Assessing and interpreting diastolic function in animal models of heart disease.

Increasing interest in identifying the causes of and treatments for heart failure with preserved ejection fraction and cardiac fibrosis has spawned a focus on measures of cardiac diastolic function. The methods, their underlying principals and mechanics, and caveats to their measurement were largely worked out decades ago, but some of this seems a bit forgotten as scientists working in the field now have backgrounds more in molecular and cellular biology. This perspective was spawned by seeing the growing number of studies where diastolic function analysis is a key parameter used to justify a given pre-clinical model or to show the consequences of a particular genetic or pharmacological therapy. The goals are to discuss what comprises and influences diastolic function, how it is measured, what the parameters mean and what their limitations are, and what comprises evidence for pathophysiologically meaningful diastolic dysfunction.

Listen to your heart: Trade-off between cardiac interoceptive processing and visual exteroceptive processing.

Internal bodily signals, such as heartbeats, can influence conscious perception of external sensory information. Spontaneous shifts of attention between interoception and exteroception have been proposed as the underlying mechanism, but direct evidence is lacking. Here, we used steady-state visual evoked potential (SSVEP) frequency tagging to independently measure the neural processing of visual stimuli that were concurrently presented but varied in heartbeat coupling in healthy participants. Although heartbeat coupling was irrelevant to participants' task of detecting brief color changes, we found decreased SSVEPs for systole-coupled stimuli and increased SSVEPs for diastole-coupled stimuli, compared to non-coupled stimuli. These results suggest that attentional and representational resources allocated to visual stimuli vary according to fluctuations in cardiac-related signals across the cardiac cycle, reflecting spontaneous and immediate competition between cardiac-related signals and visual events. Furthermore, frequent coupling of visual stimuli with stronger cardiac-related signals not only led to a larger heartbeat evoked potential (HEP) but also resulted in a smaller color change evoked N2 component, with the increase in HEP amplitude associated with a decrease in N2 amplitude. These findings indicate an overall or longer-term increase in brain resources allocated to the internal domain at the expense of reduced resources available for the external domain. Our study highlights the dynamic reallocation of limited processing resources across the internal-external axis and supports the trade-off between interoception and exteroception.

The influence of the cardiac cycle on the halo sign and its impact on the ultrasound diagnosis of giant cell arteritis.

OBJECTIVES: To investigate whether hypoechoic wall thickness is influenced by the systole or diastole moment in the cardiac cycle and if this can influence ultrasound (US) assessments of giant cell arteritis (GCA). METHODS: US videos of 100 consecutive patients (50 with GCA, 50 without) performed between January 2021 and June 2023 were reviewed. Intima-media thickness (IMT) of temporal (including common trunk, frontal and parietal branches), axillary and subclavian arteries were measured at two different time points, at systolic peak (SP) and at the end-diastole (ED). Differences between SP IMT and ED IMT, as well as in the halo count (HC) and in the OMERACT GCA Ultrasonography Score (OGUS) between these two times, were analyzed. RESULTS: IMT was significantly higher (4.8-5%) at ED in all arteries, in both GCA and non-GCA groups. HC and OGUS were also higher in ED in both groups. In 4 non-GCA patients (8%), the HC was positive in ED and negative in SP; in all of them the HC in ED was 1. In the GCA group, the timing of the cardiac cycle did not influence the final US diagnosis; however, it did modify the HC in 14 patients (28%). CONCLUSION: IMT can fluctuate during the cardiac cycle, with higher measurements occurring at ED. This variability could potentially impact the accuracy of US diagnoses and assessments of GCA. If further research corroborates these findings, it may be imperative to revise the guidelines for employing US in diagnosing GCA in order to incorporate these nuanced aspects.

Predictive value of Doppler echocardiography parameters for cardiovascular events in patients with systemic lupus erythematosus.

BACKGROUND AND OBJECTIVES: This study aimed to assess the utility of Doppler echocardiography in evaluating left ventricular diastolic function, and prognosis in patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: A total of 286 SLE patients were selected along with 100 age- and gender-matched healthy individuals who underwent physical examinations. Clinical baseline characteristics were collected. Various Doppler echocardiographic parameters were measured and analyzed, including left ventricular posterior wall thickness (LVPWT), interventricular septal diameter (IVSD), left ventricular mass (LVM), LVM index (LVMI), and others. RESULTS: Compared to the control group, SLE patients exhibited significantly higher levels of C-reactive protein and lower levels of complement (C) 3 and C4 (p < .001). Doppler echocardiographic parameters showed significant differences between SLE patients and healthy controls, including increased LVPWT, IVSD, LVM, LVMI, peak A, PWI + Tei, E/e', TDI-Tei, and decreased e' and E/A (p < .001). Subgroup analyses indicated more severe ventricular diastolic dysfunction in patients with higher SLE activity and those who experienced cardiovascular events. Correlation analysis revealed positive associations of PWI + Tei, TDI-Tei, and GLS with SLE activity and cardiovascular events (p < .01). Multivariate logistic regression analysis identified LVMI, PWI + Tei, TDI-Tei, and GLS as significant predictors of cardiovascular events (p < .05). CONCLUSION: Doppler echocardiography is a valuable tool for the early diagnosis of left ventricular diastolic dysfunction in SLE patients. Key echocardiographic parameters, including LVMI, PWI + Tei, TDI-Tei, and GLS, are effective in predicting cardiovascular events, underscoring the importance of comprehensive cardiac function assessments in these patients.

Effects of the cardiac cycle on auditory processing: A preregistered study on mismatch negativity.

The systolic and diastolic phases of the cardiac cycle are known to affect perception and cognition differently. Higher order processing tends to be facilitated at systole, whereas sensory processing of external stimuli tends to be impaired at systole compared to diastole. The current study aims to examine whether the cardiac cycle affects auditory deviance detection, as reflected in the mismatch negativity (MMN) of the event-related brain potential (ERP). We recorded the intensity deviance response to deviant tones (70 dB) presented among standard tones (60 or 80 dB, depending on blocks) and calculated the MMN by subtracting standard ERP waveforms from deviant ERP waveforms. We also assessed intensity-dependent N1 and P2 amplitude changes by subtracting ERPs elicited by soft standard tones (60 dB) from ERPs elicited by loud standard tones (80 dB). These subtraction methods were used to eliminate phase-locked cardiac-related electric artifacts that overlap auditory ERPs. The endogenous MMN was expected to be larger at systole, reflecting the facilitation of memory-based auditory deviance detection, whereas the exogenous N1 and P2 would be smaller at systole, reflecting impaired exteroceptive sensory processing. However, after the elimination of cardiac-related artifacts, there were no significant differences between systole and diastole in any ERP components. The intensity-dependent N1 and P2 amplitude changes were not obvious in either cardiac phase, probably because of the short interstimulus intervals. The lack of a cardiac phase effect on MMN amplitude suggests that preattentive auditory processing may not be affected by bodily signals from the heart.

Heartfelt choices: The influence of cardiac phase on free-choice actions.

The influence of cardiac phases on cognitive and sensorimotor functions is noteworthy. Specifically, during systole, as opposed to diastole, there is an observed enhancement in tasks demanding the suppression of instructed responses. This suggests that systole contributes to inhibitory control in motor functions. However, the extent to which systolic inhibition is significant in volitional free-choice actions, such as choosing to execute or refrain from a cue-initiated response, remains to be clarified. To fill this gap in the current literature, the purpose of this study was to test whether during the systole phase, compared with the diastole phase, the tendency to enact volitional actions decreased due to the systolic inhibitory effect. We used a modified version of the Go/No-Go task with an added condition for volitional free-choice actions, where participants could decide whether to respond or not, to test whether systolic inhibition could affect the volitional decision to act. The results showed that participants' responses were less frequent in systole than in diastole in the volitional action condition. Then, to test the robustness of the cardiac effect on volitional actions, we used two established manipulations: the Straw Breathing Manipulation and the Cold Pressor Test, which were able to induce anxiety and increase the heart rate, respectively. Results showed that the systole/diastole difference in the number of volitional action trials in which participants decided to respond tended to remain the same despite all manipulations. Overall, our results provide convergent evidence for the effect of the heart on the decision to act, an effect that appears independent of manipulations of both the physiological and psychological state of the individual.

The Contractile Machines of the Heart.

This chapter will describe basic structural and functional features of the contractile apparatus of muscle cells of the heart, namely, cardiomyocytes and smooth muscle cells. Cardiomyocytes form the contractile myocardium of the heart, while smooth muscle cells form the contractile coronary vessels. Both muscle types have distinct properties and will be considered with respect to their cellular appearance (brick-like cross-striated versus spindle-like smooth), arrangement of contractile proteins (sarcomeric versus non-sarcomeric organization), calcium activation mechanisms (thin-filament versus thick-filament regulation), contractile features (fast and phasic versus slow and tonic), energy metabolism (high oxygen versus low oxygen demand), molecular motors (type II myosin isoenzymes with high adenosine diphosphate [ADP]-release rate versus myosin isoenzymes with low ADP-release rates), chemomechanical energy conversion (high adenosine triphosphate [ATP] consumption and short duty ratio versus low ATP consumption and high duty ratio of myosin II cross-bridges [XBs]), and excitation-contraction coupling (calcium-induced calcium release versus pharmacomechanical coupling). Part of the work has been published (Neuroscience - From Molecules to Behavior", Chap. 22, Galizia and Lledo eds 2013, Springer-Verlag; with kind permission from Springer Science + Business Media).

The Effect of Young Coconut Water on Blood Pressure in Hypertensive Patients.

Objective: To determine the effect of young coconut water on reducing blood pressure in hypertensive patients. METHODS: The quasi-experimental study was conducted in the work area of the Perhentian Luas Public Health Centre, Kuantan Singingi district, Riau province, Indonesia, from June 12 to 26, 2022, and comprised people aged >35 years with stage I hypertension. They were divided into intervention group A and control group B. Group A received young coconut water 150ml for 1 week once a day in the morning. Data was collected using observation sheets and blood pressure monitoring. Data was analysed using SPSS 20. RESULTS: Of the 30 subjects, 15(50%) were each in each of the two groups. All the 15(100%) respondents in group A were females, while there were 10(66.7%) males and 5(33.3%) females in group B. In both the groups, there were 8(53.3%) subjects aged 26-45 years and 7(46.7%) aged >45 years. Systolic and diastolic blood pressure before and after the intervention showed significant difference in group A (p<0.05), while the difference in group B was not significant (p>0.05). Conclusion: Consuming young coconut water every day for 7 days reduced blood pressure in hypertensive patients.

Cardiac myxoma as a rare acute heart failure etiology in paediatrics: A case report.

Cardiac myxoma is extremely rare in children. However, if not treated immediately, it may cause varying symptoms until sudden death. A-9-years old male Javanese child was brought to the emergency department of Prof. Soekandar General Hospital, Mojokerto with progressive dyspnoea since one month which got worse in the left decubitus position. There was no significant past medical history. Physical examination revealed hypotension, mitral stenosis, tricuspid regurgitation, and pulmonary congestion. Transthoracic echocardiography revealed a round pedunculated 3x3.3 cm mass in the Left Atrium that swingingly moved to the Left Ventricle during diastole. This was diagnosed provisionally as Myxoma with a differential of thrombus. After stabilization, he was referred to a tertiary hospital for emergency excision. Histopathology confirmed the myxoma. There were no symptoms and activity limitations during the 6 months follow-up. To the best of our knowledge, this is the first paediatric cardiac myxoma with Acute Heart Failure symptoms reported in Indonesia. Echocardiography is imperative for diagnosing myxoma. Appropriate and timely management results in an excellent outcome.

Myocardial steatosis impairs left ventricular diastolic-systolic coupling in healthy humans.

Mounting evidence suggests that myocardial steatosis contributes to left ventricular diastolic dysfunction, but definitive evidence in humans is lacking due to confounding comorbidities. As such, we utilized a 48-h food restriction model to acutely increase myocardial triglyceride (mTG) content - measured by 1 H magnetic resonance spectroscopy - in 27 young healthy volunteers (13 men/14 women). Forty-eight hours of fasting caused a more than 3-fold increase in mTG content (P < 0.001). Diastolic function - defined as early diastolic circumferential strain rate (CSRd) - was unchanged following the 48-h fasting intervention, but systolic circumferential strain rate was elevated (P < 0.001), indicative of systolic-diastolic uncoupling. Indeed, in a separate control experiment in 10 individuals, administration of low-dose dobutamine (2 µg/kg/min) caused a similar change in systolic circumferential strain rate as was found during 48 h of food restriction, along with a proportionate increase in CSRd, such that the two metrics remained coupled. Taken together, these data indicate that myocardial steatosis contributes to diastolic dysfunction by impairing diastolic-systolic coupling in healthy adults, and suggest that steatosis may contribute to the progression of heart disease. KEY POINTS: Preclinical evidence strongly suggests that myocardial lipid accumulation (termed steatosis) is an important mechanism driving heart disease. Definitive evidence in humans is limited due to the confounding influence of multiple underlying comorbidities. Using a 48-h food restriction model to acutely increase myocardial triglyceride content in young healthy volunteers, we demonstrate an association between myocardial steatosis and left ventricular diastolic dysfunction. These data advance the hypothesis that myocardial steatosis may contribute to diastolic dysfunction and suggest myocardial steatosis as a putative therapeutic target.

Isolated cardiac muscle contracting against a real-time model of systemic and pulmonary cardiovascular loads.

Isolated cardiac tissues allow a direct assessment of cardiac muscle function and enable precise control of experimental loading conditions. However, current experimental methods do not expose isolated tissues to the same contraction pattern and cardiovascular loads naturally experienced by the heart. In this study, we implement a computational model of systemic-pulmonary impedance that is solved in real time and imposed on contracting isolated rat muscle tissues. This systemic-pulmonary model represents the cardiovascular system as a lumped-parameter, closed-loop circuit. The tissues performed force-length work-loop contractions where the model output informed both the shortening and restretch phases of each work-loop. We compared the muscle mechanics and energetics associated with work-loops driven by the systemic-pulmonary model with that of a model-based loading method that only accounts for shortening. We obtained results that show simultaneous changes of afterload and preload or end-diastolic length of the muscle, as compared with the static, user-defined preload as in the conventional loading method. This feature allows assessment of muscle work output, heat output, and efficiency of contraction as functions of end-diastolic length. The results reveal the behavior of cardiac muscle as a pump source to achieve load-dependent work and efficiency outputs over a wider range of loads. This study offers potential applications of the model to investigate cardiac muscle response to hemodynamic coupling between systemic and pulmonary circulations in an in vitro setting.NEW & NOTEWORTHY We present the use of a "closed-loop" model of systemic and pulmonary circulations to apply, for the first time, real-time model-calculated preload and afterload to isolated cardiac muscle preparations. This method extends current experimental protocols where only afterload has been considered. The extension to include preload provides the opportunity to investigate ventricular muscle response to hemodynamic coupling and as a pump source across a wider range of cardiovascular loads.

Cardiac Magnetic Resonance Left Ventricular Filling Pressure Is Associated with NT-proBNP in Patients with New Onset Heart Failure.

Background and Objectives: Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping and estimating left ventricular (LV) filling pressure (LVFP). The N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is released from cardiac myocytes in response to mechanical load and wall stress. This study sought to investigate if CMR-derived LVFP is associated with the serum levels of NT-proBNP and, in addition, if it provides any incremental prognostic value in heart failure (HF). Materials and Methods: This study recruited 380 patients diagnosed with HF who underwent same-day CMR and clinical assessment between February 2018 and January 2020. CMR-derived LVFP was calculated, as previously, from long- and short-axis cines. During CMR assessment, serum NT-proBNP was measured. The pathological cut-offs were defined as follows: NT-proBNP ≥ 125 pg/mL and CMR LVFP > 15 mmHg. The incidence of HF hospitalisation was treated as a clinical outcome. Results: In total, 305 patients had NT-proBNP ≥ 125 pg/mL. Patients with raised NT-proBNP were older (54 ± 14 vs. 64 ± 11 years, p < 0.0001). Patients with raised NT-proBNP had higher LV volumes and mass. In addition, CMR LVFP was higher in patients with raised NT-proBNP (13.2 ± 2.6 vs. 15.4 ± 3.2 mmHg, p < 0.0001). The serum levels of NT-proBNP were associated with CMR-derived LVFP (R = 0.42, p < 0.0001). In logistic regression analysis, this association between NT-proBNP and CMR LVFP was independent of all other CMR variables, including LV ejection fraction, LV mass, and left atrial volume (coefficient = 2.02, p = 0.002). CMR LVFP demonstrated an independent association with the incidence of HF hospitalisation above NT-proBNP (hazard ratio 2.7, 95% confidence interval 1.2 to 6, p = 0.01). Conclusions: A CMR-modelled LVFP is independently associated with serum NT-proBNP levels. Importantly, it provides an incremental prognostic value over and above serum NT-proBNP levels.

Linear and Nonlinear Mendelian Randomization Analyses of the Association Between Diastolic Blood Pressure and Cardiovascular Events: The J-Curve Revisited.

BACKGROUND: Recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggest that excessive diastolic blood pressure (DBP) lowering might increase the risk of myocardial infarction (MI), reflecting a J- or U-shaped relationship. METHODS: We analyzed 47 407 participants from 5 cohorts (median age, 60 years). First, to corroborate previous observational analyses, we used traditional statistical methods to test the shape of association between DBP and cardiovascular disease (CVD). Second, we created polygenic risk scores of DBP and systolic blood pressure and generated linear Mendelian randomization (MR) estimates for the effect of DBP on CVD. Third, using novel nonlinear MR approaches, we evaluated for nonlinearity in the genetic relationship between DBP and CVD events. Comprehensive MR interrogation of DBP required us to also model systolic blood pressure, given that the 2 are strongly correlated. RESULTS: Traditional observational analysis of our cohorts suggested a J-shaped association between DBP and MI. By contrast, linear MR analyses demonstrated an adverse effect of increasing DBP increments on CVD outcomes, including MI (MI hazard ratio, 1.07 per unit mm Hg increase in DBP; P<0.001). Furthermore, nonlinear MR analyses found no evidence for a J-shaped relationship; instead confirming that MI risk decreases consistently per unit decrease in DBP, even among individuals with low values of baseline DBP. CONCLUSIONS: In this analysis of the genetic effect of DBP, we found no evidence for a nonlinear J- or U-shaped relationship between DBP and adverse CVD outcomes; including MI.

Multisensory integration of anticipated cardiac signals with visual targets affects their detection among multiple visual stimuli.

Many studies have elucidated the multisensory processing of different exteroceptive signals (e.g., auditory-visual stimuli), but less is known about the multisensory integration of interoceptive signals with exteroceptive information. Here, we investigated the perceptual outcomes and electrophysiological brain mechanisms of cardio-visual integration by using participants' electrocardiogram signals to control the color change of a visual target in dynamically changing displays. Reaction times increased when the target change coincided with strong cardiac signals concerning the state of cardiovascular arousal (i.e., presented at the end of ventricular systole), compared to when the target change occurred at a time when cardiac arousal was relatively low (i.e., presented at the end of ventricular diastole). Moreover, the concurrence of the target change and cardiac arousal signals modulated the event-related potentials and the beta power in an early period (~100 ms after stimulus onset), and decreased the N2pc and the beta lateralization in a later period (~200 ms after stimulus onset). Our results suggest that the multisensory integration of anticipated cardiac signals with a visual target negatively affects its detection among multiple visual stimuli, potentially by suppressing sensory processing and reducing attention toward the visual target. This finding highlights the role of cardiac information in visual processing and furthers our understanding of the brain dynamics underlying multisensory perception involving both interoception and exteroception.

Dual-phase imaging of cardiac metabolism using hyperpolarized pyruvate.

PURPOSE: Previous cardiac imaging studies using hyperpolarized (HP) [1-13 C]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED. METHODS: A dual-phase 13 C MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1-13 C]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP 13 C metabolites at each cardiac phase was correlated to multiphase 1 H MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane. RESULTS: In addition to mechanical changes, metabolic profiles of the heart detected by HP [1-13 C]pyruvate differed between ES and ED. The myocardial signal of [13 C]bicarbonate relative to [1-13 C]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism. CONCLUSION: The study demonstrates that metabolic profiles of the heart, measured by HP [1-13 C]pyruvate, are affected by the cardiac cycle in which that the data are acquired.

Cardiovascular magnetic resonance for the diagnosis and management of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by an impaired ventricular filling resulting in the development of dyspnea and other HF symptoms. Even though echocardiography is the cornerstone to demonstrate structural and/or functional alterations of the heart as the underlying cause for the clinical presentation, cardiovascular magnetic resonance (CMR) represents the noninvasive gold standard to assess cardiac morphology, function, and tissue changes. Indeed, CMR allows quantification of biventricular volumes, mass, wall thickness, systolic function, and intra- and extracardiac flows; diastolic functional indices include transmitral and pulmonary venous velocities, left ventricular and left atrial filling velocities from volumetric changes, strain analysis from myocardial tagging, tissue phase contrast, and feature tracking. Moreover, CMR allows superior tissue characterization of the myocardium and the pericardium, which are crucial for a noninvasive etiological and histopathological assessment of HFpEF: conventional T1-weighted, T2-weighted, and post-contrast sequences are now complemented by quantitative mapping sequences, including T1 and T2 mapping as well as extracellular volume quantification. Further experimental sequences comprise diffusion tensor analysis, blood oxygenation-dependent sequences, hyperpolarized contrast agents, spectroscopy, and elastography. Finally, artificial intelligence is beginning to help clinicians deal with an increasing amount of information from CMR exams.

The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications.

Normal cardiac function requires that intracellular Ca2+ concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca2+ concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca2+ concentration. It then considers how the control of systolic and diastolic intracellular Ca2+ concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.

Pre-operative point-of-care assessment of left ventricular diastolic dysfunction, an observational study.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is an acknowledged peri-operative risk factor that should be identified before surgery. This study aimed to evaluate a simplified echocardiographic method using e' and E/e' for identification and grading of diastolic dysfunction pre-operatively. METHODS: Ninety six ambulatory surgical patients were consecutively included to this prospective observational study. Pre-operative transthoracic echocardiography was conducted prior to surgery, and diagnosis of LV diastolic dysfunction was established by comprehensive and simplified assessment, and the results were compared. The accuracy of e'-velocities in order to discriminate patients with diastolic dysfunction was established by calculating accuracy, efficiency, positive (PPV) and negative predictive (NPV) values, and area under the receiver operating characteristic curve (AUROC). RESULTS: Comprehensive assessment established diastolic dysfunction in 77% (74/96) of patients. Of these, 22/74 was categorized as mild dysfunction, 43/74 as moderate dysfunction and 9/74 as severe dysfunction. Using the simplified method with e' and E/e', diastolic dysfunction was established in 70.8% (68/96) of patients. Of these, 8/68 was categorized as mild dysfunction, 36/68 as moderate dysfunction and 24/68 as severe dysfunction. To discriminate diastolic dysfunction of any grade, e'-velocities (mean < 9 cm s- 1) had an AUROC of 0.901 (95%CI 0.840-0.962), with a PPV of 55.2%, a NPV of 90.9% and a test efficiency of 0.78. CONCLUSIONS: The results of this study indicate that a simplified approach with tissue Doppler e'-velocities may be used to rule out patients with diastolic dysfunction pre-operatively, but together with E/e' ratio the severity of diastolic dysfunction may be overestimated. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier: NCT03349593 . Date of registration 21/11/2017. https://clinicaltrials.gov .

Effects of High Intensity Interval Training Rehabilitation Protocol after an Acute Coronary Syndrome on Myocardial Work and Atrial Strain.

Background andObjectives: Current guidelines on cardiac rehabilitation (CR) suggest moderate-intensity physical activity after acute coronary syndrome (ACS). Recent report have shown that high-intensity interval training (HIIT) could be more effective than moderate-intensity continuous training (MCT) in improving cardiac performance. Our aim was to analyze the effects of HIIT protocol after ACS on advanced echocardiographic parameters of myocardial function. Materials and Methods: In total, 75 patients with recent ACS, with or without ST segment elevation, were enrolled and compared with a control group of 50 age- and sex-comparable healthy subjects. Patients were randomized to perform a MCT training or HIIT-based rehabilitation program. A complete echocardiographic evaluation, including left ventricular (LV) and left atrial (LA) global longitudinal strain (GLS) and myocardial work (MW) through speckle-tracking analysis, was performed for all patients, before and after cardiac rehabilitation training. A cardiopulmonary exercise testing (CPET) was also performed at the end of the rehabilitation program. Results: Patients who followed the HIIT rehabilitation program showed improved LV diastolic function compared to the MCT group (E/e': 3.4 ± 3.1 vs. 6.4 ± 2.8, respectively, p < 0.01). Similarly, LV systolic function showed significant improvement in the group of patients performing HIIT (ejection fraction: 53.1 ± 6.4 vs. 52.3 ± 5.4%, p < 0.01; GLS: −17.8 ± 3.8 vs. −15.4 ± 4.3, p < 0.01). In addition, LA strain was improved. MW efficiency was also increased in the HIIT group (91.1 ± 3.3 vs. 87.4 ± 4.1%, p < 0.01), and was closely related to peak effort measurements expressed in peak VO2 by CPET. Conclusions: In patients with recent ACS, the HIIT rehabilitation program determined reverse cardiac remodeling, with the improvement of diastolic and systolic function, assessed by standard echocardiography. In addition, cardiac deformation index as GLS, LA strain and MW efficiency improved significantly after HIIT, and were associated with functional capacity during effort.

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. METHODS: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. RESULTS: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. CONCLUSIONS: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.