Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

The effect of two calcium silicate-based and one epoxy resin-based root canal sealer on postoperative pain: a randomized controlled trial.

AIM: To compare the effect of two calcium silicate-based (Endoseal MTA and EndoSequence BC Sealer) and an epoxy resin-based (AH Plus) root canal sealer on postoperative pain following single-visit root canal treatment on molar teeth. METHODOLOGY: Patients (n = 90) having one first or second molar tooth diagnosed with asymptomatic irreversible pulpitis were randomly divided into three groups according to the sealer used (n = 30) and were treated by two endodontists having at least 10 years of experience. All patients received a single-visit root canal treatment. After the treatments, postoperative pain scores and analgesic intake were recorded at 6, 12, 24 and 48 h, and 3, 4, 5, 6 and 7 days. The data were analysed statistically using non-parametric Kruskal-Wallis tests (for the comparisons of the age and VAS scores), Friedman tests (for the assessments of the changes in pain scores over time), chi-squared tests (for the comparisons of categorical variables) and Spearman's correlation test (for the correlation assessments of the age and gender factors with postoperative pain; α = 0.05). RESULTS: There were no significant differences amongst the groups in terms of postoperative pain at any time-points assessed (P > 0.05) nor for analgesic intake of patients amongst the groups (P > 0.05). Analgesic intake decreased significantly after 12 h in all groups (P < 0.05). CONCLUSIONS: The sealers tested in this study were associated with similar levels of postoperative pain and were associated with a similar intake of analgesics.

Evaluation of fracture resistance in root canal-treated teeth restored using different techniques.

OBJECTIVE: This study aimed to evaluate the effects of different coronal restoration techniques on fracture resistance of root canal-treated mandibular premolars with mesio-occluso-distal (MOD) cavities. MATERIALS AND METHODS: A total of 105 mandibular premolars were selected and randomly distributed into seven groups (n = 15). MOD cavities were prepared except the control group. Root canal treatments were performed. Each tooth was embedded in acrylic resin. Groups were classified as follows; G1: intact teeth (control), G2: unfilled MOD cavity, G3: MOD + composite resin, G4: 10-mm-long fiber post + composite resin, G5: 5-mm-long fiber post + composite resin, G6: Ribbond in the occlusal surface + composite resin, and G7: horizontal fiber post + composite resin. Specimens were loaded using a universal testing machine until fracture occurs. Fracture loads were recorded and statistical interpretations were made (α = 0.05). RESULTS: In Groups 1, 6, and 7, the greatest fracture resistance was shown and there were no significant differences among these groups (P > 0.05). No significant differences were detected among the Groups 3, 4, and 5 (P > 0.05), whereas the fracture resistances of Groups 1, 6, and 7 were significantly greater than these three groups (P < 0.05). Group 2 had the lowest fracture resistance of all groups (P < 0.05). CONCLUSION: Usage of horizontal post or occlusal Ribbond usage increased the fracture resistance of root canal-treated premolars with MOD cavities.

The efficiency of different irrigation solutions and techniques for the removal of triple antibiotic paste from simulated immature root canals.

INTRODUCTION: The purpose of this study was to evaluate the efficiencies of different irrigation protocols in the removal of triple antibiotic paste (TAP) from root canals. MATERIALS AND METHODS: A total of 127 extracted human maxillary incisor teeth were prepared. Then, root-end resection of 3 mm was accomplished to simulate immature apex model. The root canals were filled with TAP, after 21 days, randomly divided into nine groups according to irrigation systems and solutions (n = 13). Conventional irrigation (CI) groups - Group 1: Root canal irrigation was performed with CI by Peracetic acid (PAA) solution, Group 2: Root canal irrigation was performed with CI by etidronic acid 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) + sodium hypochlorite (NaOCl) solution, Group 3: Root canal irrigation was performed with CI by ethylenediaminetetraacetic acid (EDTA)/NaOCl solutions. Vibringe system groups - Group 4: Root canal irrigation was performed with Vibringe system by PAA solution, Group 5: Root canal irrigation was performed with Vibringe system by HEBP + NaOCl solution, Group 6: Root canal irrigation was performed with Vibringe system by EDTA/NaOCl solution. EndoVac system groups - Group 7: Root canal irrigation was performed with EndoVac system by PAA solution, Group 8: Root canal irrigation was performed with EndoVac system by HEBP + NaOCl solution, Group 9: Root canal irrigation was performed with EndoVac system by EDTA/NaOCl solution. Control Group: (n = 0). Samples were sectioned vertically, and the amount of remaining medicament was scored for each root half and data were statistically analyzed. RESULTS: Among the irrigation systems, CI groups showed the highest scores at both apical and coronal parts (P < 0.05). In comparisons among the solutions, at the apical part, PAA groups showed the highest scores (P < 0.05). At the coronal part, EDTA + NaOCl groups showed the lowest score values (P < 0.05). CONCLUSION: The use of irrigation systems improved the removal of TAP from the simulated immature root canals. Also, as an irrigation solution EDTA gives more promising results than PAA and HEBP solutions.

Adiponectin protects against incident hypertension independent of body fat distribution: observations from the Dallas Heart Study.

BACKGROUND: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population. METHODS: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot. RESULTS: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model. CONCLUSION: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution.

Efficacy of polishing kits on the surface roughness and color stability of different composite resins.

OBJECTIVE: Different polishing kits may have different effects on the composite resin surfaces. The aim of this study was to evaluate the surface roughness and color stability of four different composites which was applied different polishing technique. MATERIALS AND METHODS: Thirty specimens were made for each composite resin group (nanohybrid, GrandioSo-GS; nanohybrid, Clearfil Majesty Esthetic-CME; hybrid, Valux Plus-VP; micro-hybrid, Ruby Comp-RC; [15 mm in diameter and 2 mm height]), with the different monomer composition and particle size from a total of 120 specimens. Each composite group was divided into three subgroups (n = 10). The first subgroup of the each composite subgroups served as control (C) and had no surface treatment. The second subgroup of the each composite resin groups was polished with finishing discs (Bisco Finishing Discs; Bisco Inc., Schaumburg, IL, USA). The third subgroup of the each composite resin was polished with polishing wheel (Enhance and PoGo, Dentsply, Konstanz, Germany). The surface roughness and the color differences measurement of the specimens were made and recorded. The data were compared using Kruskal-Wallis test, and regression analysis was used in order to examine the correlation between surface roughness and color differences of the specimens (α = 0.05). RESULTS: The Kruskal-Wallis test indicated significant difference among the composite resins in terms of ΔE (P < 0.05), and there was no statistically significant difference among composite resins in terms of surface roughness (P > 0.05). Result of the regression analysis indicated statistically significant correlation between Ra and ΔE values (P < 0.05, r2 = 0.74). CONCLUSION: The findings of the present study have clinical relevance in the choice of polishing kits used.

Evaluation of calcium silicate cement bond strength after using gutta-percha solvents.

OBJECTIVES: To determine the effect of different gutta-percha solvents (chloroform, Endosolv E, orange oil, and eucalyptol) on the push-out bond strength of calcium silicate cements (CSCs; white mineral trioxide aggregate [WMTA]; capsule-form mineral trioxide aggregate [CMTA], and Biodentine). MATERIALS AND METHODS: One hundred and fifty extracted single-rooted human mandibular premolars were sectioned into 3-mm-thick slices. The canal lumens were enlarged for 1.35-mm-diameter standardized cavities. The samples were randomly divided into five groups (n = 30) according to the solvent type: G1, chloroform; G2, Endosolv E; G3, eucalyptol; G4, orange oil; G5, no solvent (control). After application of the solvents for 5 min, the specimens were divided into three subgroups (n = 10): (i) WMTA, (ii) CMTA, and (iii) Biodentine. The push-out bond strength was measured. Two-way ANOVA analysis of variance and post hoc Tukey tests were used for analyses (P = 0.05). RESULTS: The highest push-out bond strength was observed in the Biodentine (P < 0.05), and the values of WMTA and CMTA were not significantly different in all solvent groups (P > 0.05). There were no statistically significant differences among the gutta-percha solvents and control group in WMTA (P > 0.05). CONCLUSIONS: Gutta-percha solvents used during retreatment decreased the bond strength of Biodentine and CMTA to root dentin. The bond strength of WMTA was not affected by the use of gutta-percha solvents.

Efficacy of manual and mechanical instrumentation techniques for removal of overextended root canal filling material.

OBJECTIVE: To compare the efficacy of manual and mechanical instrumentation techniques, including ProTaper Universal retreatment system, Mtwo retreatment system, Reciproc system, and Hedström files, regarding removal of overextended root canal filling material. MATERIALS AND METHODS: Eighty extracted human mandibular premolar teeth were prepared at the apical foramen level using Revo-S rotary files and subsequently obturated. The root canal filling material was deliberately extruded from the apex. Samples were transferred to glass vials that simulated the periapical area. Eighty samples of overfilled teeth were randomly assigned to four equal groups (n = 20) for removal of the root filling material with ProTaper Universal retreatment files (Group 1), Mtwo retreatment files (Group 2), Reciproc system (Group 3), and hand files (Group 4). Removal of the root canal filling material and additional preparation were performed by individual instruments from each different system up to a #40 size. The external apical surface of the teeth and the surrounding glass vials were checked using a dental operation microscope with ×12.5 magnification. Samples were divided into two groups based on whether removal of the overextended root canal filling material was successful or not. The Fisher's exact test was used to detect any significant difference between the groups (α = 0.05). RESULTS: The success rate for removal of overextended gutta-percha was greater for the Mtwo (30%) and hand files (30%) compared with the ProTaper (20%) and Reciproc (10%). However, no significant statistical differences existed among the experimental groups (P > 0.05). CONCLUSIONS: This study demonstrated that all tested systems had similar efficacy in removing overextended root canal filling material.

The effects of different irrigation protocols on removing calcium hydroxide from the root canals.

OBJECTIVE: The aim of this study was to evaluate the efficiencies of different irrigation protocols and solutions in the removal of calcium hydroxide (Ca[OH]2). MATERIALS AND METHODS: Sixty-eight maxillary incisors were used. Root canals were prepared and filled with Ca(OH)2. Two control (n = 4) and six experimental groups (n = 10) were adjusted: Group 1:1% peracetic acid (PAA) + master apical file (MAF); Group 2: 17% ethylenediaminetetraacetic acid (EDTA) + MAF; Group 3: 9% 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) + MAF; Group 4: 1% PAA + ultrasonic activation (UA); Group 5: 17% EDTA + UA; Group 6: 9% HEBP + UA. The cleanliness of root canal thirds were evaluated with scanning electron microscopy. Statistical analysis were performed (α = 0.05). RESULTS: At coronal thirds; PAA + UA was superior to EDTA + MAF, HEBP + MAF; and PAA + MAF was superior to EDTA + MAF, HEBP + MAF (P < 0.05). At middle thirds; PAA + MAF and PAA + UA were superior to EDTA + MAF and EDTA + UA; and, PAA + UA was superior to HEBP + MAF (P < 0.05). There were no significant differences among the rest of the experimental groups (P > 0.05). CONCLUSION: Complete removal of Ca(OH)2could not be achieved by none of the irrigants at all root thirds.

Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy.

BACKGROUND: Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. METHODS AND RESULTS: Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA's cardioprotective effects. CONCLUSIONS: The US Food and Drug Administration-approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.

Inaccuracy of estimated resting oxygen uptake in the clinical setting.

BACKGROUND: The Fick principle (cardiac output = oxygen uptake ( O2)/systemic arterio-venous oxygen difference) is used to determine cardiac output in numerous clinical situations. However, estimated rather than measured O2 is commonly used because of complexities of the measurement, though the accuracy of estimation remains uncertain in contemporary clinical practice. METHODS AND RESULTS: From 1996 to 2005, resting O2 was measured via the Douglas bag technique in adult patients undergoing right heart catheterization. Resting O2 was estimated by each of 3 published formulae. Agreement between measured and estimated O2 was assessed overall, and across strata of body mass index, sex, and age. The study included 535 patients, with mean age 55 yrs, mean body mass index 28.4 kg/m2; 53% women; 64% non-white. Mean (±standard deviation) measured O2 was 241 ± 57 ml/min. Measured O2 differed significantly from values derived from all 3 formulae, with median (interquartile range) absolute differences of 28.4 (13.1, 50.2) ml/min, 37.7 (19.4, 63.3) ml/min, and 31.7 (14.4, 54.5) ml/min, for the formulae of Dehmer, LaFarge, and Bergstra, respectively (P<0.0001 for each). The measured and estimated values differed by >25% in 17% to 25% of patients depending on the formula used. Median absolute differences were greater in severely obese patients (body mass index > 40 kg/m2), but were not affected by sex or age. CONCLUSIONS: Estimates of resting O2 derived from conventional formulae are inaccurate, especially in severely obese individuals. When accurate hemodynamic assessment is important for clinical decision-making, O2 should be directly measured.

Adipose tissue biology and cardiomyopathy: translational implications.

It is epidemiologically established that obesity is frequently associated with the metabolic syndrome and poses an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. The molecular links that connect the phenomenon of obesity, per se, with insulin resistance and cardiovascular disease are still not fully elucidated. It is increasingly apparent that fully functional adipose tissue can be cardioprotective by reducing lipotoxic effects in other peripheral tissues and by maintaining a healthy balance of critical adipokines, thereby allowing the heart to maintain its full metabolic flexibility. The present review highlights both basic and clinical findings that emphasize the complex interplay of adipose tissue physiology and adipokine-mediated effects on the heart exerted by either direct effects on cardiac myocytes or indirect actions via central mechanisms through sympathetic outflow to the heart.

Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections.

The purpose of this investigation was to compare the efficacy of colistin-based therapies in extremely drug-resistant Acinetobacter spp. bloodstream infections (XDR-ABSI). A retrospective study was conducted in 27 tertiary-care centers from January 2009 to August 2012. The primary end-point was 14-day survival, and the secondary end-points were clinical and microbiological outcomes. Thirty-six and 214 patients [102 (47.7%): colistin-carbapenem (CC), 69 (32.2%): colistin-sulbactam (CS), and 43 (20.1%: tigecycline): colistin with other agent (CO)] received colistin monotherapy and colistin-based combinations, respectively. Rates of complete response/cure and 14-day survival were relatively higher, and microbiological eradication was significantly higher in the combination group. Also, the in-hospital mortality rate was significantly lower in the combination group. No significant difference was found in the clinical (p = 0.97) and microbiological (p = 0.92) outcomes and 14-day survival rates (p = 0.79) between the three combination groups. Neither the timing of initial effective treatment nor the presence of any concomitant infection was significant between the three groups (p > 0.05) and also for 14-day survival (p > 0.05). Higher Pitt bacteremia score (PBS), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Charlson comorbidity index (CCI), and prolonged hospital and intensive care unit (ICU) stay before XDR-ABSI were significant risk factors for 14-day mortality (p = 0.02, p = 0.0001, p = 0.0001, p = 0.02, and p = 0.01, respectively). In the multivariable analysis, PBS, age, and duration of ICU stay were independent risk factors for 14-day mortality (p < 0.0001, p < 0.0001, and p = 0.001, respectively). Colistin-based combination therapy resulted in significantly higher microbiological eradication rates, relatively higher cure and 14-day survival rates, and lower in-hospital mortality compared to colistin monotherapy. CC, CS, and CO combinations for XDR-ABSI did not reveal significant differences with respect to 14-day survival and clinical or microbiological outcome before and after propensity score matching (PSM). PBS, age, and length of ICU stay were independent risk factors for 14-day mortality.

Feasibility of exergaming for upper extremity rehabilitation in people with multiple sclerosis: prospective clinical trial.

BACKGROUND: Exergaming has been suggested as a rehabilitation method since it is more motivational for people with multiple sclerosis (MS, pwMS). However, the major disadvantage of this method is the lack of specific scenarios designed for pwMS. OBJECTIVES: This study aims to assess the feasibility of exergaming, which was developed for pwMS. METHODS: This unblinded prospective clinical trial was performed in the outpatient MS Clinic of Dokuz Eylül University Hospital. Exergaming scenarios were developed in collaboration with medical personnel consisting of physiotherapists and doctors, and computer engineers. A total of 30 participants who had definite MS diagnoses were included. The exergaming scenarios were implemented using the Microsoft Kinect. A physiotherapist applied custom-made exergames for one session. All the participants were assessed immediately after the session. The User Satisfaction Evaluation Questionnaire was used to assess the user's satisfaction with the system and exergaming. RESULTS: The mean age was 41.5, the mean Expanded Disability Status Scale was 4.5 (range between 0 and 7), and the mean disease duration was 10.0 years. Twenty patients were relapsing-remitting, and 10 were secondary-progressive. The mean scores of the User Satisfaction Evaluation Questionnaire were 4.33 (SD = 0.84) for helpfulness for rehabilitation, 1.63 (SD = 1.1) for not disturbing, 4.50 (SD = 1.07) for understandability, 4.0 (SD = 0.91) for easiness to control, and 4.33 (SD = 0.84) for enjoyability. CONCLUSION: These results showed that our custom-made exergaming scenario could be feasible in upper extremity rehabilitation in MS. More research is needed to investigate its effectiveness in the rehabilitation of upper limbs.

Using metabolomics to assess myocardial metabolism and energetics in heart failure.

There is a long history of investigation into the metabolism of the failing heart. Congestive heart failure is marked both by severe disruptions in myocardial energy supply and an inability of the heart to efficiently uptake and oxidize fuels. Despite the many advancements in our understanding, there are still even more outstanding questions in the field. Metabolomics has the power to assist our understanding of the metabolic derangements which accompany myocardial dysfunction. Metabolomic investigations in animal models of heart failure have already highlighted several novel, potentially important pathways of substrate selection and toxicity. Metabolomic biomarker studies in humans, already successfully applied to other forms of cardiovascular disease, have the potential to improve diagnosis and patient care. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Correlations between physician-perceived functional status, patient-perceived health status, and cardiopulmonary exercise results in hypertrophic cardiomyopathy.

BACKGROUND: Dyspnea and the resulting functional impairment are a common complication in hypertrophic cardiomyopathy (HCM). The relationship between physician-perceived functional status, patient-perceived health status, and objective exercise test results has not been evaluated in this condition. PURPOSE: To evaluate the correlation between the Kansas City Cardiomyopathy Questionnaire (KCCQ) and (1) physician's perceived (NYHA class) and (2) objective measurement (cardiopulmonary exercise test) of functional capacity in patients with HCM. METHODS: In 24 outpatients with HCM at a single, referral center, the KCCQ instrument was administered and cardiopulmonary exercise testing (CPX) was performed. Severity of symptoms as determined by physician (NYHA classification) and patient (KCCQ instrument) was obtained before exercise test results were known. Pearson correlation was used to assess the independent correlation between KCCQ score and the various exercise parameters; Spearman correlation was used to assess correlation between KCCQ score and NYHA class. RESULTS: KCCQ results demonstrated moderate reductions in all domains, with greatest reduction in quality-of-life domain. CPX testing showed reduction in peak oxygen consumption (mean absolute VO2 20.5 ± 7.8 ml/kg/min and percent predicted VO2 76.8 ± 4.1 %). There were negative correlations between NYHA class and all KCCQ components except the self-efficacy score. The strongest correlations were between NYHA class and the overall summary score (r = -0.623, p = 0.001) as well as the physical limitation score (r = -0.604, p = 0.002). Similarly, there were statistically significant positive correlations between the KCCQ components and percent predicted peak VO2. The strongest correlation was between percent predicted peak VO2 and the physical limitation score (r = 0.474, p = 0.019), but there was also correlation between percent predicted peak VO2 and the quality-of-life score (r = 0.456, p = 0.025), the functional status score (r = 0.455, p = 0.025), and the clinical summary score (r = 0.444, p = 0.030). CONCLUSIONS: The multiple domains of the KCCQ provide data on patient-perceived health status, which correlate with physician-perceived and objective measurement of functional capacity in HCM. Additional studies are needed to evaluate the sensitivity of the KCCQ to changes in functional capacity over time or in response to therapies for this condition.

Randomized Controlled Trial of Moderate- and High-Intensity Exercise Training in Patients With Hypertrophic Cardiomyopathy: Effects on Fitness and Cardiovascular Response to Exercise.

Background Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy. Methods and Results Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (V˙O2; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak V˙O2 by 1.3 mL/kg per min (P=0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise P=0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL P=0.005). HIT increased left ventricular end-diastolic volume (+17 mL, group×exercise P=0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred. Conclusions This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03335332.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.