Use of Statins in Heart Failure with Preserved Ejection Fraction: Current Evidence and Perspectives.

Systemic inflammation and coronary microvascular endothelial dysfunction are essential pathophysiological factors in heart failure (HF) with preserved ejection fraction (HFpEF) that support the use of statins. The pleiotropic properties of statins, such as anti-inflammatory, antihypertrophic, antifibrotic, and antioxidant effects, are generally accepted and may be beneficial in HF, especially in HFpEF. Numerous observational clinical trials have consistently shown a beneficial prognostic effect of statins in patients with HFpEF, while the results of two larger trials in patients with HFrEF have been controversial. Such differences may be related to a more pronounced impact of the pleiotropic properties of statins on the pathophysiology of HFpEF and pro-inflammatory comorbidities (arterial hypertension, diabetes mellitus, obesity, chronic kidney disease) that are more common in HFpEF. This review discusses the potential mechanisms of statin action that may be beneficial for patients with HFpEF, as well as clinical trials that have evaluated the statin effects on left ventricular diastolic function and clinical outcomes in patients with HFpEF.

Supervised exercise training in patients with advanced heart failure and left ventricular assist device: A multicentre randomized controlled trial (Ex-VAD trial).

AIMS: Small studies and observations suggested that exercise training may improve peak oxygen consumption (peakVO2 ) in patients with advanced heart failure and left ventricular assist device (LVAD). We investigated whether in this patient group a supervised exercise training can improve exercise capacity. METHODS AND RESULTS: In this multicentre, prospective, randomized, controlled trial, patients with stable heart failure and LVAD were randomly assigned (2:1) to 12 weeks of supervised exercise training or usual care, with 12 weeks of follow-up. The primary endpoint was the change in peakVO2 after 12 weeks (51 patients provided a power of 90% with an expected group difference in peakVO2 of 3 ml/kg/min). Secondary endpoints included changes in submaximal exercise capacity and quality of life. Among 64 patients enrolled (97% male, mean age 56 years), 54 were included in the analysis. Mean difference in the change of peakVO2 after 12 weeks was 0.826 ml/min/kg (95% confidence interval [CI] -0.37, 2.03; p = 0.183). There was a positive effect of exercise training on 6-min walk distance with a mean increase in the intervention group by 43.4 m (95% CI 16.9, 69.9; p = 0.0024), and on the Kansas City Cardiomyopathy Questionnaire physical domain score (mean 14.3, 95% CI 3.7, 24.9; p = 0.0124), both after 12 weeks. The overall adherence was high (71%), and there were no differences in adverse events between groups. CONCLUSION: In patients with advanced heart failure and LVAD, 12 weeks of exercise training did not improve peakVO2 but demonstrated positive effects on submaximal exercise capacity and physical quality of life.

Blood Immune Cell Alterations in Patients with Hypertensive Left Ventricular Hypertrophy and Heart Failure with Preserved Ejection Fraction.

(1) Background: Chronic inflammation and fibrosis are key players in cardiac remodeling associated with left ventricular hypertrophy (LVH) and heart failure with a preserved ejection fraction (HFpEF). Monocytes and T-helpers (Th) are involved in both pro-inflammatory and fibrotic processes, while regulatory T-cells (Treg) could be considered to suppress chronic inflammation in the hypertrophied myocardium. We aimed to estimate the relationship between the frequencies of circulating CD4+ T-cell and monocyte subpopulations and the variables of left ventricular (LV) diastolic function in patients with LVH depending on the presence of HFpEF. (2) Methods: We enrolled 57 patients with asymptomatic hypertensive LVH (n = 21), or LVH associated with HFpEF (n = 36). A clinical assessment and echocardiographs were analyzed. CD4+ Treg, activated Th (Th-act), and monocyte (classical, intermediate, and non-classical) subpopulations were evaluated via direct immunofluorescence and flow cytometry. (3) Results: Patients with HFpEF had a lower Treg/Th-act ratio (p = 0.001). Though asymptomatic patients and patients with HFpEF were comparable in terms of both the total monocyte number and monocyte subsets, there were moderate correlations between intermediate monocyte count and conventional and novel echocardiographic variables of LV diastolic dysfunction in patients with HFpEF. (4) Conclusions: In patients with LVH, the clinical deterioration (transition to HFpEF) and progression of LV diastolic dysfunction are probably associated with T-cell disbalance and an increase in intermediate monocyte counts.

Ten-Year Survival of Heart Failure Patients with Left Ventricular Ejection Fraction of 40-59%: A Potential Phenotypic Classification? / Sobrevida em 10 Anos de Pacientes com Insuficiência Cardíaca com FEVE 40-59%: Uma Classificação Fenotípica Viável?

Definitions of left ventricular ejection fraction (LVEF) cut-off values for HF with mildly reduced LVEF (HFmrEF) have been a subject of debate, in the face of evidence that some drugs used in the treatment of HF with LFEV < 40% (HFrEF) are also effective in patients with LVEF < 60%. The aim of this study was to compare overall survival and cardiovascular survival in HF patients with LVEF of 40-59% in patients with HFrEF and HF with LVEF ≥ 60%. Patients with decompensated HF who met the Framingham diagnostic criteria at hospital admission between 2009 and 2011 were included. Patients were divided into HFrEF, HF with LVEF 40-59%, and HF with LVEF ≥ 60%. The Kaplan-Meier was used to determine ten-year overall survival and cardiovascular survival. The statistical significance was established at p<0.05. A total of 400 patients were included, with a mean age of 69 ± 14 years. Cardiovascular survival in patients with HF and LVEF of 40-59% was not significantly different than in patients with HFrEF (adjusted Hazard Ratio [HR] 0.86; 95% Confidence Interval [CI] 0.61-1.22, Ptrend = NS), but was statistically different compared with patients with LVEF ≥ 60% (adjusted HR of 0.64; 95% CI 0.44-0.94, Ptrend = 0.023). No difference was found in 10-year survival between the LVEF groups. Patients with HF and LVEF ≥ 60% had significantly higher cardiovascular survival compared with the other groups.

Os limites da fração de ejeção do ventrículo esquerdo (FEVE) para a insuficiência cardíaca (IC) com FEVE levemente reduzida (ICFElr) têm sido questionados, já que evidências demonstram que alguns medicamentos utilizados para IC com FEVE <40% (ICFEr) demonstram eficácia também em populações com FEVE < 60%. Objetivo do estudo foi comparar a sobrevida total e cardiovascular de pacientes com IC com FEVE 40-59% com paciente com ICFEr e IC com FEVE ≥ 60%. Foram incluídos pacientes com IC descompensada que preencheram os critérios diagnósticos de Framingham na admissão hospitalar entre 2009 e 2011. Os pacientes foram divididos em ICFEr, IC com FEVE 40-59% e IC com FEVE ≥ 60%. O método de Kaplan-Meier foi usado para detectar a sobrevida geral e cardiovascular em 10 anos. A significância estatística foi estabelecida em p <0,05. Foram incluídos 400 pacientes, com idade média de 69 ± 14 anos. A sobrevida cardiovascular nos pacientes com IC e FEVE 40-59% não foi diferente em comparação aos pacientes com ICFEr [Hazard Ratio (HR) ajustado 0,86 ­ Intervalo de Confiança (IC) 95% 0,61-1,22; Ptrend = NS], mas foi estatisticamente diferente em comparação aos com FEVE ≥ 60% (HR ajustado = 0,64 - IC95% 0,44-0,94; Ptrend = 0,023). Não houve diferença na taxa de sobrevida de 10 anos entre diferentes grupos de FEVE. O grupo de pacientes com IC e FEVE ≥ 60% teve maior sobrevida cardiovascular que os outros grupos.

Sobrevida em 10 Anos de Pacientes com Insuficiência Cardíaca com FEVE 40-59%: Uma Classificação Fenotípica Viável? / Ten-Year Survival of Heart Failure Patients with Left Ventricular Ejection Fraction of 40-59%: A Potential Phenotypic Classification?

Resumo Os limites da fração de ejeção do ventrículo esquerdo (FEVE) para a insuficiência cardíaca (IC) com FEVE levemente reduzida (ICFElr) têm sido questionados, já que evidências demonstram que alguns medicamentos utilizados para IC com FEVE <40% (ICFEr) demonstram eficácia também em populações com FEVE < 60%. Objetivo do estudo foi comparar a sobrevida total e cardiovascular de pacientes com IC com FEVE 40-59% com paciente com ICFEr e IC com FEVE ≥ 60%. Foram incluídos pacientes com IC descompensada que preencheram os critérios diagnósticos de Framingham na admissão hospitalar entre 2009 e 2011. Os pacientes foram divididos em ICFEr, IC com FEVE 40-59% e IC com FEVE ≥ 60%. O método de Kaplan-Meier foi usado para detectar a sobrevida geral e cardiovascular em 10 anos. A significância estatística foi estabelecida em p <0,05. Foram incluídos 400 pacientes, com idade média de 69 ± 14 anos. A sobrevida cardiovascular nos pacientes com IC e FEVE 40-59% não foi diferente em comparação aos pacientes com ICFEr [Hazard Ratio (HR) ajustado 0,86 - Intervalo de Confiança (IC) 95% 0,61-1,22; Ptrend = NS], mas foi estatisticamente diferente em comparação aos com FEVE ≥ 60% (HR ajustado = 0,64 - IC95% 0,44-0,94; Ptrend = 0,023). Não houve diferença na taxa de sobrevida de 10 anos entre diferentes grupos de FEVE. O grupo de pacientes com IC e FEVE ≥ 60% teve maior sobrevida cardiovascular que os outros grupos.

Abstract Definitions of left ventricular ejection fraction (LVEF) cut-off values for HF with mildly reduced LVEF (HFmrEF) have been a subject of debate, in the face of evidence that some drugs used in the treatment of HF with LFEV < 40% (HFrEF) are also effective in patients with LVEF < 60%. The aim of this study was to compare overall survival and cardiovascular survival in HF patients with LVEF of 40-59% in patients with HFrEF and HF with LVEF ≥ 60%. Patients with decompensated HF who met the Framingham diagnostic criteria at hospital admission between 2009 and 2011 were included. Patients were divided into HFrEF, HF with LVEF 40-59%, and HF with LVEF ≥ 60%. The Kaplan-Meier was used to determine ten-year overall survival and cardiovascular survival. The statistical significance was established at p<0.05. A total of 400 patients were included, with a mean age of 69 ± 14 years. Cardiovascular survival in patients with HF and LVEF of 40-59% was not significantly different than in patients with HFrEF (adjusted Hazard Ratio [HR] 0.86; 95% Confidence Interval [CI] 0.61-1.22, Ptrend = NS), but was statistically different compared with patients with LVEF ≥ 60% (adjusted HR of 0.64; 95% CI 0.44-0.94, Ptrend = 0.023). No difference was found in 10-year survival between the LVEF groups. Patients with HF and LVEF ≥ 60% had significantly higher cardiovascular survival compared with the other groups.

Left atrial dysfunction as the major driver of heart failure with preserved ejection fraction syndrome.

Left atrial (LA) dysfunction seems to play a central role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), is associated with disease severity and poor outcomes and potentially impacts management. Identifying LA myopathy can help guide tailored therapy for HFpEF. Echocardiography allows the accurate measurement of atrial size and function, where LA strain appears to be a sensitive measure of intrinsic LA myopathy. Several therapies and devices that decompress of left atrium are being tested for HFpEF. Further investigation is required to understand the specific atrial effects of statins, mineralocorticoid receptor antagonists, and other therapies.

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, "precapillary" alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.

Nitric oxide metabolites: associations with cardiovascular biomarkers and clinical parameters in patients with HFpEF.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is one of the most rapidly growing cardiovascular health burden worldwide, but there is still a lack of understanding about the HFpEF pathophysiology. The nitric oxide (NO) signalling pathway has been identified as a potential key element. The aim of our study was to investigate markers of NO metabolism [l-arginine (l-Arg), homoarginine (hArg), and asymmetric and symmetric dimethylarginine (ADMA and SDMA)], additional biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), endothelin-1 (ET-1), mid-regional pro-adrenomedullin (MR-proADM), copeptin, and high-sensitivity C-reactive protein (hsCRP)], and the endothelial function in an integrated approach focusing on associations with clinical characteristics in patients with HFpEF. METHODS AND RESULTS: Seventy-three patients, prospectively enrolled in the 'German HFpEF Registry', were analysed. Inclusion criteria were left ventricular ejection fraction (LVEF) ≥ 50%; New York Heart Association functional class ≥ II; elevated levels of NT-proBNP > 125 pg/mL; and at least one additional criterion for structural heart disease or diastolic dysfunction. All patients underwent transthoracic echocardiography, cardiopulmonary exercise testing, and pulse amplitude tonometry (EndoPAT™). Patients were categorized in two groups based on their retrospectively calculated HFA-PEFF score. Serum concentrations of l-Arg, hArg, ADMA, SDMA, NT-proBNP, ET-1, MR-proADM, copeptin, and hsCRP were determined. Patients had a median age of 74 years, 47% were female, and median LVEF was 57%. Fifty-two patients (71%) had an HFA-PEFF score ≥ 5 (definitive HFpEF), and 21 patients (29%) a score of 3 to 4 (risk for HFpEF). Overall biomarker concentrations were 126 ± 32 µmol/L for l-Arg, 1.67 ± 0.55 µmol/L for hArg, 0.74 (0.60;0.85) µmol/L for SDMA, and 0.61 ± 0.10 µmol/L for ADMA. The median reactive hyperaemia index (RHI) was 1.55 (1.38;1.87). SDMA correlated with NT-proBNP (r = 0.291; P = 0.013), ET-1 (r = 0.233; P = 0.047), and copeptin (r = 0.381; P = 0.001). ADMA correlated with ET-1 (r = 0.250; P = 0.033) and hsCRP (r = 0.303; P = 0.009). SDMA was associated with the left atrial volume index (ß = 0.332; P = 0.004), also after adjustment for age, sex, and comorbidities. Biomarkers were non-associated with the RHI. A principal component analysis revealed two contrary clusters of biomarkers. CONCLUSIONS: Our findings suggest an impaired NO metabolism as one possible key pathogenic determinant in at least a subgroup of patients with HFpEF. We argue for further evaluation of NO-based therapies. Upcoming studies should clarify whether subgroups of HFpEF patients can take more benefit from therapies that are targeting NO metabolism and pathway.

Asymptomatic Left Ventricular Hypertrophy Is a Potent Risk Factor for the Development of HFpEF but Not HFrEF: Results of a Retrospective Cohort Study.

(1) Background: The structural and functional features of the natural history of asymptomatic hypertensive left ventricular hypertrophy (LVH) are not clearly defined. (2) Objective: To determine structural and functional changes in asymptomatic hypertensive LVH, as well as the incidence and predictors of the transition to different phenotypes of heart failure (HF) after a long-term follow-up. (3) Methods: Based on the assessment of chart reviews, we retrospectively selected 350 asymptomatic patients with hypertensive concentric LVH and LV ejection fraction (EF) ≥ 50%. After a median follow-up of 8.1 years, 223 patients had a re-assessment. The final diagnosis (HF with reduced EF [HFrEF], or HF with preserved EF [HFpEF]) was established according to current recommendations. (4) Results: After a follow-up, only 13% of patients remained asymptomatic, 72% developed HFpEF, and 15% developed HFrEF. The transition to HFpEF was associated with an increase in LV diastolic dysfunction grade in 62% of patients. Multivariable analysis identified age, duration of hypertension, interval changes in LV mass, and a lack of statin treatment as independent predictors of HFpEF. Among 34 patients who developed HFrEF, 16 patients (7% of the whole group) had no interval myocardial infarction, corresponding to an internal mechanism of systolic dysfunction. All these 16 patients had mild systolic dysfunction (LVEF > 40%). Baseline LVEF and LV end-diastolic dimension, and interval atrial fibrillation were identified as predictors of internal HFrEF. (5) Conclusions: The majority of patients with asymptomatic LVH developed HFpEF after long-term follow-up, which was associated with the deterioration of LV diastolic dysfunction and a lack of statin treatment. In contrast, the transition to HFrEF was infrequent and characterized by mild LV systolic dysfunction.

Peak O2 -pulse predicts exercise training-induced changes in peak V̇O2 in heart failure with preserved ejection fraction.

AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (V̇O2  × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2 , is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak V̇O2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak V̇O2 .

Left atrial strain predicts exercise capacity in heart failure independently of left ventricular ejection fraction.

AIMS: We hypothesized that left atrial (LA) remodelling and function are associated with poor exercise capacity as prognostic marker in chronic heart failure (CHF) across a broad range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: One hundred seventy-one patients with CHF were analysed [age 65 ± 11 years, 136 males (80%); 86 heart failure with reduced ejection fraction (HFrEF), 27 heart failure with mid-range ejection fraction (HFmrEF), 58 heart failure with preserved ejection fraction (HFpEF)]. All patients underwent echocardiography and maximal cardiopulmonary exercise testing and were classified according to a prognostic cut-off of peak VO2 (pVO2 ; 14 mL/kg/min). Seventy-seven (45%) patients reached pVO2  < 14 and 94 (55%) pVO2  ≥ 14 mL/kg/min. Between the two groups, there was a considerable difference in both left atrial volume (LAVi, 53 ± 24 vs. 44 ± 18 mL/m2 , P = 0.005) and function (LA reservoir strain 12 ± 5 vs. 20 ± 10%, P < 0.0001). Receiver-operating characteristic curves identified LA reservoir strain (area under the curve: 0.73 [0.65-0.80], P < 0.0001) as strong predictor for impaired pVO2 among all echocardiographic variables; LA reservoir strain < 23% had 37% specificity but a very high sensitivity (96%) in identifying a severely reduced pVO2 . In logistic regression analysis, LA reservoir strain < 23% was associated with a highly increased risk of pVO2  < 14 mL/kg/min (odds ratio 16.0 [4.7-54.6]; P < 0.0001). The multivariate analysis showed that a reduced LA reservoir strain was associated with pVO2  < 14 mL/kg/min after adjustment for age, body mass index (BMI), and clinical variables, that is, New York Heart Association class, atrial fibrillation, haemoglobin, and creatinine (b 0.22 [95% confidence interval, CI, 0.12-0.31]; P < 0.0001), and after adjustment for echocardiographic variables, that is, LVEF or left ventricular global longitudinal strain (LVGLS) and tricuspid annular plane systolic excursion (TAPSE) (b 0.16 [95% CI 0.08-0.24]; P < 0.0001). Patients with HFrEF, HFmrEF, and HFpEF were separately analysed. Among LA reservoir strain, LAVi, LVEF, LVGLS, and TAPSE, LA reservoir strain was the only one significantly associated with pVO2 in all subgroups (after adjustment for sex and BMI, P = 0.003, 0.04, and 0.01, respectively). CONCLUSIONS: In patients with CHF, an impaired LA reservoir function is independently associated with a severely reduced pVO2 . LA dysfunction represents a marker of poor prognosis across LVEF borders in the CHF population.

miR-181c level predicts response to exercise training in patients with heart failure and preserved ejection fraction: an analysis of the OptimEx-Clin trial.

AIMS: In patients with heart failure with preserved ejection fraction (HFpEF), exercise training improves the quality of life and aerobic capacity (peakV·O2). Up to 55% of HF patients, however, show no increase in peakV·O2 despite adequate training. We hypothesized that circulating microRNAs (miRNAs) can distinguish exercise low responders (LR) from exercise high responders (HR) among HFpEF patients. METHODS AND RESULTS: We selected HFpEF patients from the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx) study which attended ≥70% of training sessions during 3 months (n = 51). Patients were defined as HR with a change in peakV·O2 above median (6.4%), and LR as below median (n = 30 and n = 21, respectively). Clinical, ergospirometric, and echocardiographic characteristics were similar between LR and HR. We performed an miRNA array (n = 377 miRNAs) in 14 age- and sex-matched patients. A total of 10 miRNAs were upregulated in LR, of which 4 correlated with peakV·O2. Validation in the remaining 37 patients indicated that high miR-181c predicted reduced peakV·O2 response (multiple linear regression, ß = -2.60, P = 0.011), and LR status (multiple logistic regression, odds ratio = 0.48, P = 0.010), independent of age, sex, body mass index, and resting heart rate. Furthermore, miR-181c decreased in LR after exercise training (P-group = 0.030, P-time = 0.048, P-interaction = 0.037). An in silico pathway analysis identified several downstream targets involved in exercise adaptation. CONCLUSIONS: Circulating miR-181c is a marker of the response to exercise training in HFpEF patients. High miR-181c levels can aid in identifying LR prior to training, providing the possibility for individualized management.

The Predictive Value of Right Ventricular Longitudinal Strain in Pulmonary Hypertension, Heart Failure, and Valvular Diseases.

Right ventricular (RV) systolic function has an important role in the prediction of adverse outcomes, including mortality, in a wide range of cardiovascular (CV) conditions. Because of complex RV geometry and load dependency of the RV functional parameters, conventional echocardiographic parameters such as RV fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), have limited prognostic power in a large number of patients. RV longitudinal strain overcame the majority of these limitations, as it is angle-independent, less load-dependent, highly reproducible, and measure regional myocardial deformation. It has a high predictive value in patients with pulmonary hypertension, heart failure, congenital heart disease, ischemic heart disease, pulmonary embolism, cardiomyopathies, and valvular disease. It enables detection of subclinical RV damage even when conventional parameters of RV systolic function are in the normal range. Even though cardiac magnetic resonance-derived RV longitudinal strain showed excellent predictive value, echocardiography-derived RV strain remains the method of choice for evaluation of RV mechanics primarily due to high availability. Despite a constantly growing body of evidence that support RV longitudinal strain evaluation in the majority of CV patients, its assessment has not become the part of the routine echocardiographic examination in the majority of echocardiographic laboratories. The aim of this clinical review was to summarize the current data about the predictive value of RV longitudinal strain in patients with pulmonary hypertension, heart failure and valvular heart diseases.

Case Report: Assessing the Position of Pacemaker Leads via Transthoracic Echocardiography: Additional Value of the Subcostal En Face View.

There is an association between presence of cardiac implantable electronic devices (CIED) and development of tricuspid regurgitation (TR). Mechanisms proposed to explain CIED-induced TR can be classified as implantation-related, lead-related, and pacing-related. Lead-related TR results from the direct interaction of the lead with the tricuspid valve (TV). The localization of the lead at the TV level directly influences the probability of subsequent development of significant TR. A transthoracic subcostal en face view of the TV can be acquired in most patients through a 90° rotation from the subcostal 4-chamber view with clear anatomic delineation of the TV and the commissures including lead position. This case-series presents three examples where the transthoracic en face view could add incremental information on the position of the pacemaker leads and on the mechanism of TR. Conclusion: When performing transthoracic echocardiography in patients with trans-tricuspid CIED lead(s), an en face view of the TV with exact reporting of the position of the lead(s) should be included.

The Prognostic Importance of Right Ventricular Longitudinal Strain in Patients with Cardiomyopathies, Connective Tissue Diseases, Coronary Artery Disease, and Congenital Heart Diseases.

Right ventricular (RV) systolic function represents an important independent predictor of adverse outcomes in many cardiovascular (CV) diseases. However, conventional parameters of RV systolic function (tricuspid annular plane excursion (TAPSE), RV myocardial performance index (MPI), and fractional area change (FAC)) are not always able to detect subtle changes in RV function. New evidence indicates a significantly higher predictive value of RV longitudinal strain (LS) over conventional parameters. RVLS showed higher sensitivity and specificity in the detection of RV dysfunction in the absence of RV dilatation, apparent wall motion abnormalities, and reduced global RV systolic function. Additionally, RVLS represents a significant and independent predictor of adverse outcomes in patients with dilated cardiomyopathy (CMP), hypertrophic CMP, arrhythmogenic RV CMP, and amyloidosis, but also in patients with connective tissue diseases and patients with coronary artery disease. Due to its availability, echocardiography remains the main imaging tool for RVLS assessment, but cardiac magnetic resonance (CMR) also represents an important additional imaging tool in RVLG assessment. The findings from the large studies support the routine evaluation of RVLS in the majority of CV patients, but this has still not been adopted in daily clinical practice. This clinical review aims to summarize the significance and predictive value of RVLS in patients with different types of cardiomyopathies, tissue connective diseases, and coronary artery disease.

Left atrial function and maximal exercise capacity in heart failure with preserved and mid-range ejection fraction.

AIMS: Exercise intolerance is the leading manifestation of heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF), and left atrial (LA) function might contribute to modulating left ventricular filling and pulmonary venous pressures. We aim to assess the association between LA function and maximal exercise capacity in patients with HFpEF or HFmrEF. METHODS AND RESULTS: Sixty-five patients, prospectively enrolled in the German HFpEF Registry, were analysed. Inclusion criteria were New York Heart Association functional class ≥ II, left ventricular ejection fraction > 40%, structural heart disease or diastolic dysfunction, and elevated levels of N terminal pro brain natriuretic peptide (NT-proBNP). LA function was evaluated through speckle-tracking echocardiography by central reading in the Charité Academic Echocardiography core lab. All patients underwent maximal cardiopulmonary exercise test and were classified according to a peak VO2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO2  < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO2  ≥ 14 mL/kg/min (mean value 19.4 ± 3.9). There was no significant difference in left ventricular ejection fraction (60 ± 9 vs. 59 ± 8%), left ventricular mass (109 ± 23 vs. 112 ± 32 g/m2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m2 ), or E/e´ (13.1 ± 4.7 vs. 13.0 ± 6.0) between these groups. In contrast, all LA strain measures were impaired in patients with lower peak VO2 (reservoir strain 14 ± 5 vs. 21 ± 9%, P = 0.002; conduit strain 9 ± 2 vs. 13 ± 4%, P = 0.001; contractile strain 7 ± 4 vs. 11 ± 6%, P = 0.02; reported lower limits of normality for LA reservoir, conduit and contractile strains: 26.1%, 12.0%, and 7.7%). In linear regression analysis, lower values of LA reservoir strain were associated with impaired peak VO2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [ß 0.29, 95% confidence interval (CI) 0.02-0.30, P = 0.02], with an odds ratio 1.22 (95% CI 1.05-1.42, P = 0.01) for peak VO2  < 14 mL/kg/min for LA reservoir strain decrease after adjustment for these five covariates. Adding left ventricular ejection fraction, it did not influence the results. On the other hand, the addition of LA strain to the adjustment parameters alone described above provided a significant increase of the predictive value for lower peak VO2 values (R2 0.50 vs. 0.45, P = 0.02). With receiver operating characteristic curve analysis, we identified LA reservoir strain < 22% to have 93% sensitivity and 49% specificity in predicting peak VO2  < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO2  < 14 mL/kg/min in logistic regression analysis after comprehensive adjustment for age, sex, body mass index, heart rhythm, and log-NTproBNP [odds ratio 95% CI 10.4 (1.4-74), P = 0.02]. CONCLUSIONS: In this HFpEF and HFmrEF cohort, a reduction in LA reservoir strain was a sensible marker of decreased peak exercise capacity. Therefore, LA reservoir strain might be of clinical value in predicting exercise capacity in patients with HFpEF or HFmrEF.