The findings from this study provide important insights regarding the potential usefulness and clinical relevance of adding LA strain to LAVI in the detection of LVDD in patients with preserved LVEF.

Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle-brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first-line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first-line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted.

Heart failure with preserved ejection fraction (HFpEF) is a common disease with high incidence and increasing prevalence. Patients suffer from functional limitation, poor health-related quality of life, and reduced prognosis. A pilot study in a smaller group of HFpEF patients showed that structured, supervised exercise training (ET) improves maximal exercise capacity, diastolic function, and physical quality of life. However, the long-term effects of ET on patient-related outcomes remain unclear in HFpEF. The primary objective of the Exercise training in Diastolic Heart Failure (Ex-DHF) trial is to investigate whether a 12 month supervised ET can improve a clinically meaningful composite outcome score in HFpEF patients. Components of the outcome score are all-cause mortality, hospitalizations, NYHA functional class, global self-rated health, maximal exercise capacity, and diastolic function. After undergoing baseline assessments to determine whether ET can be performed safely, 320 patients at 11 trial sites with stable HFpEF are randomized 1:1 to supervised ET in addition to usual care or to usual care alone. Patients randomized to ET perform supervised endurance/resistance ET (3 times/week at a certified training centre) for 12 months. At baseline and during follow-up, anthropometry, echocardiography, cardiopulmonary exercise testing, and health-related quality of life evaluation are performed. Blood samples are collected to examine various biomarkers. Overall physical activity, training sessions, and adherence are monitored and documented throughout the study using patient diaries, heart rate monitors, and accelerometers. The Ex-DHF trial is the first multicentre trial to assess the long-term effects of a supervised ET programme on different outcome measures in patients with HFpEF.

AimsThe purpose of this pilot study was to assess the potential usefulness of diastolic stress test (DST) echocardiography in patients with suspected heart failure with preserved ejection fraction (HFpEF).Methods and resultsPatients with suspected HFpEF (left ventricular ejection fraction ≥ 50%, exertional dyspnoea, septal E/e′ at rest 9–14, and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) at rest < 220 pg/mL; n = 13) and a control group constituted from asymptomatic patients with arterial hypertension (n = 19) and healthy subjects (n = 18) were included. All patients were analysed by two‐dimensional and Doppler echocardiography at rest and during exercise (DST) and underwent cardiopulmonary exercise testing and NT‐proBNP analysis during exercise. HFpEF during exercise was defined as exertional dyspnoea and peak VO2 ≤ 20.0 mL/min/kg. In patients with suspected HFpEF at rest, 84.6% of these patients developed HFpEF during exercise, whereas in the group of asymptomatic patients with hypertension and healthy subjects, the rate of developed HFpEF during exercise was 0%. Regarding the diagnostic performance of DST to detect HFpEF during exercise, an E/e′ ratio >15 during exercise was the most accurate parameter to detect HFpEF (accuracy 86%), albeit a low sensitivity (45.5%). Nonetheless, combining E/e′ with tricuspid regurgitation (TR) velocity > 2.8 m/s during exercise provided a significant increase in the sensitivity to detect patients with HFpEF during exercise (sensitivity 72.7%, specificity 79.5%, and accuracy 78%). Consistent with these findings, an increase of E/e′ was significantly linked to worse peak VO2, and the combination of an increase of both E/e′ and TR velocity was associated with elevated NT‐proBNP values during exercise.ConclusionsThe findings of this pilot study suggest that DST using E/e′ ratio and TR velocity could be of potential usefulness to diagnose HFpEF during exercise in patients with suspected HFpEF at rest.

Left ventricular filling pressure (LVFP) is a marker for diastolic dysfunction and heart failure (HF) with preserved ejection fraction (pEF). The interaction between arterial stiffness (AS) and elevated LVFP has not been sufficiently investigated. In 257 patients with preserved left ventricular ejection fraction (mean age: 66 years, 53% female, mean left ventricular ejection fraction: 61%) and at least one cardiovascular risk factor (eg, hypertension and diabetes) for the development of HF or a previous diagnosis of HF, LVFP was estimated in accordance with the recommendations of the American Society of Echocardiography (elevated when E/e' ≥ 13, left atrial volume index ≥ 34 mL/m). LVFP was correlated with radial pulse wave analysis (augmentation index normalized by 75 b/min [AIx@75]) and carotid-femoral pulse wave velocity (cfPWV). Thirty-eight percent of patients demonstrated an elevated LVFP. These patients were significantly older (68.3 ± 7.4 vs. 63.5 ± 7.6 years, P < .001), demonstrated a higher body mass index (29.8 ± 4.6 vs. 28.0 ± 5.0; P < .01), presented more often with hypertension (89.7% vs. 73.1%, P < .01), hypercholesterolemia (32.0% vs. 21.3%, P < .05), dyspnea on exertion (28.4% vs. 16.6%, P < .05), and peripheral edema (25.3% vs. 10.2%, P < .01). cfPWV and AIx@75 and were significantly elevated in patients with elevated LVFP (12.2 ± 2.7 m/s vs. 10.5 ± 2.6 m/s, P < .001, an 29.2 ± 6.7% vs. 27.4 ± 6.7%, P < .05 respectively). cfPWV and AIx@75 were correlated with echocardiographic parameters, that is, posterior wall thickness (r = 0.292, P < .001; r = 0.167, P < .01), left ventricular mass index (r = 0.255, P < .001; r = -0.192, P < .01), e' (r = -0.508, P < .001; r = -0.159, P < .05), and E/e' (r = 0.380, P < .001; r = 0.200, P < .01). cfPWV correlated with left atrial volume index (r = 0.189, P < .05) and increasing E/A ratio (r = -0.334, P < .001). Multivariate linear regression analysis demonstrated age and PWV as most important and independent predictors of LVFP elevation in the cohort. Increased AS measured by cfPWV was associated with an elevated LVFP in patients with preserved systolic function. Whether targeting AS as a major component of diastolic dysfunction and HF with preserved ejection fraction needs to be further investigated.

In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted.

AimsHeart failure with preserved ejection fraction (HFpEF) remains a common condition with no pharmacological treatment. Physical activity (PA) improves symptoms and quality of life (QoL), but no clear recommendations exist on PA in HFpEF patients. We investigated the association of PA (amount/intensity) on clinical phenotype in HFpEF.Methods and resultsThe Aldosterone in Diastolic Heart Failure trial investigated spironolactone vs. placebo in stable HFpEF patients. At baseline, all patients underwent detailed phenotypization including echocardiography, cardiopulmonary exercise testing, 6 minute walking test (6MWT), and QoL assessment (36‐item Short‐Form questionnaire). PA was assessed by a self‐report questionnaire, classified in metabolic equivalents of task (MET) and analysed with regard to exercise capacity, diastolic function, and QoL. Four hundred twenty‐two patients (52% women, age 67 ± 8 years, New York Heart Association II and III) were classified by weekly MET hours into a low (<70), middle (70–140), or high (>140) level of PA. Total PA correlated positively with 6MWT distance (r = 0.17; P = 0.002) and physical function of QoL (r = 0.10; P = 0.05), but not with peak oxygen uptake (peakVO2). In contrast, both 6MWT distance and peakVO2 were significantly higher in patients who performed high‐intensity PA for >8 h/week (P < 0.001, P = 0.02, respectively). Time of high‐intensity PA was related to higher 6MWT distance (r = 0.21, P < 0.001), peakVO2, and better physical function of QoL (both r = 0.13, P = 0.01), whereas low‐intensity PA did not show significant associations. Interestingly, PA was not related to any measure of diastolic function.ConclusionsA higher amount of PA is related to higher submaximal exercise capacity and physical function of QoL. Regarding maximal exercise capacity, only high‐intensity PA showed significant association in HFpEF patients.

The prevalence of peripheral arterial disease (PAD) is on the rise in an aging population, significantly affecting quality of life, morbidity and mortality. Besides medical treatment and surgical or interventional revascularization, supervised exercise programs are a primary treatment modality for PAD. Training may significantly increase pain-free walking time (+ 180 %) while avoiding the associated complications of (repeated) invasive revascularization. Training effects rely on an improvement of risk factor management, muscle function, economy of movement, hemorheology, vascular growth and collateral vessel growth. Exercise training upregulates pulsatile fluid shear stress on the vascular endothelium, prompting an improvement of endothelial function (eNOS, NO) and an outgrowth of preexistent collaterals (arteriogenesis) to functional conductance arteries outside the ischemic area at risk. However, the necessary intense minimum training intervals compromise patient compliance, and the impaired functional status of many PAD patients limits active exercise training. Strategies are necessary to a) increase training compliance, b) make the benefits of exercise training available to patients unable to exercise actively and c) therapeutically enhance the adaptive growth of biological bypasses (arteriogenesis). A modified form of “passive exercise training” derived from enhanced external counterpulsation (low-pressure ECP) which was originally developed for the therapy of heart failure, may prove to be an option for this group of patients. Therefore, this review article suggests a tailored combination therapy, consisting of a facilitating revascularization procedure to restore arterial inflow, succeeded by supervised exercise training, which has yielded promising therapeutic results in clinical trials. Further studies, using appropriate imaging methods and controls, are under way to (a) establish the efficacy of low-pressure EECP in PAD patients and (b) to directly correlate training-induced improvements of collateral flow to the functional improvements seen with exercise training.