Amelia Rudd

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.

Effect of a tomato-rich diet on markers of cardiovascular disease risk in moderately overweight, disease-free, middle-aged adults: a randomized controlled trial

BACKGROUND Cardiovascular disease (CVD) is a major cause of mortality in the United Kingdom. Epidemiologic studies suggest that consumption of tomato-based foods may lower CVD risk. Such potential benefits have been ascribed in part to high concentrations of lycopene in the tomatoes. However, these findings have not yet been validated by comprehensive intervention trials. OBJECTIVE The aim of this study was to conduct a single-blind, randomized controlled intervention trial with healthy middle-aged volunteers to assess whether the consumption of tomato-based foods affects recognized biomarkers of CVD risk. DESIGN After a 4-wk run-in period with a low-tomato diet, 225 volunteers (94 men and 131 women) aged 40-65 y were randomly assigned into 1 of 3 dietary intervention groups and asked to consume a control diet (low in tomato-based foods), a high-tomato-based diet, or a control diet supplemented with lycopene capsules (10 mg/d) for 12 wk. Blood samples were collected at baseline, at 6 wk, and after the intervention and were analyzed for carotenoid and lipid profiles and inflammatory markers. Blood pressure, weight, and arterial stiffness were also measured. Dietary intake was also determined during the intervention. RESULTS None of the systemic markers (inflammatory markers, markers of insulin resistance and sensitivity) changed significantly after the dietary intervention. Moreover, lipid concentrations and arterial stiffness were also unaffected by the interventions. CONCLUSION These data indicate that a relatively high daily consumption of tomato-based products (equivalent to 32-50 mg lycopene/d) or lycopene supplements (10 mg/d) is ineffective at reducing conventional CVD risk markers in moderately overweight, healthy, middle-aged individuals. This trial was registered at isrctn.org as ISRCTN34203810.

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/&ggr;-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.

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.

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.

Randomized double-blind placebo- controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome

Recently heart failure with preserved ejection fraction (HFpEF) has emerged as a huge epidemic. Increasing evidence shows the role of energy deficiency in the pathophysiology of HFpEF. In the current study, we hypothesize that the use of metabolic modulator perhexiline would correct myocardial energy deficiency and improve exercise capacity and diastolic abnormalities in patients with this syndrome.

Author's Reply: Persistence of Deformation Abnormalities and Detection of Fibrosis at 4-Month Follow-up in Patients with Takotsubo Syndrome

magnetic resonance imaging and echocardiography at 1-year followup, or at any time between 4months and 1 year (as the authors allude to), to evaluate their course of recovery and the possible presence or absence of restoration to normalcy. Third, a ‘‘chronic TTS condition’’ (i.e., persisting symptoms both at rest andwith exercise) has been suspected, and the authors provide us with the diagnostic blueprint for the objective evaluation of such patients with TTS at follow-up. Fourth, was there any correlation between the acute and 4-month echocardiographic or cardiac magnetic resonance imaging metrics and the peak levels of troponin I, C-reactive protein, and brain natriuretic peptide? Fifth, the intriguing finding of persistently increased extracellular matrix volume at 4-month follow-up on cardiac magnetic resonance imaging testing, attributed tomicroscopic fibrosis, by the timemyocardial edema has probably subsided, and affecting the heart globally (i.e., both the acutely abnormally and normally or supernormally contracting myocardial regions), may have pathophysiologic connotations. Probably there are acute cardiomyocyte injurious influences (no matter the mechanism of TTS) also affecting normally and supernormally (i.e., base of the heart) functioning cardiac territories.

Response to Letter Regarding Article, “The Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction”

We thank de Dios for their comments related to the differences in outcomes noted between our observations and previously published work exploring the role of ivabradine in patients with heart failure with preserved ejection fraction (HFpEF).1 We acknowledge the central issue: namely, the heterogeneity of patients recruited related to the lack of clear consensus regarding the pathophysiology of HFpEF and the inability of traditional diagnostic techniques, such as resting echocardiography, to diagnose this condition. We used inclusion criteria similar to previously published work such as …