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

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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 [GraphicO2 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 GraphicO2 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 GraphicO2 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

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

Acknowledgment: The authors would like to thank all National Health Service Consultant Colleagues at Aberdeen Royal Infirmary for help with prompt recruitment of these patients (Dr. M Metcalfe, MD, Dr. AD Stewart, MD, Dr. A Hannah, MD, Dr. A Noman, MD, Dr. P Broadhurst, MD, Dr. D Hogg, MD, and Dr. D Garg, MD) and to Dr. Gordon Prescott, PhD for help and advice with the statistical methods. This work was supported by a Tenovus Scotland, Nice, France award to Dr. Dawson and presented in part at the Society for Cardiovascular Magnetic Resonance Imaging/EuroCMR 2015 Joint Scientific Sessions from February 5 2015 to February 7, 2015Peer reviewedPostprin

Erratum:Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome (Future Cardiology (2014) 10:6 (693-698))

Following publication of the Clinical Trial Protocol by Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus McKiddie, Chim Lang, Dana Dawson and Michael Frenneaux, titled ‘Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome’, which appeared in the December 2014 issue of Future Cardiology (Future Oncol. 10[6], 693–698 [2014]), it has been brought to our attention that the author names were presented incorrectly as:Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus Mckiddie, Peter Nightingale, Chim Lang, Dana Dawson and Michael Frenneaux.The correct presentation should be:Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus Mckiddie, Chim Lang, Dana Dawson and Michael Frenneaux.The authors and editors of Future Cardiology would like to sincerely apologize for any inconvenience or confusion this may have caused our readers.<br/

Erratum:Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome (Future Cardiology (2014) 10:6 (693-698))

Following publication of the Clinical Trial Protocol by Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus McKiddie, Chim Lang, Dana Dawson and Michael Frenneaux, titled ‘Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome’, which appeared in the December 2014 issue of Future Cardiology (Future Oncol. 10[6], 693–698 [2014]), it has been brought to our attention that the author names were presented incorrectly as:Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus Mckiddie, Peter Nightingale, Chim Lang, Dana Dawson and Michael Frenneaux.The correct presentation should be:Satnam Singh, Roger Beadle, Donnie Cameron, Amelia Rudd, Maggie Bruce, Baljit Jagpal, Konstantin Schwarz, Gemma Brindley, Fergus Mckiddie, Chim Lang, Dana Dawson and Michael Frenneaux.The authors and editors of Future Cardiology would like to sincerely apologize for any inconvenience or confusion this may have caused our readers.<br/

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

Diastolic Ventricular Interaction in Heart Failure With Preserved Ejection Fraction

Background Exercise‐induced pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). 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 HFpEF 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 HFpEF patients, confirming development of pulmonary hypertension. End‐diastolic NRC also increased to 1.54±0.07 (P<0.001) in HFpEF 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 HFpEF patients (HFpEF, 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 HFpEF 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 HFpEF, and this restriction to left ventricular filling by the right ventricle exacerbates the pre‐existing impaired Frank‐Starling response in these patients

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: To investigate cardiovascular mortality and medication use after takotsubo syndrome.METHODS: In a case-control study, all patients with takotsubo syndrome in Scotland between 2010-2017 (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 analysed 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 [374 (15%)]; hazard ratio [HR] 1.78 [95% confidence interval 1.48-2.15], P&lt;0.0001), especially for cardiovascular (HR 2.47, [1.81-3.39], P&lt;0.001) but also non-cardiovascular (HR 1.48 [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 [0.62-0.94], P=0.012), which was attributable to lower rates of cardiovascular (HR 0.61 [0.44-0.84], P=0.002) but not non-cardiovascular (HR 0.92 [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&lt;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

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

The HEROIC study was funded by the British Heart Foundation Project Grant no. PG/15/108/31928 (D.K.D.), the Josephine Lansdell British Medical Association 2015 Award (D.K.D.), and the Chief Scientist Office CGA-16-4 Catalytic Grant (D.K.D). D.E.N. is supported by the British Heart Foundation (CH/09/002) and a Wellcome Trust Senior Investigator Award (WT103782AIA).Peer reviewedPublisher PD

Comprehensive Echocardiographic and Cardiovascular Magnetic Resonance Evaluation Differentiates Between Patients with Heart Failure with Preserved Ejection Fraction, Hypertensive Patients and Healthy Controls

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 &#60; 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 &#60; 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