resonance and echocardiographic examination for left ventricular volumetric assessment. We studied patients with heart failure and reduced ejection fraction (n = 10), acute perimyocarditis (n = 10), aortic valve stenosis (n = 10), and previous heart transplantation (n = 10) by global longitudinal (GLS), radial (GRS) and circumferential strain (GCS). Myocardial deformation analysis by FT-CMR was feasible in all but one participant. While GLS, GRS and GCS measured by FT-CMR correlated overall with STE (r = 0.74 and p < 0.001, r = 0.58 and p < 0.001, and r = 0.76 and p < 0.001), the correlations were not consistent within subgroups. GLS was systematically lower, whereas GRS and GCS were higher by FT-CMR compared to STE (p = 0.04 and p < 0.0001). Inter- and intra-observer reproducibility were comparable for FT-CMR and STE overall and across subgroups. In conclusion, myocardial deformation can be evaluated using FT-CMR applied to routine cine-CMR images in patients with a variety of cardiovascular diseases. However, correlation between FT-CMR and STE was modest and agreement was not optimal due to systematic bias regarding GLS and GCS. Consequently, FT-CMR and STE should not be used interchangeably for myocardial strain evaluation.

Influence of Cardiovascular Risk Factors, Comorbidities, Medication Use and Procedural Variables on Remote Ischemic Conditioning Efficacy in Patients with ST-Segment Elevation Myocardial Infarction.

Remote ischemic conditioning (RIC) confers cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI). Despite intense research, the translation of RIC into clinical practice remains a challenge. This may, at least partly, be due to confounding factors that may modify the efficacy of RIC. The present review focuses on cardiovascular risk factors, comorbidities, medication use and procedural variables which may modify the efficacy of RIC in patients with STEMI. Findings of such efficacy modifiers are based on subgroup and post-hoc analyses and thus hold risk of type I and II errors. Although findings from studies evaluating influencing factors are often ambiguous, some but not all studies suggest that smoking, non-statin use, infarct location, area-at-risk of infarction, pre-procedural Thrombolysis in Myocardial Infarction (TIMI) flow, ischemia duration and coronary collateral blood flow to the infarct-related artery may influence on the cardioprotective efficacy of RIC. Results from the on-going CONDI2/ERIC-PPCI trial will determine any clinical implications of RIC in the treatment of patients with STEMI and predefined subgroup analyses will give further insight into influencing factors on the efficacy of RIC.

Impact of hyperglycemia on myocardial ischemia-reperfusion susceptibility and ischemic preconditioning in hearts from rats with type 2 diabetes.

BACKGROUND: The mechanisms underlying increased mortality in patients with diabetes and admission hyperglycemia after an acute coronary syndrome may involve reduced capacity for cardioprotection. We investigated the impact of hyperglycemia on exogenously activated cardioprotection by ischemic preconditioning (IPC) in hearts from rats with type 2 diabetes mellitus (T2DM) that were endogenously cardioprotected by an inherent mechanism, and the involvement of myocardial glucose uptake (MGU) and myocardial O-linked ß-N-acetylglucosamine (O-GlcNAc). METHODS AND RESULTS: In isolated, perfused rat hearts subjected to ischemia-reperfusion, infarct size (IS) was overall larger during hyper- ([Glucose] = 22 mmol/L]) than normoglycemia ([Glucose] = 11 mmol/L]) (p < 0.001). IS was smaller in 12-week old Zucker diabetic fatty rats with recent onset T2DM (fa/fa) than in rats without T2DM (fa/+) (n = 8 in each group) both during hyperglycemia (p < 0.05) and normoglycemia (p < 0.05). IPC (2 × 5 min cycles) reduced IS during normo- (p < 0.01 for both groups) but not during hyperglycemia independently of the presence of T2DM. During hyperglycemia, an intensified IPC stimulus (4 × 5 min cycles) reduced IS only in hearts from animals with T2DM (p < 0.05). IPC increased MGU and O-GlcNAc levels during reperfusion in animals with and without T2DM at normoglycemia (MGU: p < 0.05, O-GlcNAc: p < 0.01 for both groups) but not during hyperglycemia. Intensified IPC at hyperglycemia increased MGU (p < 0.05) and O-GlcNAc levels (p < 0.05) only in hearts from animals with T2DM. CONCLUSION: While the effect of IPC is reduced during hyperglycemia in rats without T2DM, endogenous cardioprotection in animals with T2DM is not influenced by hyperglycemia and the capacity for exogenous cardioprotection by IPC is preserved. MGU and O-GlcNAc levels are increased by exogenously induced cardioprotection by IPC but not by endogenous cardioprotection in animals with T2DM reflecting different underlying mechanisms by exogenous and endogenous cardioprotection.

Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling.

Background. Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischemic heart failure (CIHF). Methods. Prespecified post-hoc analysis of a prospective, exploratory and outcome-assessor blinded study. Twenty-one patients with compensated CIHF and 21 matched controls without heart failure or ischemic heart disease were treated with RIC once daily for 28 ± 4 days. RIC was conducted as 4 cycles of 5 minutes upper arm ischemia followed by 5 minutes of reperfusion. We evaluated circulating markers of inflammation and cardiac remodeling at baseline and following long-term RIC. Results. RIC reduced C-reactive protein from 1.5 (0.6-2.5) to 1.3 (0.6-2.1) mg/l following long-term RIC treatment (p = .02) and calprotectin from 477 (95% CI 380 to 600) to 434 (95% CI 354 to 533) ng/ml (p = .03) in patients with CIHF, but not in matched controls. Overall, RIC did not affect circulating markers related to adaptive or innate immunology or cardiac remodeling in patients with CIHF. Among patients with CIHF and N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels above the geometric mean of 372 ng/l, long-term RIC treatment reduced soluble ST2 (n = 9) from 22.0 ± 3.7 to 20.3 ± 3.9 ng/ml following long-term RIC treatment (p = .01). Conclusion. Our findings suggest that long-term RIC treatment has mild anti-inflammatory effects in patients with compensated CIHF and anti-remodeling effects in those with increased NT-proBNP levels. This should be further investigated in a randomized sham-controlled trial.

Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.

BACKGROUND: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. RESULTS: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. CONCLUSIONS: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.

Fatal right-sided heart failure due to leukostasis in a patient with leukemic transformation of myelodysplastic syndrome.

We document leukostasis leading to acute fatal right-sided heart failure. In patients presenting with leukostasis and cardiopulmonary symptoms, clinicians should aim to assess for cardiac involvement, that is, by ECG and acute echocardiogram, since early recognition of right ventricular disease may provide an opportunity to treat this potentially reversible condition.

Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning.

Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.

Effect of remote ischemic conditioning on myocardial perfusion in patients with suspected ischemic coronary artery disease.

BACKGROUND: Remote ischemic conditioning (RIC) confers protection against myocardial ischemia-reperfusion injury and may modulate coronary blood flow. We investigated whether RIC affects resting myocardial perfusion (MP) in patients with suspected ischemic coronary artery disease by quantitative MP imaging. METHODS AND RESULTS: We included 49 patients with suspected ischemic coronary artery disease. Resting MP was quantified by 82Rubidium positron emission tomography/computed tomography (82Rb-PET/CT) imaging before and after RIC, performed as four cycles of 5 minutes upper arm ischemia and reperfusion. Subsequent adenosine 82Rb-PET/CT stress-imaging identified non-ischemic and reversibly ischemic myocardial segments. MicroRNA-144 plasma levels were measured before and after RIC. Normalized for rate pressure product, RIC did not affect MP globally (P = .64) or in non-ischemic myocardial segments (P = .58) but decreased MP in reversibly ischemic myocardial segments (-0.11 mL/min/g decrease in MP following RIC; 95% CI -0.17 to -0.06, P < .001). However, we found no effect of RIC when MP was normalized for cardiac work. MicroRNA-144 plasma levels increased following RIC (P = .006) but did not correlate with a change in global MP in response to RIC (P = .40). CONCLUSIONS: RIC did not substantially affect resting MP globally or in non-ischemic and reversibly ischemic myocardial territories in patients with suspected ischemic coronary artery disease.

Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure.

Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may also have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischaemic heart failure (CIHF). In a parallel group study, 22 patients with compensated CIHF and 21 matched control subjects without heart failure or ischemic heart disease were evaluated by cardiac magnetic resonance imaging, cardiopulmonary exercise testing, skeletal muscle function testing, blood pressure measurement and blood sampling before and after 28 ± 4 days of once daily RIC treatment. RIC was conducted as four cycles of 5 min upper arm ischemia followed by 5 min of reperfusion. RIC did not affect left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) in patients with CIHF (p = 0.63 and p = 0.11) or matched controls (p = 0.32 and p = 0.20). RIC improved GLS in the subgroup of patients with CIHF and with NT-proBNP plasma levels above the geometric mean of 372 ng/l (p = 0.04). RIC did not affect peak workload or oxygen uptake in either patients with CIHF (p = 0.26 and p = 0.59) or matched controls (p = 0.61 and p = 0.10). However, RIC improved skeletal muscle power in both groups (p = 0.02 for both). In patients with CIHF, RIC lowered systolic blood pressure (p < 0.01) and reduced NT-proBNP plasma levels (p = 0.02). Our findings suggest that long-term RIC treatment does not improve LVEF but increases skeletal muscle function and reduces blood pressure and NT-proBNP in patients with compensated CIHF. This should be investigated in a randomized sham-controlled trial.

Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and α-hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia.

INTRODUCTION: Remote ischemic conditioning (RIC) is a maneuver by which short non-lethal ischemic events are applied on distant organs or limbs to reduce ischemia and reperfusion injuries caused by e.g. myocardial infarct. Although intensively investigated, the specific mechanism of this protective phenomenon remains incompletely understood and in particular, knowledge on the role of small metabolites is scarce. OBJECTIVES: In this study, we aimed to study perturbations in the plasma metabolome following RIC and gain insight into metabolic changes by the intervention as well as to identify potential novel cardio-protective metabolites. METHODS: Blood plasma samples from ten healthy males were collected prior to and after RIC and tested for bioactivity in a HL-1 based cellular model of ischemia-reperfusion damage. Following this, the plasma was analyzed using untargeted LC-qTOF-MS and regulated metabolites were identified using univariate and multivariate statistical analysis. Results were finally verified in a second plasma study from the same group of volunteers and by testing a metabolite ester in the HL-1 cell model. RESULTS: The analysis revealed a moderate impact on the plasma metabolome following RIC. One metabolite, α-hydroxybutyrate (AHB) however, stood out as highly significantly upregulated after RIC. AHB might be a novel and more sensitive plasma-biomarker of transient tissue ischemia than lactate. Importantly, it was also found that a cell permeable AHB precursor protects cardiomyocytes from ischemia-reperfusion damage. CONCLUSION: Untargeted metabolomics analysis of plasma following RIC has led to insight into metabolism during RIC and revealed a possible novel metabolite of relevance to ischemic-reperfusion damage.