Exercise-based rehabilitation strategies in heart transplant recipients: Focus on high-intensity interval training.

Despite progressive improvement in medical therapy and standard care, the exercise capacity of heart transplant recipients is reduced compared with age-matched healthy individuals. Exercise-based rehabilitation programs have been shown to improve the exercise capacity of transplant patients through a multifactorial effect. In this context, high-intensity interval exercise is a growing field of research, with current evidence suggesting a major benefit in heart transplant recipients compared with a conventional training protocol. Therefore, this study aimed to provide an overview of the mechanisms involved in the reduced exercise capacity of heart transplant patients and a review of current rehabilitation strategies with a special focus on the mechanisms and clinical effects of high-intensity interval training exercise.

Inotropes in Patients with Advanced Heart Failure: Not Only Palliative Care.

Patients with advanced heart failure suffer from severe and persistent symptoms, often not responding disease-modifying drugs, a marked limitation of functional capacity and poor quality of life that can ameliorate with inotropic drugs therapy. In small studies, pulsed infusions of classical inotropes (ie, dobutamine and milrinone) are associated with improvement in hemodynamic parameters and quality of life in patients with advanced heart failure. However, because of the adverse effects of these drugs, serious safety issues have been raised. Levosimendan is a calcium-sensitizing inodilators with a triple mechanism of action, whose infusion results in hemodynamic, neurohormonal, and inflammatory cytokine improvements in patients with chronic advanced HF. In addition, levosimendan has important pleiotropic effects, including protection of myocardial, renal, and liver cells from ischemia-reperfusion injury, and anti-inflammatory and antioxidant effects; these properties possibly make levosimendan an "organ protective" inodilator. In clinical trials and real-world evidence, infusion of levosimendan at fixed intervals is safe and effective in patients with advanced HF, alleviating clinical symptoms, reducing hospitalizations, and improving the quality of life. Therefore, the use of repeated doses of levosimendan could represent the therapy of choice as a bridge to transplant/left ventricular assist device implantation or as palliative therapy in patients with advanced heart failure.

Management of Bradyarrhythmias in Heart Failure: A Tailored Approach.

Patients with heart failure (HF) may develop a range of bradyarrhythmias including sinus node dysfunction, various degrees of atrioventricular block, and ventricular conduction delay. Device implantation has been recommended in these patients, but the specific etiology should be sought as it may influence the choice of the type of device required (pacemaker vs. implantable cardiac defibrillator). Also, pacing mode must be carefully set in patients with heart failure (HF) and left ventricular systolic dysfunction.In this chapter, we summarize the knowledge required for a tailored approach to bradyarrhythmias in patients with heart failure.

Vericiguat: The Fifth Harmony of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction is a chronic and progressive syndrome that continues to be a substantial financial burden for health systems in Western countries. Despite remarkable advances in pharmacologic and device-based therapy over the last few years, patients with heart failure with reduced ejection fraction have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Worsening heart failure episodes represent a critical event in the heart failure trajectory, carrying high residual risk at discharge and dismal short- or long-term prognosis. Recently, vericiguat, a soluble guanylate cyclase stimulator, has been proposed as a novel drug whose use is already associated with a reduction in heart failure-related hospitalizations in patients in guideline-directed medical therapy. In this review, we summarized the pathophysiology of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate cascade in patients with heart failure with reduced ejection fraction, the pharmacology of vericiguat as well as the evidence regarding their use in patients with HFrEF. Finally, tips and tricks for its use in standard clinical practice are provided.

How to Select Patients for Left Ventricular Assist Devices? A Guide for Clinical Practice.

In recent years, a significant improvement in left ventricular assist device (LVAD) technology has occurred, and the continuous-flow devices currently used can last more than 10 years in a patient. Current studies report that the 5-year survival rate after LVAD implantation approaches that after a heart transplant. However, the outcome is influenced by the correct selection of the patients, as well as the choice of the optimal time for implantation. This review summarizes the indications, the red flags for prompt initiation of LVAD evaluation, and the principles for appropriate patient screening.

Levosimendan as a "Bridge to Optimization" in Patients with Advanced Heart Failure with Reduced Ejection-A Single-Center Study.

Background: Patients with advanced heart failure with reduced ejection fraction often cannot tolerate target doses of guideline-directed medical therapy due to symptomatic hypotension, renal dysfunction, and associated electrolyte abnormalities. While levosimendan can facilitate the titration of ß-blockers in patients with advanced HFrEF, it is unclear whether ambulatory levosimendan infusions would offer the same benefit. In this prospective study, we investigate the effects of intermittent ambulatory levosimendan infusions on the uptitration of disease-modifying drugs. Methods: We enrolled 37 patients with advanced HFrEF who received repeated ambulatory infusions of levosimendan between January 2018 and January 2021. The demographic, clinical, and laboratory data were acquired 24 h before the first and the last ambulatory levosimendan infusion. Results: At the 1 year follow-up, the enrolled patients were on significantly higher doses of guideline-directed medical therapy, including bisoprolol (3.2 ± 2.8 mg vs. 5.9 ± 4.1 mg; p = 0.02), sacubitril/valsartan (41.67 ± 32.48 mg vs. 68.5 ± 35.72 mg; p = 0.01), and eplerenone (12.7 ± 8.5 mg vs. 22.8 ± 13.6 mg; p = 0.03). Furthermore, a substantial decrease in the furosemide dose was observed (123.2 ± 32.48 mg vs. 81.6 ± 19.47 mg; p < 0.0001). Conclusions: Levosimendan facilitates the optimization of disease-modifying heart failure medications in previously intolerant advanced HFrEF patients.

Right ventricular ejection fraction and left ventricular dyssynchrony by 3D echo correlate with functional impairment in patients with dilated cardiomyopathy.

BACKGROUND: The aim of the study was to detect if right ventricular (RV) ejection fraction assessed by real-time 3-dimensional echocardiography (RT3DE) could predict patients with dilated cardiomyopathy (DCM) with greater functional impairment in response to cardiopulmonary exercise. METHODS AND RESULTS: Seventy chronic heart failure patients with DCM (55.5 ± 9.1 years; 48 males; 30 ischemic; New York Heart Association Class III: 48) underwent both left ventricular (LV) and RV analysis by RT3DE. Postprocessing software provided data of RT3DE systolic dyssynchrony index of 16 LV segments (systolic dyssynchrony index [SDI]) and of both LV and RV ejection fraction. Cardiac magnetic resonance was performed in a subgroup of 40 DCM patients to confirm RT3DE measurements. All the patients underwent also bicycle cardiopulmonary exercise test with evaluation of oxygen consumption (VO2) peak% (percentage of the predicted value), VE/VCO2 slope, and circulatory power (CP). Mean LV ejection fraction was 29.8 ± 4.6%. RT3DE LV SDI index was 8.4.4 ± 4.2, and RV ejection fraction was 51.3 ± 4.6%. By cardiopulmonary test, mean VO2 peak was 15.2 ± 4.4 mL·kg·min, and mean CP was 2.1 ± 0.8. By univariable analyses, significant correlations were detectable between SDI index and VO2 peak% (r = -0.56; P < .0001) and peak CP (r = -0.48; P < .0005). Also RV ejection fraction directly correlated with VO2 peak% (r = 0.58; P < .0001) and inversely with VE/VCO2 slope (r = -0.44; P < .001). By multivariable analysis, SDI index (ß coefficient = -0.46; P < .001) and 3D RV ejection fraction (ß coefficient = 0.42; P < .001) emerged as the only independent determinants of VO2 peak% during cardiopulmonary test. CONCLUSIONS: Increased LV electromechanical dyssynchrony and impaired RV function in DCM patients are independently associated with worse ability to perform aerobic exercise.

The Role of Echocardiography in the Management of Heart Transplant Recipients.

Transthoracic echocardiography is the primary non-invasive modality for the investigation of heart transplant recipients. It is a versatile tool that provides comprehensive information on cardiac structure and function. Echocardiography is also helpful in diagnosing primary graft dysfunction and evaluating the effectiveness of therapeutic approaches for this condition. In acute rejection, echocardiography is useful with suspected cellular or antibody-mediated rejection, with findings confirmed and quantified by endomyocardial biopsy. For identifying chronic rejection, ultrasound has a more significant role and, in some specific patients (e.g., patients with renal failure), it may offer a role comparable to coronary angiography to identify cardiac allograft vasculopathy. This review highlights the usefulness of echocardiography in evaluating normal graft function and its role in the management of heart transplant recipients.

Left Ventricular Assist Device Implantation in a Thrombosed Apical Aneurysm.

Left ventricular assist device implantation is a challenging procedure in the presence of a giant thrombosed aneurysm, and no standard surgical techniques are currently recommended in this setting. In this case, we report the successful implantation of a left ventricular assist device (HeartMate III) in a patient with a massive thrombosed apical aneurysm. The patient presented with extended antero-apical necrosis as a result of a delay in hospital admission for acute coronary syndrome due to the patient's concerns about the COVID-19 pandemic outbreak.

Use of sacubitril/valsartan as 'bridge to transplant' in patients with end-stage hypertrophic cardiomyopathy.

The end stage or burned-out phase is an uncommon but challenging clinical evolution of hypertrophic cardiomyopathy (HCM). The management of end-stage HCM is empirically based on the use of drugs approved for heart failure with reduced ejection fraction; however, cardiac transplantation often represents the best option to improve survival. In our case, we describe the use of sacubitril/valsartan as a 'bridge to transplant' in a patient with end-stage HCM. After introducing the drug, enhancements in functional capacity, a reduction in natriuretic peptides and an increase in left ventricular ejection fraction occurred. Given their improved volume of oxygen consumption (VO2) peak and hemodynamic parameters, our patient was left off the waiting list for cardiac transplant and continues to be regularly followed-up with every 3 months.

Left atrial volume index in highly trained athletes.

BACKGROUND: Increase of left atrial (LA) diameter in trained athletes has been regarded as another component of the "athlete's heart". AIMS: To evaluate the possible impact of competitive training on LA volume and to define reference values of LA volume index in athletes. METHODS AND RESULTS: Six hundred fifteen consecutive elite athletes (370 endurance- [ATE] vs 245 strength-trained athletes [ATS]; 385 men; 28.4 +/- 10.2 years, range 18-40 years) underwent a comprehensive transthoracic echocardiography exam. LA maximal volume was measured at the point of mitral valve opening using the biplane area-length method, and corrected for body surface area. LA mild dilatation was defined as a LA volume index between 29 and 33 mL/m(2), while a moderate dilatation was identified by a LA volume index > or =34 mL/m(2). Left ventricular (LV) mass index and ejection fraction did not significantly differ between the 2 groups. Conversely, ATS showed increased body surface area, sum of wall thickness (septum + LV posterior wall), LV circumferential end-systolic stress (ESSc) and relative wall thickness, whereas LA volume index, LV stroke volume and LV end-diastolic volume were greater in ATE. The range of LA volume index was 26 to 36 mL/m(2) (mean 28.2 +/- 9.2) in men and 22 to 33 mL/m(2) (mean 26.5 +/- 7.2) in women (P < .01). LA volume index was mildly enlarged in 150 athletes (24.3%) and moderately enlarged only in 20, all males (3.2%). Mild mitral regurgitation was observed in 64 athletes (10.3%). LA volume index was significantly greater in ATE (P < .01). By multivariate analysis, the overall population type (P < .01) and duration (P < .01) of training and LV end-diastolic volume (P < .001) were the only independent predictors of LA volume index. CONCLUSIONS: In a large population of highly trained athletes, a mild enlargement of LA volume index was relatively common and may be regarded as a physiologic adaptation to exercise conditioning.

Right ventricular myocardial involvement in either physiological or pathological left ventricular hypertrophy: an ultrasound speckle-tracking two-dimensional strain analysis.

AIMS: To analyse right ventricular (RV) myocardial deformation in patients with left ventricular (LV) hypertrophy secondary to either hypertrophic cardiomyopathy (HCM) or athlete's competitive endurance training. METHODS AND RESULTS: Standard Doppler echo, exercise stress echo, and 2D speckle-tracking strain echocardiography (2DSE) of RV longitudinal deformation in RV septal and lateral walls were performed in 50 top-level endurance athletes and in 35 patients with HCM, all men, having evidence of LV hypertrophy. Right ventricular global longitudinal strain (GLS) was calculated by averaging local strains along the entire right ventricle. The two groups were comparable for age and blood pressure, whereas athletes showed lower heart rate and increased body surface area than HCM. Interventricular septal thickness was higher in HCM, whereas both LV and RV end-diastolic diameters (LVEDD and RVEDD) and LV stroke volume were increased in athletes. Right ventricular tricuspid annulus systolic excursion was comparable between the two groups. Conversely, RV GLS and regional peaks of RV myocardial strain were significantly impaired in patients with HCM (all P < 0.001). Multiple linear regression models detected an independent association between RV GLS and LVEDD (beta-coefficient = -0.68, P < 0.0001) in athletes, as well as an independent correlation of the same RV GLS with septal thickness (beta = 0.63, P < 0.0001) in HCM. An RV GLS cut-off value of -0.16% differentiated athletes and HCM with an 86% sensitivity and a 92% specificity. Furthermore, in the overall population, RV GLS (beta = 0.51, P < 0.0001) was a powerful independent predictor of maximal workload during exercise stress echo. CONCLUSION: Right ventricular myocardial systolic deformation is positively influenced by preload increase in athletes and negatively associated with increased septal thickness in HCM. Therefore, 2DSE may represent a useful tool in the differential diagnosis between athlete's heart and HCM, underlining the different involvement of RV myocardial function in either physiological or pathological LV hypertrophy.

Effects of Sacubitril/Valsartan on the Right Ventricular Arterial Coupling in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: right ventricle-pulmonary artery (RV-PA) coupling assessed by measuring the tricuspid anular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio has been recently proposed as an early marker of right ventricular dysfunction in patients with heart failure with a reduced ejection fraction (HFrEF). METHODS: As the effects of sacubitril/valsartan therapy on RV-PA coupling remain unknown, this study aimed to analyse the effect of this drug on TAPSE/PASP in patients with HFrEF. We retrospectively analysed all outpatients with HFrEF referred to our unit between October 2016 and July 2018. RESULTS: At the 1-year follow-up, sacubitril/valsartan therapy was associated with a significant improvement in TAPSE (18.26 ± 3.7 vs. 19.6 ± 4.2 mm, p < 0.01), PASP (38.3 ± 15.7 vs. 33.7 ± 13.6, p < 0.05), and RV-PA coupling (0.57 ± 0.25 vs. 0.68 ± 0.30 p < 0.01). These improvements persisted at the 2-year follow-up. In the multivariable analysis, the improvement in the RV-PA coupling was independent of the left ventricular remodelling. CONCLUSIONS: in patients with HFrEF, sacubitril/valsartan improved the RV-PA coupling; however, further trials are necessary to evaluate the role of sacubitril/valsartan in the treatment of right ventricle (RV) dysfunction either associated or not associated with left ventricular dysfunction.

Prevalence and clinical significance of red flags in patients with hypertrophic cardiomyopathy.

INTRODUCTION: We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). METHODS: We studied 129 consecutive patients (23.7 ±â€¯20.9 years, range 0-74 years; male/female 68%/32%). Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography; imaging; and laboratory. Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and predictive accuracy of RF were analyzed in the genotyped population. RESULTS: In the overall cohort of 129 patients, 169 RF were identified in 62 patients (48%). Prevalence of RF was higher in infants (78%) and in adults >55 years old (58%). Following targeted genetic and clinical evaluation, 94 patients (74%) had a definite diagnosis (sarcomeric HCM or specific causes of HCM). We observed 14 RF in 13 patients (21%) with sarcomeric gene disease, 129 RF in 34 patients (97%) with other specific causes of HCM, and 26 RF in 15 patients (45%) with idiopathic HCM (p < 0.0001). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and > 55yo. Se, Sp, PPV, NPV and PA of RF were 97%, 70%, 55%, 98% and 77%, respectively. Single and clinical combination of RF (clusters) had an high specificity, NPV and predictive accuracy for the specific etiologies (syndromes/metabolic/infiltrative disorders associated with HCM). CONCLUSIONS: An extensive diagnostic work up, focused on analysis of specific diagnostic RF in patients with unexplained LVH facilitates a clinical diagnosis in 74% of patients with HCM.

Long-term prognostic role of diabetes mellitus and glycemic control in heart failure patients with reduced ejection fraction: Insights from the MECKI Score database.

BACKGROUND: The prognostic role of diabetes mellitus (DM) in heart failure (HF) patients is undefined, since DM is outweighed by several DM-related variables when confounders are considered. We determined the prognostic role of DM, treatment, and glycemic control in a real-life HF population. METHODS: 3927 HF patients included in the Metabolic Exercise Cardiac Kidney Index (MECKI) score database were evaluated with a median follow-up of 3.66 years (IQR 1.70-6.67). Data analysis considered survival between DM (n = 897) vs. non-DM (n = 3030) patients, and, in diabetics, between insulin (n = 304), oral antidiabetics (n = 479), and dietary only (n = 88) treatments. The role of glycemic control was evaluated grouping DM patients according to glycated hemoglobin (HbA1c): <7% (n = 266), 7.1-8% (n = 133), >8% (n = 149). All analyses were performed also adjusting for ejection fraction, renal function, hemoglobin, sodium, exercise peak oxygen uptake, and ventilation/carbon dioxide relationship slope. Study primary endpoint was the composite of cardiovascular death, urgent heart transplantation, or left ventricular assist device implantation. Secondary endpoints were cardiovascular and all causes death. RESULTS: For all endpoints, upon adjustment for confounders, DM status and insulin treatment or dietary regimen were not significantly associated with adverse long-term prognosis compared to non-DM and oral antidiabetic treated patients, respectively. A worse prognosis was observed in HbA1c >8% patients (Log-Rank p < 0.001), even after correction for confounding factors. All results were replicated by hazard ratio analysis. CONCLUSION: In HF patients, DM, insulin treatment and dietary regimen are not adverse outcome predictors. The only condition related to long-term prognosis, considering potential confounders, is poor glycemic control.

Effects of global longitudinal strain and total scar burden on response to cardiac resynchronization therapy in patients with ischaemic dilated cardiomyopathy.

AIMS: To evaluate whether quantification of the extent of scarred left ventricular (LV) tissue by speckle-tracking strain echo (2DSE) can predict response to cardiac resynchronization therapy (CRT) in patients with ischaemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Forty-five patients (58.3 +/- 8.3 years; 24 males) with ischaemic DCM scheduled for CRT, and 25 controls were studied. A week before implantation all the patients underwent standard Doppler echo, 2DSE, and contrast-enhanced magnetic resonance (MR). Clinical and echocardiographic evaluation was repeated 6 months after CRT. The patients were considered as responders to CRT if LV end-systolic volume decreased by 15%. In DCM patients, LV ejection fraction was 29.2 +/- 5.1%. By evaluating the 765 segments with MR, subendocardial infarct was identified in 17.0% and transmural infarct in 18.3%. With 2DSE, the average global longitudinal strain (GLS) was -23.1 +/- 3.6% in controls and -15.1 +/- 5.1% in DCM (P = 0.001). GLS showed a close correlation with total scar burden using MR (r = 0.64, P < 0.001). At follow-up, patients were subdivided into responders (n = 30; 66.7%) and non-responders (n = 15; 33.3%) to CRT. GLS was significantly different in non-responders than in responders (GLS: -10.4 +/- 5.1 in non-responders vs. -18.4 +/- 14% in responders, P < 0.001). In a multivariable analysis, GLS (P < 0.0001) and radial intraventricular dyssynchrony (P < 0.001) were powerful independent determinants of response to CRT. CONCLUSION: GLS is strongly associated with total scar burden assessed by MR, and is an excellent independent predictor of response to CRT.

Right ventricular myocardial function in patients with either idiopathic or ischemic dilated cardiomyopathy without clinical sign of right heart failure: effects of cardiac resynchronization therapy.

OBJECTIVE: In dilated cardiomyopathy (DCM), right ventricular (RV) dysfunction has been reported and attributed both to altered loading conditions and to RV involvement in the myopathic process. The aim of the study was to detect RV myocardial function in DCM using two-dimensional (2D) strain echocardiography and to assess the effects of cardiac resynchronization therapy (CRT) on RV myocardial strain during a 6-month follow-up. METHODS AND RESULTS: A total of 110 patients (mean age: 55.4 +/- 11.2 years) with either idiopathic (n = 60) or ischemic (n = 50) DCM, without overt clinical signs of RV failure, underwent standard echo and 2D strain analysis of RV longitudinal strain in RV septal and lateral walls. The two groups were comparable for clinical variables (New York Heart Association class III in 81.8%). Left ventricular volumes, ejection fraction, stroke volume, and mitral valve effective regurgitant orifice were similar between the two groups. No significant differences were evidenced in Doppler mitral and tricuspid inflow measurements. RV diameters were mildly increased in patients with idiopathic DCM, while RV tricuspid annulus systolic excursion and Tei-index were comparable between the two groups. RV global longitudinal strain and regional peak myocardial strain were significantly impaired in patients with idiopathic DCM compared with those having ischemic DCM (all P < 0.001). Using left ventricular end-systolic volume as marker for response to CRT, 70 patients (63.3%) were long-term responders. Ischemic DCM patient responders to CRT showed a significant improvement in RV peak systolic strain. Conversely, in patients with idiopathic DCM and in ischemic patients nonresponders to CRT, no improvement in RV function was evidenced. By multivariable analysis, in the overall population, ischemic etiology of DCM (P < 0.0001), positive response to CRT (P < 0.001), and longitudinal intraventricular dyssynchrony (P <0.01) emerged as the only independent determinants of RV global longitudinal strain after CRT. CONCLUSIONS: Two-dimensional strain represents a promising noninvasive technique to assess RV myocardial function in patients with DCM. RV myocardial deformation at baseline and after CRT are more impaired in idiopathic compared with ischemic DCM patients. Future longitudinal studies are warranted to understand the natural history of RV myocardial function, the extent of reversibility of RV dysfunction with CRT, and the possible prognostic impact of such indexes in patients with congestive heart failure.

Clinical outcome in patients with intermediate stenosis of left anterior descending coronary artery after deferral of revascularization on the basis of noninvasive coronary flow reserve measurement.

BACKGROUND: Several reports suggest that noninvasive measurements of coronary flow reserve (CFR) by use of echocardiography may support decision making in intermediate stenosis of the left anterior descending coronary artery (LAD). The aim of the present study was therefore to analyze the clinical outcome in patients with intermediate stenosis of LAD after deferral of coronary revascularization on the basis of noninvasive CFR measurement. METHODS: the study population included 280 patients with intermediate LAD stenosis (50-70% by angiography) (62.2 +/- 9.6 years). All the patients underwent transthoracic CFR assessment of LAD (after dipyridamole infusion) within 2 weeks from coronary angiography. If CFR of LAD was < or = 2, PTCA was recommended; if CFR was > 2, medical treatment was chosen. Primary end points were cardiac death, myocardial infarction, coronary revascularization procedure, and unstable angina. RESULTS: mean follow-up was 43 +/- 11 months (range 12-52 months). In 150 patients (53.6%) (CFR < or = 2), coronary artery revascularization was performed (PTCA group); the remaining 130 patients (46.4%) (CFR > 2) were medically treated (medical group). Survival from cardiac death was 94% in the PTCA group and 92.4% in the medical group (P = 0.56). As for all cardiac events, the Kaplan-Meier percentage survival from cardiac events was 88.3% in the PTCA group and 86.4% in the medical group (P = 0.36). CONCLUSIONS: even if CFR as a "stand-alone" diagnostic criterion suffers from several structural limitations, a combined strategy including also other clinical and instrumental measurements before undergoing interventional procedures could improve the cost-benefit practice, in particular, for the management of patients with intermediate LAD stenosis.