Viability and Outcomes With Revascularization or Medical Therapy in Ischemic Ventricular Dysfunction: A Prespecified Secondary Analysis of the REVIVED-BCIS2 Trial.

Importance: In the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not improve outcomes for patients with ischemic left ventricular dysfunction. Whether myocardial viability testing had prognostic utility for these patients or identified a subpopulation who may benefit from PCI remained unclear. Objective: To determine the effect of the extent of viable and nonviable myocardium on the effectiveness of PCI, prognosis, and improvement in left ventricular function. Design, Setting, and Participants: Prospective open-label randomized clinical trial recruiting between August 28, 2013, and March 19, 2020, with a median follow-up of 3.4 years (IQR, 2.3-5.0 years). A total of 40 secondary and tertiary care centers in the United Kingdom were included. Of 700 randomly assigned patients, 610 with left ventricular ejection fraction less than or equal to 35%, extensive coronary artery disease, and evidence of viability in at least 4 myocardial segments that were dysfunctional at rest and who underwent blinded core laboratory viability characterization were included. Data analysis was conducted from March 31, 2022, to May 1, 2023. Intervention: Percutaneous coronary intervention in addition to optimal medical therapy. Main Outcomes and Measures: Blinded core laboratory analysis was performed of cardiac magnetic resonance imaging scans and dobutamine stress echocardiograms to quantify the extent of viable and nonviable myocardium, expressed as an absolute percentage of left ventricular mass. The primary outcome of this subgroup analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were all-cause death, cardiovascular death, hospitalization for heart failure, and improved left ventricular function at 6 months. Results: The mean (SD) age of the participants was 69.3 (9.0) years. In the PCI group, 258 (87%) were male, and in the optimal medical therapy group, 277 (88%) were male. The primary outcome occurred in 107 of 295 participants assigned to PCI and 114 of 315 participants assigned to optimal medical therapy alone. There was no interaction between the extent of viable or nonviable myocardium and the effect of PCI on the primary or any secondary outcome. Across the study population, the extent of viable myocardium was not associated with the primary outcome (hazard ratio per 10% increase, 0.98; 95% CI, 0.93-1.04) or any secondary outcome. The extent of nonviable myocardium was associated with the primary outcome (hazard ratio, 1.07; 95% CI, 1.00-1.15), all-cause death, cardiovascular death, and improvement in left ventricular function. Conclusions and Relevance: This study found that viability testing does not identify patients with ischemic cardiomyopathy who benefit from PCI. The extent of nonviable myocardium, but not the extent of viable myocardium, is associated with event-free survival and likelihood of improvement of left ventricular function. Trial Registration: ClinicalTrials.gov Identifier: NCT01920048.

Challenges in heart failure care in four European countries: a comparative study.

BACKGROUND: In Europe, more than 15 million people live with heart failure (HF). It imposes an enormous social, organizational and economic burden. As a reaction to impending impact on healthcare provision, different country-specific structures for HF-care have been established. The aim of this report is to provide an overview and compare the HF-care approaches of Germany, Ireland, the Netherlands and the UK, and to open the possibility of learning from each other's experience. METHODS: A mixed methods approach was implemented that included a literature analysis, interviews and questionnaires with HF-patients and caregivers, and expert interviews with representatives from healthcare, health service research and medical informatics. RESULTS: The models of HF-care in all countries analyzed are based on the European Society of Cardiology guidelines for diagnosis and treatment of HF. Even though the HF-models differed in design and implementation in practice, key challenges were similar: (i) unequal distribution of care between urban and rural areas, (ii) long waiting times, (iii) unequal access to and provision of healthcare services, (iv) information and communication gaps and (v) inadequate implementation and financing of digital applications. CONCLUSION: Although promising approaches exist to structure and improve HF-care, across the four countries, implementation was reluctant to embrace novel methods. A lack of financial resources and insufficient digitalization making it difficult to adopt new concepts. Integration of HF-nurses seems to be an effective way of improving current models of HF-care. Digital solutions offer further opportunities to overcome communication and coordination gaps and to strengthen self-management skills.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction.

BACKGROUND: Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown. METHODS: We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores. RESULTS: A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months. CONCLUSIONS: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).

Determinants of acceptance of patients with heart failure and their informal caregivers regarding an interactive decision-making system: a qualitative study.

OBJECTIVE: Heart failure is a growing challenge to healthcare systems worldwide. Technological solutions have the potential to improve the health of patients and help to reduce costs. Acceptability is a prerequisite for the use and a successful implementation of new disruptive technologies. This qualitative study aimed to explore determinants that influence the acceptance of patients and their informal caregivers regarding a patient-oriented digital decision-making solution-a doctor-at-home system. DESIGN: We applied a semistructured design using an interview guide that was based on a theoretical framework influenced by established acceptance theories. The interviews were analysed using a content analysis. SETTING: A multicentred study in four European countries. PARTICIPANTS: We interviewed 49 patients and 33 of their informal caregivers. Most of the patients were male (76%) and aged between 60 and 69 years (43%). Informal caregivers were mostly female (85%). The majority of patients (55%) suffered from heart failure with mild symptoms. RESULTS: Four main categories emerged from the data: needs and expectations, preferences regarding the care process, perceived risk and trust. Participants expressed clear wishes and expectations regarding a doctor-at-home, especially the need for reassurance and support in the management of heart failure. They were receptive to changes to the current healthcare processes. However, trust was identified as an important basis for acceptance and use. Finally, perceived risk for decision-making errors is a crucial topic in need of attention. CONCLUSION: Patients and informal caregivers see clear benefits of digitalisation in healthcare. They perceive that an interactive decision-making system for patients could empower and enable effective self-care. Our results provide important insights for development processes of patient-centred decision-making systems by identifying facilitators and barriers for acceptance. Further research is needed, especially regarding the influence and mitigation of patients and informal caregivers' perceived risks.

Late gadolinium enhancement is common in patients with hypertrophic cardiomyopathy and no clinical risk factors for sudden cardiac death: A single center experience.

BACKGROUND: Cardiac magnetic resonance (CMR) is used in the diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) and can detect myocardial replacement fibrosis (anindependent predictor of adverse cardiac outcomes) using late gadolinium enhancement (LGE). METHODS: We retrospectively analysed CMR studies carried out over a 2 year period identifying those which were diagnostic of HCM. 117 cases were analysed. Mean age of subjects was 53 years and 78 (67%) were male. Mean ejection fraction (EF) was 68.3% with a mean left ventricular (LV) mass index of 89.4 g/m². Hypertrophy was predominantly asymmetric in 94 (80%). RESULTS: All subjects received gadolinium and 80 (68%) had evidence of LGE. LVEF was lower (67 vs. 71%; p = 0.015) and LV mass index higher (94 vs. 81 g/m²; p = 0.007) in the LGE group. The proportion of patients with at least 1 clinical risk factor for sudden cardiac death (SCD) was similar in groups with and without LGE (48% vs. 32%; p = 0.160). In this study, a significant proportion (62%) of patients without clinical risk factors for SCD were found to have LGE on CMR. These patients would not currently be considered for therapy with an implantable cardiac defibrillator. CONCLUSIONS: 1. Patients with HCM are at increased risk of SCD, but identifying patients who may benefit from implantable defibrillators is difficult. 2. LGE is associated with adverse cardiovascular outcomes in HCM, but is present in a large proportion of patients. 3. Many patients without clinical risk factors for SCD have LGE and would not currently be considered for an implantable cardiac device.

Takotsubo cardiomyopathy in two preoperative patients with pain.

Reversible stress-induced cardiomyopathy, i.e., Takotsubo cardiomyopathy, rarely presents in preoperative patients. We provide the case reports of two patients who presented with Takotsubo cardiomyopathy, which we surmise was due to excess endogenous catecholamine production in response to acute pain. Electrocardiogram revealed T-wave inversion, with peak Troponin-T elevation in each case, i.e., 0.66 microg/L and 0.14 microg/L (normal range <0.03 microg/L). Despite these findings consistent with acute myocardial infarction, neither patient had obstructive coronary disease at angiography. Left ventriculography showed apical ballooning, a typical feature of the Takotsubo syndrome. Ventricular dysfunction had resolved completely at repeat echocardiography 2 wk later, after adequate analgesia and surgery.

Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure.

We investigated the effects of omega-3 fatty acids administration on endothelium-dependent vasodilation in patients > or =65 years old who received treatment for chronic heart failure (CHF). Twenty patients (mean age 73 years; 15 men) with grade II and III CHF who were on maximal medical management were recruited. Patients were randomized in a double-blind, crossover fashion to 6 weeks of omega-3 fatty acid (1.8 g ecosapentaenoic acid and 1.2 g docosahexaenoic acid) or olive oil. Forearm blood flow (FBF) responses to incremental doses of intra-arterial sodium nitroprusside, acetycholine (ACH), angiotensin-II, and N(g)-nitro-L-arginine methyl ester were assessed by venous occlusion strain gauge plethysmography. The endothelium-dependent increase in FBF was greater in response in ACH infusion after omega-3 fatty acid administration (7.9, 95% confidence interval [CI] 4.81 to 11.08 to 11.3, 95% CI 7.31 to 15.23 arbitrary units (p <0.05) compared with baseline (7.95, 95% CI 4.8 to 11.08 arbitrary units) and olive oil administration (7.27, 95% CI 4.66 to 9.88 arbitrary units) (p = NS for both). Neither omega-3 fatty acid nor olive oil altered endothelium-independent vasodilation in response to infusion of sodium nitroprusside, nor did they influence vasoconstrictor responses to angiotensin-II or N(g)-nitro-L-arginine methyl ester. Dietary omega-3 fatty acid supplementation was accompanied by an increase in FBF response to ACH, which represents enhanced endothelium-dependent vasodilation in CHF. Further studies are warranted to assess the mechanism responsible for the beneficial actions of omega-3 fatty acids in CHF.

Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase.

BACKGROUND: Hypertension and diabetes are important independent risk factors for increased oxidative stress and increased cardiovascular risk. The combination of hypertension and diabetes results in a dramatic increase in cardiovascular risk. Enhanced oxidative stress in hypertension and diabetes is linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O(2)(*-)), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, NO synthase III (NOS III) can also produce O(2)(*-). We studied platelet superoxide production in patients with hypertension alone and in patients with coexistent diabetes mellitus, investigating the contribution of NOS III uncoupling to platelet superoxide production. METHODS AND RESULTS: Gel-filtered platelets were obtained and were stimulated with Phorbol 12-myristate 13-acetate, and O(2)(*-) production was detected using lucigenin-enhanced chemiluminescence. Superoxide production was significantly higher in patients with diabetes and hypertension (6.4 +/- 1.6 pmol/min/10(8) platelets) than in patients with hypertension (1.6 +/- 0.6 pmol/min/10(8) platelets) (P < .04). After incorporation of N(omega)-nitro-l-arginine methyl ester (L-NAME, 1 mmol/L), O(2)(*-) detection increased in 40% of patients with diabetes and hypertension and in 87% of patients with hypertension. This expected response results from L-NAME inhibition of NO production preventing NO scavenging of O(2)(*-). A reduction in O(2)(*-) production in response to L-NAME occurred in the remaining patients and indicates O(2)(*-) production by the uncoupled NOS III enzyme. CONCLUSIONS: This study provides first published evidence that NOS III can reside in the uncoupled state in patients with hypertension and, to a greater extent, in patients with coexisting hypertension and diabetes, and that it contributes significantly to increased superoxide production in these disease states.

NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.

OBJECTIVES: Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system. We employed this tissue model to explore mechanisms involved in AngII-mediated superoxide production. DESIGN AND METHODS: Platelet suspensions from hypertensive patients' blood were activated with AngII or phorbol 12-myristate 13-acetate (PMA). Inhibitors of NAD(P)H oxidase, PKC, and the AT1 receptor were employed to study their effects on superoxide production. RESULTS: Superoxide production was stimulated by AngII and PMA and attenuated by AT1 receptor antagonists (mean percentage reduction 80.2%, P<0.01) and inhibitors of PKC (mean reduction 94.8%, P<0.001) and NAD(P)H oxidase (mean reduction 100%, P< 0.001). CONCLUSIONS: AngII stimulates platelet superoxide production through activation of vascular NAD(P)H oxidase via the AT1 receptor and PKC.

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure.

BACKGROUND: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study. AIMS: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure. METHODS AND RESULTS: 24 patients and 15 controls were recruited, patients were maintained on their usual medications. Forearm blood flow responses were measured by venous occlusion plethysmography in response to incremental doses of sodium nitroprusside (SNP) (6, 9 and 12 nmol/min), acetylcholine (ACH) (120, 180 and 240 nmol/min), angiotensin II (AII) (1, 10 and 100 nmol/min) and N(g)-Nitro-L-arginine methyl ester (L-NAME) (1, 2 and 4 nmol/min) infused into the non-dominant brachial artery. FBF responses to SNP were impaired in patients compared with controls (13.7(9.9,17.4) vs. 24.8(18.6,30.9)) arbitrary units, P<0.001). Similarly FBF responses to ACH were reduced in patients compared with controls (7.5(4.2,10.9) vs. 24.8(16.4,33.2)) arbitrary units, P<0.001. Decreased FBF was noted in response to AII and L-NAME but was significant only for AII and did not differ between groups. CONCLUSIONS: In elderly patients with CHF, endothelium-dependent and independent vasodilator responses were blunted compared with controls. Defects in nitric oxide bioavailability and smooth muscle responsiveness are not reversed by modern medical management of the heart failure syndrome.

Reduction in hospitalization rates following cardiac resynchronisation therapy in cardiac failure: experience from a single centre.

AIMS: Frequent, lengthy hospital admissions for congestive cardiac failure (CCF) result in excessive health care costs. Cardiac resynchronisation therapy (CRT) is a novel treatment option for patients with CCF and associated cardiac conduction defects. We investigated whether CRT resulted in significant improvements in New York Heart Association (NYHA) symptom class, exercise tolerance, and hospitalization rates in such patients. METHODS: Twenty-seven patients who underwent CRT in a single centre were studied, with NYHA symptom class, exercise tolerance and hospitalization rates noted in the 12 months prior to and following CRT. RESULTS: Following 12 months of CRT, NYHA symptom class improved from 3.3 +/- 0.5 to 2.1 +/- 0.4 (P < 0.05). Exercise tolerance, assessed by 6 min hall walk test increased by 64% from 195 +/- 114 m to 320 +/- 85 m (P = 0.007). Days in hospital for stabilisation of cardiac failure decreased by 98% from 472 to 9 days (P < 0.001). Significant hospitalization cost savings of 201,684 euros were calculated, with an overall saving of 12,420 euros. CONCLUSIONS: These data demonstrate that CRT results in significant improvement in clinical parameters, and considerable reductions in hospital admissions, and costs in patients with CCF.

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

BACKGROUND: Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2*-), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2*-. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. METHODS AND RESULTS: We employed the platelet as a compartmentalized ex-vivo model to examine O2*- and NO production. When eNOS is functioning normally, incorporation of Nomega-Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O2*- detection, as inhibition of NO production prevents NO scavenging of O2*-. This was observed in controls and 9 of the CCF patients, in whom O2*- detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O2*- production by 39%, indicating O2*- production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8+/-1.4 versus 0.9+/-0.4 pmol/108 platelets, P=0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. CONCLUSIONS: This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate.

BACKGROUND: The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. METHODS AND RESULTS: We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2*-] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O2*- production from 1.0+/-1.17 to 2.52+/-0.88 pmol/10(8) platelets and 13.2+/-4.8 to 72.5+/-34.4 pmol/10(8) platelets, respectively (P<0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9+/-11.0 to 65.3+/-13.6 pmol O2*- min/mg protein and cGMP content from 0.60+/-0.10 to 0.89+/-0.16 pmol/10(9) platelets (P<0.05 for both). Administration of NTG/ascorbate attenuated both NO and O2*- release in platelets. CONCLUSIONS: Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O2*- production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.