Myocardial and Systemic Inflammation in Acute Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Acute stress-induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable with that of myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. METHODS: In a multicenter study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age-, sex-, and comorbidity-matched control subjects. During the index event and at the 5-month follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched control subjects underwent investigation at a single time point. RESULTS: Subjects were predominantly middle-aged (64±14 years) women (90%). Compared with control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 milliseconds versus 10.5±0.9 milliseconds; P<0.001) and nonballooning (12.9±0.6 milliseconds versus 10.5±0.9 milliseconds; P=0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 pg/mL versus 6.5±5.8 pg/mL; P<0.001) and chemokine (C-X-C motif) ligand 1 (1903±168 pg/mL versus 1272±177 pg/mL; P=0.01) concentrations and classic CD14++CD16- monocytes (90±0.5% versus 87±0.9%; P=0.01) were also increased whereas intermediate CD14++CD16+ (5.4±0.3% versus 6.9±0.6%; P=0.01) and nonclassic CD14+CD16++ (2.7±0.3% versus 4.2±0.5%; P=0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium, although persistent elevations in serum interleukin-6 concentrations ( P=0.009) and reductions in intermediate CD14++CD16+ monocytes (5.6±0.4% versus 6.9±0.6%; P=0.01) remained. CONCLUSIONS: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. Many of these changes persisted for at least 5 months, suggesting a low-grade chronic inflammatory state. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02897739.

Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined. METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy. RESULTS: Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/Vco2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, -16±1.0 versus -23±1.5%, P<0.001; global longitudinal strain, -17±1 versus -20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001). CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.

Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF. METHODS AND RESULTS: We conducted a randomized, crossover study comparing selective heart rate reduction with the If blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [o2 peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in o2 peak. Secondary outcomes included tissue Doppler-derived E/e' at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm; P<0.0001) and hypertensive (127 versus 145 bpm; P=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in o2 peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg(-1)·min(-1); P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable. CONCLUSION: Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354573.

Cardiovascular and Noncardiovascular Prescribing and Mortality After Takotsubo Comparison With Myocardial Infarction and General Population.

Background: Takotsubo syndrome is an increasingly common cardiac emergency with no known evidence-based treatment. Objectives: The purpose of this study was to investigate cardiovascular mortality and medication use after takotsubo syndrome. Methods: In a case-control study, all patients with takotsubo syndrome in Scotland between 2010 and 2017 (n = 620) were age, sex, and geographically matched to individuals in the general population (1:4, n = 2,480) and contemporaneous patients with acute myocardial infarction (1:1, n = 620). Electronic health record data linkage of mortality outcomes and drug prescribing were analyzed using Cox proportional hazard regression models. Results: Of the 3,720 study participants (mean age, 66 years; 91% women), 153 (25%) patients with takotsubo syndrome died over the median of 5.5 years follow-up. This exceeded mortality rates in the general population (N = 374 [15%]; HR: 1.78 [95% CI: 1.48-2.15], P < 0.0001), especially for cardiovascular (HR: 2.47 [95% CI: 1.81-3.39], P < 0.001) but also noncardiovascular (HR: 1.48 [95% CI: 1.16-1.87], P = 0.002) deaths. Mortality rates were lower for patients with takotsubo syndrome than those with myocardial infarction (31%, 195/620; HR: 0.76 [95% CI: 0.62-0.94], P = 0.012), which was attributable to lower rates of cardiovascular (HR: 0.61 [95% CI: 0.44-0.84], P = 0.002) but not non-cardiovascular (HR: 0.92 [95% CI: 0.69-1.23], P = 0.59) deaths. Despite comparable medications use, cardiovascular therapies were consistently associated with better survival in patients with myocardial infarction but not in those with takotsubo syndrome. Diuretic (P = 0.01), anti-inflammatory (P = 0.002), and psychotropic (P < 0.001) therapies were all associated with worse outcomes in patients with takotsubo syndrome. Conclusions: In patients with takotsubo syndrome, cardiovascular mortality is the leading cause of death, and this is not associated with cardiovascular therapy use.

Prevalence of asymptomatic valvular heart disease in the elderly population: a community-based echocardiographic study.

AIMS: With an ageing population, the presence of asymptomatic valvular heart disease (VHD) in the community remains unknown. The aim of this study is to determine the prevalence and associated factors of asymptomatic VHD in individuals ≥60 years old and to evaluate the feasibility of echocardiographic screening for VHD in this population. METHODS AND RESULTS: This was a prospective cohort study conducted between 2007 and 2016 in the UK. Asymptomatic patients with no prior indication for echocardiography were invited to participate and evaluated with a health questionnaire, clinical examination, and transthoracic echocardiography. A total of 10,000 individuals were invited through their general practices. A total of 5429 volunteered to participate, of whom 4237 were eligible for inclusion. VHD was diagnosed in more than a quarter of patients (28.2%). The most common types of VHD were regurgitation of the tricuspid (13.8%), mitral (12.8%), and aortic (8.3%) valves (trivial regurgitation was not included). The rate of prevalence of clinically significant VHD was 2.4% (2.2% moderate and 0.2% severe), with mitral and aortic regurgitation being the most common. The only parameter associated with significant VHD was age (odds ratio 1.07 per 1 year increment, 95% confidence interval 1.05-1.09, P < 0.001). The number needed to scan to diagnose one clinically significant case of VHD is 42 for individuals ≥60 and 15 for those ≥75 years old. CONCLUSION: Asymptomatic VHD is present in a significant proportion of otherwise healthy individuals without known VHD over 60 years old. Age is strongly associated with an increased incidence of significant VHD.

Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes.

Despite opposing insulin sensitivity and cardiometabolic risk, both athletes and patients with type 2 diabetes have increased skeletal myocyte fat storage: the so-called "athlete's paradox". In a parallel non-randomised, non-blinded trial (NCT03065140), we characterised and compared the skeletal myocyte lipid signature of 29 male endurance athletes and 30 patients with diabetes after undergoing deconditioning or endurance training respectively. The primary outcomes were to assess intramyocellular lipid storage of the vastus lateralis in both cohorts and the secondary outcomes were to examine saturated and unsaturated intramyocellular lipid pool turnover. We show that athletes have higher intramyocellular fat saturation with very high palmitate kinetics, which is attenuated by deconditioning. In contrast, type 2 diabetes patients have higher unsaturated intramyocellular fat and blunted palmitate and linoleate kinetics but after endurance training, all were realigned with those of deconditioned athletes. Improved basal insulin sensitivity was further associated with better serum cholesterol/triglycerides, glycaemic control, physical performance, enhanced post insulin receptor pathway signalling and metabolic sensing. We conclude that insulin-resistant, maladapted intramyocellular lipid storage and turnover in patients with type 2 diabetes show reversibility after endurance training through increased contributions of the saturated intramyocellular fatty acid pools. Clinical Trial Registration: NCT03065140: Muscle Fat Compartments and Turnover as Determinant of Insulin Sensitivity (MISTY).

Structural and Functional Brain Changes in Acute Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress. OBJECTIVES: The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation. METHODS: Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox. RESULTS: There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05). CONCLUSIONS: The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients' rehabilitation.

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer.

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin. METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy. RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013). CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Lycopene-rich diets modulate HDL functionality and associated inflammatory markers without affecting lipoprotein size and distribution in moderately overweight, disease-free, middle-aged adults: A randomized controlled trial.

Background: The consumption of lycopene-rich foods may lower cardiovascular disease (CVD) risk. Lycopene circulates in the blood bound to lipoproteins, including high-density lipoproteins (HDLs). Preliminary data from our group showed that increased consumption of tomato-based food or lycopene supplement in middle-aged subjects led to functional changes to HDL's sub-fractions, HDL2 and HDL3. These changes were also associated with a decrease in serum amyloid A (SAA), potentially enhancing their anti-atherogenic properties. Objective: We carried out a comprehensive randomized controlled intervention trial with healthy middle-aged volunteers to assess whether the consumption of tomato-based foods or lycopene supplements affects HDL functionality and associated inflammatory markers, and lipoprotein subfractions size and distribution. Design: Volunteers (225, aged 40-65 years) were randomly assigned to one of three dietary intervention groups and asked to consume a control diet (low in tomato-based foods, <10 mg lycopene/week), a lycopene-rich diet (224-350 mg lycopene/week), or the control diet with a lycopene supplement (70 mg lycopene/week). HDL2 and HDL3 were isolated by ultracentrifugation. Compliance was monitored by assessing lycopene concentration in serum. Systemic and HDL-associated inflammation was assessed by measuring SAA concentrations. HDL functionality was determined by monitoring paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP), and lecithin cholesterol acyltransferase (LCAT) activities. The lipoprotein subfractions profile was assessed by NMR. Results: Lycopene in serum and HDL significantly increased following consumption of both the high tomato diet and lycopene supplement (p ≤ 0.001 for both). Lycopene, either as a tomato-rich food or a supplement, enhanced both serum- and HDL3-PON-1 activities (p ≤ 0.001 and p = 0.036, respectively), while significantly reducing HDL3-SAA-related inflammation (p = 0.001). Lycopene supplement also significantly increased HDL3-LCAT activity (p = 0.05), and reduced the activity of both HDL2- and HDL3-CETP (p = 0.005 and p = 0.002, respectively). These changes were not associated with changes in the subclasses distribution for all lipoprotein fractions or the size of lipoprotein subclasses. Conclusion: Our results showed that dietary lycopene can significantly enhance HDL functionality, without associated changes in particle size and distribution, by modulating the activity of HDL-associated enzymes. Concomitantly, dietary lycopene significantly decreased serum- and HDL3-associated SAA, confirming that SAA may represent a sensitive inflammatory biomarker to dietary change. Clinical Trial Register: (https://www.isrctn.com), ISRCTN34203810.

Renin-Angiotensin and Endothelin Systems in Patients Post-Takotsubo Cardiomyopathy.

Background We investigate if renin-angiotensin and endothelin-1 response pathways follow the same pattern of recovery as left ventricular ejection fraction in patients with takotsubo cardiomyopathy. Methods and Results Ninety patients with takotsubo cardiomyopathy (n=30 in each of "acute," "convalescent" [3-5 months] and "recovered" [>1 year] groups) who were on minimal or no medication and were free of any significant cardiac/metabolic comorbidities, and 30 controls were studied. Serum concentrations of renin, angiotensin-converting enzyme, angiotensin II, big endothelin-1, endothelin-1 were measured using commercially available ELISA, and B-type natriuretic peptide was measured using an immunoassay. Mean left ventricular ejection fraction was <40% during the acute phase in all groups, but recovered to 63% in convalescent and 64% in the recovered groups, respectively. Serum renin concentrations remain persistently elevated after a episode of takotsubo cardiomyopathy (P=0.03 versus controls). Angiotensin converting enzyme levels are significantly depressed during the acute phase compared with convalescent (P=0.004), recovered takotsubo cardiomyopathy (P=0.02) or controls (P=0.03). Angiotensin II is increased in patients with takotsubo cardiomyopathy (P<0.001 versus controls) remaining persistently elevated in the chronically recovered group alone (P=0.03 versus controls). Big endothelin-1 levels are unchanged, but endothelin-1 is significantly lower after takotsubo cardiomyopathy compared with controls (P=0.03). Conclusions Despite "normalization" of the left ventricular ejection fraction, there is long-term maladaptive activation of renin-angiotensin system in patients with takotsubo cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02897739, NCT02989454.

A systematic review of biomarkers in Takotsubo syndrome: A focus on better understanding the pathophysiology.

BACKGROUND: The diagnosis of Takotsubo syndrome is made based on clinical presentation, ECG, biomarker, imaging and coronary angiography. There is a lack of diagnostic biomarkers that can discriminate patients with Takotsubo syndrome from those with acute myocardial infarction (AMI) and provide clinical monitoring and prognostic information in the long-term. METHODS: A literature search of published Takotsubo syndrome biomarkers from PubMed was performed. All studies that included numerical biomarker data on Takotsubo syndrome was included. Exclusion criteria was any study without an AMI cohort for comparison in the acute phase biomarkers or due to the absence of numerical values. The results were tabulated in table form with results expressed as either mean ± SD or median (interquartile range). RESULTS: The literature search produced 14 relevant studies that met search criteria. The results showed; high sensitivity Troponin I (3.21 ± 4.4 vs 34.4 ± 37 ng/ml), BNP [972 (578.5-1671.0) pg/L vs 358 (50.5-688.0) pg/L in NSTEMI and vs 381 (106.0-934.0) pg/L in STEMI] and BNP/Troponin I ratio [642 (331.8-1226.5) vs 184.5 (50.5-372.3) pg/ug in NSTEMI and 7.5 (2.0-29.6) pg/ug in STEMI] patients. DISCUSSION: This study is limited by many studies being retrospective cohort studies. This data shows that acutely troponin is raised in Takotsubo syndrome but not enough to be discriminating from AMI. BNP level is significantly raised in Takotsubo syndrome compared to AMI. CONCLUSION: Current specificity of acute and chronic biomarkers for Takotsubo syndrome is lacking and further work is needed to address the gap in knowledge.

The early dynamic of ECG in Takotsubo syndrome presenting with ST-elevation: A comparison with age and gender-matched ST-elevation myocardial infarction.

BACKGROUND: Takotsubo syndrome mimics acute myocardial infarction (MI) at presentation. OBJECTIVES: To explore differences in ECG time-course that could further help distinguish the two conditions. METHODS: Serial ECG's (day 0-4) of 27 acute takotsubo and 37 MI patients, all presenting with anterior ST-elevation, were analysed for detailed morphology and timing of de/re-polarisation. All underwent cardiac magnetic resonance. RESULTS: The presenting ECG (day 0) showed significantly fewer total abnormal leads (p = .001), comparable number of ST-elevation leads but lesser total magnitude of ST-elevation (p = .003), smaller sum of positive T wave amplitude (p = .006) and lesser number of pathological Q waves (p = .005) in takotsubo vs the MI group. After day 0, takotsubo patients developed more widespread T wave inversion (p = .001, day 3) and/or deeper T waves compared to MI, (sum of the T-wave amplitude slope of change between days 0-3: -43.1 ± 9.6 vs - 16.6 ± 5.4 mm, p = .02). Although there was no difference in mean QTc between the groups on any day, between days 0-3 there was a progressive increase in QTc in takotsubo vs a decrease in MI (34.1 ± 12.2 vs -29.5 ± 9.3 ms, slope of change p < .001). There was significantly more myocardial oedema (native T1 mapping) in takotsubo vs MI (p = .02), which resulted in increased left ventricular mass index in takostubo (p = .04). CONCLUSIONS: The differences in presenting (day 0) ECG between takotsubo and MI are significant but subtle, reinforcing the importance of acute cardiac catheterisation for accurate diagnosis. During the next 3 days there is progressive increase in the depth and spread of T-waves and QTc duration in takotsubo vs MI - these may aid the diagnostic confidence in patients with bystander non-obstructive coronary disease.

Diastolic Ventricular Interaction in Heart Failure With Preserved Ejection Fraction.

Background Exercise-induced pulmonary hypertension is common in heart failure with preserved ejection fraction ( HF p EF ). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HF p EF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature ( NRC ) of the interventricular septum at end-diastole and end-systole, were measured at rest and peak-exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end-diastole. At peak-exercise, end-systolic NRC increased to 1.47±0.05 ( P<0.001) in HF p EF patients, confirming development of pulmonary hypertension. End-diastolic NRC also increased to 1.54±0.07 ( P<0.001) in HF p EF patients, indicating septal flattening, and this correlated significantly with end-systolic NRC (ρ=0.51, P=0.007). In hypertensive controls and healthy controls, peak-exercise end-systolic NRC increased, but this was significantly less than observed in HF p EF patients ( HF p EF , P=0.02 versus hypertensive controls; P<0.001 versus healthy). There were also small, non-significant increases in end-diastolic NRC in both groups (hypertensive controls, +0.17±0.05, P=0.38; healthy, +0.06±0.03, P=0.93). In HF p EF patients, peak-exercise end-diastolic NRC also negatively correlated ( r=-0.40, P<0.05) with the change in left ventricular end-diastolic volume with exercise (ie, the Frank-Starling mechanism), and a trend was noted towards a negative correlation with change in stroke volume ( r=-0.36, P=0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HF p EF , and this restriction to left ventricular filling by the right ventricle exacerbates the pre-existing impaired Frank-Starling response in these patients.

Comprehensive Echocardiographic and Cardiac Magnetic Resonance Evaluation Differentiates Among Heart Failure With Preserved Ejection Fraction Patients, Hypertensive Patients, and Healthy Control Subjects.

OBJECTIVES: The aim of this study was to investigate the utility of a comprehensive imaging protocol including echocardiography and cardiac magnetic resonance in the diagnosis and differentiation of hypertensive heart disease and heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Hypertension is present in up to 90% of patients with HFpEF and is a major etiological component. Despite current recommendations and diagnostic criteria for HFpEF, no noninvasive imaging technique has as yet shown the ability to identify any structural differences between patients with hypertensive heart disease and HFpEF. METHODS: We conducted a prospective cross-sectional study of 112 well-characterized patients (62 with HFpEF, 22 with hypertension, and 28 healthy control subjects). All patients underwent cardiopulmonary exercise and biomarker testing and an imaging protocol including echocardiography with speckle-tracking analysis and cardiac magnetic resonance including T1 mapping pre- and post-contrast. RESULTS: Echocardiographic global longitudinal strain (GLS) and extracellular volume (ECV) measured by cardiac magnetic resonance were the only variables able to independently stratify among the 3 groups of patients. ECV was the best technique for differentiation between hypertensive heart disease and HFpEF (ECV area under the curve: 0.88; GLS area under the curve: 0.78; p < 0.001 for both). Using ECV, an optimal cutoff of 31.2% gave 100% sensitivity and 75% specificity. ECV was significantly higher and GLS was significantly reduced in subjects with reduced exercise capacity (lower peak oxygen consumption and higher minute ventilation-carbon dioxide production) (p < 0.001 for both ECV and GLS). CONCLUSIONS: Both GLS and ECV are able to independently discriminate between hypertensive heart disease and HFpEF and identify patients with prognostically significant functional limitation. ECV is the best diagnostic discriminatory marker of HFpEF and could be used as a surrogate endpoint for therapeutic studies.

Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] µmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17.

Alterations in Cardiac Deformation, Timing of Contraction and Relaxation, and Early Myocardial Fibrosis Accompany the Apparent Recovery of Acute Stress-Induced (Takotsubo) Cardiomyopathy: An End to the Concept of Transience.

BACKGROUND: Takotsubo syndrome is an increasingly recognized cause of chest pain and occasionally of cardiogenic shock. Despite rapid improvement of the left ventricular (LV) ejection fraction, recent registry data raise concerns about long-term prognosis. The aim of this study was to test the hypothesis that restoration of normal ejection fraction after acute takotsubo syndrome is not equivalent to full functional recovery. METHODS: Fifty-two patients with takotsubo syndrome (according to the Mayo Clinic criteria plus cardiac magnetic resonance imaging to exclude myocardial infarction) and 44 healthy control subjects of the same age, gender, and cardiovascular comorbidity distribution were prospectively recruited. The focus of the investigation was on patients with takotsubo syndrome presenting with ST-segment elevation-type electrocardiographic findings or malignant arrhythmias and with LV apical ballooning variant, and a 4-month recovery endpoint was assessed. Patients underwent echocardiographic assessment of LV myocardial deformation (global longitudinal, radial, and circumferential strain; LV twist, torsion, and untwist; and time to peak twist and untwist) and assessment of LV myocardial structure by pre- and post-contrast-enhanced cardiac magnetic resonance by T1 mapping acutely and at 4-month follow-up. Control subjects underwent a single-time-point investigation. Data were analyzed using paired or unpaired tests, as appropriate for their distribution, and corrected for multiple comparisons. RESULTS: The patients' mean age was 66 years (range, 28-87 years), and 92% were women. All abnormal echocardiographic indices observed acutely in patients with takotsubo syndrome improved (but did not necessarily normalize) at follow-up. Significant mechanotemporal alterations characterizing both systole (global longitudinal strain and apical circumferential strain, P < .01 for both; LV twist, twist rate, and torsion, P < .0001 for all) and diastole (untwist rate and time to peak untwisting, P < .001 for both) persisted at 4-month follow-up compared with control subjects, despite normalization of LV ejection fraction and volumes. Although native T1 (which demonstrates edema) normalized at 4-months follow-up only in segments contracting normally during the acute phase (T1 = 1,180 ± 40.6 msec [normally contracting segments, P = .20 vs control value of 1,189 ± 16 msec] and T1 = 1,208 ± 60.3 msec [dysfunctional segments, P < .05 vs control]), the extracellular volume fraction (which demonstrates diffuse fibrosis) remained significantly abnormal in all LV segments (whether normally contracting [0.328 ± 0.043, P < .001] or ballooning during acute presentation [0.320 ± 0.044, P < .001], both vs control value of 0.273 ± 0.045). CONCLUSIONS: In patients with the most clinically severe spectrum of takotsubo cardiomyopathy, regional LV systolic and diastolic deformation abnormalities persist beyond the acute event, despite normalization of global LV ejection fraction and size. In addition, although myocardial edema partly subsides, a process of global microscopic fibrosis develops in its place, detected as early as 4 months.

Right Ventricular Involvement and Recovery After Acute Stress-Induced (Tako-tsubo) Cardiomyopathy.

Acute stress-induced (Tako-tsubo) cardiomyopathy is an increasingly recognized but insufficiently characterized syndrome. Here, we investigate the pathophysiology of right ventricular (RV) involvement in Tako-tsubo and its recovery time course. We prospectively recruited 31 patients with Tako-tsubo with predominantly ST-elevation electrocardiogram and 18 controls of similar gender, age, and co-morbidity distribution. Patients underwent echocardiography and cardiac magnetic resonance (CMR) imaging on a 3T Philips scanner in the acute phase (day 0 to 3 after presentation) and at 4-months follow-up. Visually, echocardiography was able to identify only 52% of patients who showed RV wall motion abnormalities on CMR. Only CMR-derived RV ejection fraction (p = 0.01) and echocardiography-estimated pulmonary artery pressure (p = 0.01) identify RV functional involvement in the acute phase. Although RV ejection fraction normalizes in most patients by 4 months, acutely there is RV myocardial edema in both functioning and malfunctioning segments, as measured by prolonged native T1 mapping (p = 0.02 for both vs controls), and this persists at 4 months in the acutely malfunctioning segments (p = 0.002 vs controls). The extracellular volume fraction was significantly increased acutely in all RV segments and remained increased at follow-up compared with controls (p = 0.004 for all). In conclusion, in a Tako-tsubo population presenting predominantly with ST-elevation electrocardiogram, we demonstrate that although RV functional involvement is seen in only half of the patients, RV myocardial edema is present acutely throughout the RV myocardium in all patients and results in microscopic fibrosis at 4-month follow-up.