Ultrasound-Derived Diaphragm Contractile Reserve as a Marker of Clinical Status in Patients With Cystic Fibrosis

Introduction: In patients with cystic fibrosis (CF), the monitoring of respiratory muscle activity using electromyography can provide information on the demand-to-capacity ratio of the respiratory system and act as a clinical marker of disease activity, but this technique is not adapted to routine clinical care. Ultrasonography of the diaphragm could provide an alternative, simpler and more widely available alternative allowing the real-time assessment of the diaphragm contractile reserve (DCR), but its relationship with recognized markers of disease severity and clinical outcomes are currently unknown.Methods: Stable patients with CF were prospectively recruited. Diaphragm ultrasound was performed and compared to forced expiratory volume in 1 s (FEV1), residual volume (RV), handgrip strength, fat-free mass index (FFMI), serum vitamin levels, dyspnea levels and rate of acute exacerbation (AE). Diaphragm activity was reported as DCR (the ratio of tidal-to-maximal thickening fractions, representing the remaining diaphragm contractility available after tidal inspiration) and TFmax (representing maximal diaphragm contractile strength). Inter-observer reliability of the measurement of DCR was evaluated using intra-class correlation analysis.Results: 110 patients were included [61 males, median (interquartile range), age 31 (27–38) years, FEV1 66 (46–82)% predicted]. DCR was significantly correlated to FEV1 (rho = 0.46, p < 0.001), RV (rho = −0.46, p < 0.001), FFMI (rho = 0.41, p < 0.001), and handgrip strength (rho = 0.22, p = 0.02), but TFmax was not. In a multiple linear regression analysis, both RV and FFMI were independent predictors of DCR. DCR, but not TFmax, was statistically lower in patients with > 2 exacerbations/year (56 ± 25 vs. 71 ± 17%, p = 0.001) and significantly lower with higher dyspnea levels. A ROC analysis showed that DCR performed better than FEV1 (mean difference in AUROC 0.09, p = 0.04), RV (mean difference in AUROC 0.11, p = 0.03), and TFmax at identifying patients with an mMRC score > 2. Inter-observer reliability of DCR was high (ICC = 0.89, 95% CI 0.84–0.92, p < 0.001).Conclusion: In patients with CF, DCR is a reliable and non-invasive marker of disease severity that is related to respiratory and extra-pulmonary manifestations of the disease and to clinical outcomes. Future studies investigating the use of DCR as a longitudinal marker of disease progression, response to interventions or target for therapy would further validate its translation into clinical practice.

Prognostic value of ABCDE stress echocardiography

Background Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B-lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, EKG-based heart rate reserve. Aim: to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicenter, international, effectiveness study. Methods From July 2016 to November 2020, we enrolled 3,574 all-comers (age 65±11 years, 2,070 males, 58%; ejection fraction 60±10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent ABCDE-SE. The employed stress modality was exercise (n=952, with semi-supine bike, n=887, or treadmill, n=65 with adenosine for step D) or pharmacological stress (n=2,622, with vasodilator, n=2,151; or dobutamine, n=471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only end-point. Results Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D and 37% for E step. During a median follow-up of 21 months, 73 deaths occurred. At univariable analysis, predictors of all-cause mortality were step B (hazard ratio, HR: 2.621, 95% Confidence Intervals, CI: 1.654–4.152, p<0.001), step D (HR: 2.578, 95% CI: 1.624–4.093, p<0.001), and step E (HR: 2.955, 95% CI: 1.848–4.725, p<0.001), but not step A (HR: 1.333, 95% CI: 0.731–2.430, p=0.349) and step C (HR1.581, 95% CI: 0.997–2.506, p=0.051). At multivariable analysis, ABCDE-SE was an independent predictor of mortality with score 3 (HR: 3.472, 95% CI: 1.483–8.135, p=0.004), 4 (HR: 4.045, 95% CI: 1.595–10.259, p=0.003) and 5 (HR: 5.678, 95% CI: 2.106–15.313, p=0.001) (Figure). Annual mortality rate ranged from 0.4% person/year for score 0 up to 2.4% person/year for score 5. Conclusion ABCDE-SE allows an effective risk stratification of patient global vulnerability. FUNDunding Acknowledgement Type of funding sources: None. Survival curves based on ABCDE score

Left ventricular contractile reserve, coronary flow reserve, and heart rate reserve during dipyridamole stress echocardiography predict survival in non-ischemic heart failure

Background Left ventricular contractile reserve (LVCR), coronary flow velocity reserve (CFVR), and heart rate reserve (HRR) have recognized independent impact on outcome in heart failure (HF). They all can be simultaneously measured during dipyridamole stress echocardiography (DSE). Aim To assess the value of comprehensive DSE in patients with non-ischemic heart failure. Methods We evaluated 613 patients with HF, no history of coronary artery disease and no inducible regional wall motion abnormalities: 270 patients with preserved (≥50%) ejection fraction; 147 with mid-range (40–49%) ejection fraction; 196 with HF and reduced (<40%) ejection fraction. All underwent DSE (0.84 mg/kg in 6') in 5 accredited laboratories. We measured LVCR (abnormal value ≤1.1), CFVR in left anterior descending artery (abnormal value ≤2.0), and HRR (peak/rest heart rate, abnormal value ≤1.22). All patients were followed-up. Results Abnormal CFVR, LVCR and HRR occurred in 29%, 44% and 46% of patients, respectively. After a median follow-up time of 20 months (interquartile range 12–32 months), 41 patients died. Annual mortality rate was lowest in patients (n=200) with normal response, and >10-fold higher in patients (n=96) with 3 abnormal criteria: see figure. At multivariable analysis, a reduced HRR (Hazard Ratio = 3.402, 95% Confidence Intervals 1.530–7.565, p=0.003) was the strongest SE independent predictor of all-cause death. Conclusion Abnormal LVCR, CFVR and HRR can be frequently observed during vasodilator SE in HF patients. They target different pathophysiological vulnerabilities (myocardial function, coronary microcirculation and cardiac autonomic system) and are useful for outcome prediction. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Consiglio nazionale delle ricerche - Institute of Clinical Physiology Figure 1

Coronary Flow, Left Ventricular Contractile and Heart Rate Reserve in Non-Ischemic Heart Failure

Background: Left ventricular contractile reserve (LVCR), coronary flow velocity reserve (CFVR), and heart rate reserve (HRR) affect outcome in heart failure (HF). They can be simultaneously measured during dipyridamole stress echocardiography (DSE). Aim: To assess the value of comprehensive DSE in patients with non-ischemic HF. Methods: We evaluated 610 patients with HF, no history of coronary artery disease, and no inducible regional wall motion abnormalities: 270 patients with preserved ejection fraction (≥50%), 146 patients with mid-range ejection fraction (40–49%), and 194 patients with reduced ejection fraction (<40%). All underwent DSE (0.84 mg/kg in 6’) in 7 accredited laboratories. We measured LVCR (abnormal value ≤ 1.1), CFVR in left anterior descending artery (abnormal value: ≤2.0), and HRR (peak/rest heart rate; abnormal value: ≤1.22). All patients were followed up. Results: Abnormal CFVR, LVCR, and HRR occurred in 29%, 45%, and 47% of patients, respectively (p < 0.001). After a median follow-up time of 20 months (interquartile range: 12–32 months), 113 hard events occurred in 105 patients with 41 deaths, 8 myocardial infarctions, 61 admissions for acute HF, and 3 strokes. The annual mortality rates were 0.8% in 200 patients with none abnormal criteria, 1.8% in 184 patients with 1 abnormal criterion, 7.1% in 130 patients with 2 abnormal criteria, 7.5% in 96 patients with 3 abnormal criteria. Conclusion: Abnormal LVCR, CFVR, and HRR were frequent during DSE in non-ischemic HF patients. They target different pathophysiological vulnerabilities (myocardial function, coronary microcirculation, and cardiac autonomic balance) and are useful for outcome prediction.

Design and Clinical Evaluation of Pharmacologic Stress-Test with Dalargin for SPECT Detection of Viable Myocardium in Patients after Myocardial Infarction

Purpose: To develop a functional stress-test with Dalargin used as a pharmacological stress agent and to study its diagnostic capabilities for quantifying the general and segmental systolic function of the left ventricle in patients with IHD using SPECT and echo methods. Material and methods: The study comprised 29 male patients with CHD-angina of 2-3 functional classes, studied on 15–25 days (on average 20 ± 2.8 days) after a large-focal myocardial infarction. A fractional step-wise injection of Dalargin was performed with step doses as 0.1 mg / kg (1 ml up to a total of 8 ml, with intervals of 90 seconds, for a total of 12 minutes), in a supine position. After each dose of Dalargin, blood pressure, heart rate, ECG were recorded, and an echocardiographic assessment of hemodynamic parameters and local contractility was carried out. At the peak of the effect of dalargin, 99mTc-Tetrofosmin was administered intravenously (370 – 540 MBq), followed by chest SPECT. Results: The optimal dose of dalargin for assessing the contractility of the LV was 0.3 mg/kg. From the data of myocardial perfusion SPECT, at dalargin test, the number of segments with normal regional blood supply increased statistically significantly from 56,0 % to 64,7 %, the number of hypoperfused segments decreased from 41.0% to 33.7% as compared to rest, and the number of non-perfused ones – from 3.0 % to 1.6 %. Spearman’s correlation coefficient between segmental contractility and local perfusion at the top dalargin inotropic effect was high and significant (R=0.67, p<0.01). The sensitivity and specificity of the pharmacological test with intravenous administration of dalargin for prediction of postoperative improvement of perfusion and contractility of the viable myocardium were: sensitivity 78.8 %, specificity 76.4 %, diagnostic accuracy 77.6 %. Conclusion. The use of the agonist of the μ - and δ-opioid receptors dalargin as a pharmacological stress-agent at perfusion SPECT and Stress Echocardiography to assess the contractile reserve of a dysfunctional viable myocardium is informative and appropriate. In patients with IHD who have suffered a myocardial infarction and are referred to myocardial revascularization, dalargin can be employed as an effective stress-agent for assessing the reserve of perfusion and contractility of dysfunctional left ventricular myocardium using perfusion SPECT and echocardiography.

Hemodynamic Heterogeneity of Reduced Cardiac Reserve Unmasked by Volumetric Exercise Echocardiography

Background: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. Methods: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. Results: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. Conclusions: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

Effects of Sodium‐Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice

Background Inhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy. Methods and Results Mice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31 P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet. Conclusions Ertugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.

Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction

Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction <40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.