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.

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.

Phosphodiesterase 5 inhibitor sildenafil in patients with heart failure with preserved ejection fraction and combined pre- and postcapillary pulmonary hypertension: a randomized open-label pilot study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH). METHODS: We enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg. RESULTS: The patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, - 3.3 to - 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group. CONCLUSIONS: In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH. TRIAL REGISTRATION: Russian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849 . Registered 20 April 2012. This manuscript adheres to the CONSORT guidelines.

Right heart masses in a patient with endometrial stromal sarcoma.

We present the case of a 61-year-old woman with a large tumoral infiltration extending from the pelvis throughout the inferior vena cava inferior to the right atrium, protruding into the right ventricle and right ventricular outflow tract. She had been treated 10 years before for low-grade endometrial stromal sarcoma by hysterectomy and adnexectomy followed by hormone- and radio-therapy. Due to cancer recurrence, she underwent peritonectomy, appendectomy, and resection of terminal ileum.

Intriguing relationship between antihypertensive therapy and cancer.

Arterial hypertension is the most frequent cardiovascular risk factor in the cancer patients. Anti-cancer therapy very often induces arterial hypertension and the treatment with antihypertensive medications is inevitable. Additionally, anti-cancer therapy frequently induces cardiotoxicity that has been treated or even could be prevented by use of antihypertensive medications - primarily angiotensin converting enzyme inhibitors and beta-blockers. The association between antihypertensive drugs and cancer is matter of large debate in the last several years because of the conflicting results from available studies ranging from adverse to beneficial effect of various antihypertensive classes. The mechanisms of the relationship between antihypertensives and cancer are still in domain of hypothesis. Some studies described the association between different antihypertensive groups and malignancies. There are investigations that denied negative effects of antihypertensive medications on cancer occurrence, recurrence, cancer-related complications and mortality. On the other hand, there are researches that reported a beneficial effect of antihypertensive medication by decreasing mortality in the cancer patients. One should be aware of the discrepancy of investigated antihypertensives in these researches and heterogeneity of included patients - different age, cancer type, comorbidities, demographic characteristics, and anti-cancer therapy. This comprehensive review article aimed to summarize the current knowledge regarding the relationship between antihypertensive medications and cancer.

Low-grade inflammation and tryptophan-kynurenine pathway activation are associated with adverse cardiac remodeling in primary hyperparathyroidism: the EPATH trial.

BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters. METHODS: Cross-sectional baseline data from the "Eplerenone in Primary Hyperparathyroidism" trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e'. RESULTS: Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e' as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted ß-coefficient=0.193, p=0.030) and QUIN (ß=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (ß=0.315, p<0.001), kynurenine (ß=0.256, p=0.005) and QUIN (ß=0.213, p=0.044). E/e' was related with kynurenine (ß=0.221, p=0.022) and QUIN (ß=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters. [Correction added after online publication (22 April 2017: The sentence "Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy." was corrected to "Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%."] Conclusions: Cardiac remodeling is common in pHPT and is associated with low-grade inflammation and activation of the tryptophan-kynurenine pathway. The potential role of kynurenine and QUIN as cardiovascular risk factors may be further investigated in future studies.

Clinical Relevance of Left Atrial Strain to Predict Recurrence of Atrial Fibrillation after Catheter Ablation: A Meta-Analysis.

BACKGROUND: The purpose of this meta-analysis was to analyze the clinical relevance of left atrial (LA) strain to predict recurrence of atrial fibrillation (AF) after catheter ablation (CA). METHODS AND RESULTS: We searched in different databases (Medline, EMBASE, and Cochrane) prospective studies that analyzed LA strain before CA. Eight studies (2 with only paroxysmal AF and 6 with mixed population of paroxysmal and persistent AF) were included in the final analysis (total patient number = 686). Patients with recurrence of AF were principally characterized by lower LA strain in comparison with those without AF recurrence (mean 18.4% [range 8.8-24.5%] versus 25.3% [13.6-32.7%], weighted mean difference -4.89% [95% CI -5.83% to -3.95%], P < 0.001). In addition, receiver operating curves shown that LA strain was strongly associated with recurrence of AF after CA (weighted mean: AUC 0.798 [95% CI 0.700-0.943], cutoff 22.8% [18.8-30%], sensitivity 78% [65-86%], and specificity 75% [66-100%]). In line, these results were similar using LA strain with QRS-analysis and P-analysis as well as using different software package such as Echo-Pac, QLab, TomTec, and VVI. CONCLUSION: In patients with AF candidate for CA, the analysis of the LA using LA strain could be of great usefulness to identify patients with high risk of AF recurrence. Nonetheless, further studies are needed to establish the clinical relevance of LA strain in patients with persistent AF.

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.

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.

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.

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.

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.

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.

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 .

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.