Background Diagnosis of early heart failure with preserved ejection fraction (HFpEF) may be challenging because exertional dyspnea is not specific for heart failure, and biomarkers and indicators of volume overload may be absent at rest. We aimed to characterize the contribution of abnormal left atrial (LA) mechanical properties to exercise intolerance in early HFpEF (normal left ventricular filling pressures at rest but elevated during exercise). Methods Diastolic stress testing (DST) was performed in 104 patients with left ventricular ejection fraction ≥50%, in sinus rhythm, and no more than LV diastolic dysfunction grade I, referred for assessment of exertional dyspnoea. Patients exercised supine cycle ergometry at 60 rpm starting with a 3-min period of low-level 25-W workload followed by 25-W increments in 3-minute stages to maximum tolerated levels. According to DST, 43 patients were diagnosed with HFpEF (average mitral E-to-annular e′ ratio [E/e′] > 14, and peak TR velocity >2.8 m/sec at maximal exertion) and 61 as non-cardiac dyspnea (NCD). During the test, two-dimensional images, mitral E/e′, peak tricuspid regurgitation (TR) velociry, and two-dimensional LA mechanical parameters (longitudinal LA strain [LASR] and strain rate [LASRR] during reservoir phase and LA stiffness assessed as a ratio of mitral E/e′ ratio to LASR) were analysed at baseline, and at peak. Results HFpEF and NCD patients were similar in regard to the LA volume index (34.4 [30.2;39.4] vs. 33.6 [28.4;37.1] ml/m2), and NT-proBNP level (132 [80;238] vs. 129 [80;197] pg/ml). As compared with NCD patients, HFpEF patients displayed reduced LA reservoir function assessed by LASR (22.3 [18.9;25.6] vs. 24.2 [21.2;29.8] % at rest, and 25.3 [21.4;30.2] vs. 29.0 [24.2;33.3] % with exercise) and LASRR (0.78 [0.58;0.96] vs. 0.90 [0.68;1.12] /s at rest, and 1.10 [0.79;1.31] vs. 1.24 [1.03;1.56] s–1 with exercise) with increased LA stiffness (0.57 [0.44;0.70] vs. 0.42 [0.30;0.49] mmHg/% at rest, and 0.61 [0.46;0.74] vs. 0.40 [0.32;0.51] mmHg/% with exercise, all P < 0.05). Additionally, HFpEF patients showed smaller exercise elevation in LASRR (+31 [-5;77] vs. +47 [12;85] % as compared with resting values, P < 0.05). Exercised LA stiffness and reservoir strain correlated with exercise LV filling pressures estimated by mitral E/e′ ratio (r = 0.72 and r =–0.35, P < 0.001). LA stiffness showed a good diagnostic accuracy (area under the curve 0.75), and LA stiffness > 0.46 mmHg/% demonstrated reasonable sensitivity (79%) and specificity (71%) to diagnose HFpEF. Neither LV global longitudinal strain and ejection fraction at rest nor their exercise-induced elevation differed between HFpEF and NCD. Conclusion Impaired LA reservoir function and increased stiffness are associated with exercise intolerance in patients with early HFpEF, while LV systolic function seems preserved in this stage of the disease. LA stiffness provides HFpEF diagnostic potential in ambulatory patients with dyspnea

Anthracycline-induced cardiomyopathy (AC-CMP) is more resistant or even refractory to conventional heart failure (HF) treatments and has a higher mortality rate as compared to HF associated with other diseases. Sacubitril/valsartan (S/V) significantly reduces cardiovascular mortality and hospitalization rate in HF patients with reduced left ventricular ejection fraction (HFrEF). There is lack of evidence of S/V efficacy and safety in patients with AC-CMP. We aimed to assess the efficacy and tolerability of S/V in patients with AC-CMP. Methods We enrolled 20 patients with anthracycline-induced HFrEF who met the indication criteria for S/V. Median age was 61 [51.5; 67], 100% women, 8 (40%) hypertensive, 1 (5%) diabetic. Seventeen (85%) patients had breast and 3 (15%) hematological cancers. Median time from anthracycline therapy was 3 [1; 11] years. Surgery due to cancer and radiation therapy were performed in 15 (75%) cases. All patients had been receiving ACE inhibitors or angiotensin II receptor blockers and were switched to S/V. 85% of patients were treated with beta-blockers, 60% – mineralocorticoid antagonists, 50% – loop diuretics. The exam (at admission and after 6 months) included 6-MWT, echo/speckle tracking, creatinine, potassium and NTproBNP level. Results Eleven (55%) patients achieved the target dose of S/V. The mean S/V dose was 289±149.1 mg. Symptomatic hypotension, hyperpotassemia or creatinine level elevation were the reasons for S/V dose reduction in 8, 1 and 2 patients, respectively. S/V wasn't withdrawn in any patient. No hospitalization due to HF or need for loop diuretics increase occurred during the follow-up. After 6 months 6-MWD increased from 416 [347.5; 477.5] to 465 [395; 513.5] m, p=0.0004. NYHA functional class improved in 50% of patients. We revealed LVEDVI decrease (61.7 [55.9; 71.6] to 57.1 [53.4; 60.1] ml/m2 p=0.002), LVEF and GLS increase (39 [34.7; 41] to 45 [39; 47]%, p=0.001 and 11 [8.7; 13.9] to 13.4 [11.9; 15.5]%, p=0.002, respectively), LAVI decrease (40.7 [32; 43.9] to 31.3 [28.6; 37.4] ml/m2, p=0.003), E/A and E/e ratios decrease (1.37 [0.7; 2.23] to 0.69 [0.64; 0.83], p=0.04, and 13 [11.3; 17.8] to 10.7 [6.9; 13.6], p=0.01, respectively). NTproBNP blood level declined from 1659 [1090; 2316] to 377 [206.8; 920] pg/ml, p<0.001. There was change in serum creatinine level but in normal ranges (from 70.3 [66.8; 80; 6] to 77 [68.6; 96.3] micromol/l, p=0.02). No significant changes in potassium level were observed. Conclusions In this pilot study S/V was well tolerated in patients with AC-CMP, but cardiologic assessment was needed for accurate dose adjustment. Therapy with S/V was associated with improvement in HF functional class and LV systolic and diastolic function as well as neurohumoral status in patients with AC-CMP. Funding Acknowledgement Type of funding source: None

During exercise an increase in oxygen delivery to working muscles is achieved through well‑coordinated interaction of many organs and systems: the heart, lungs, blood vessels, skeletal muscles, and the autonomic nervous system. In heart failure with preserved left ventricular ejection fraction, all mechanisms involved in the normal exercise tolerance are impaired. In the first part of this review, the impairments of the left heart chambers are considered ‑ left ventricular diastolic dysfunction, the weakening of the contractile and chronotropic reserves, left atrium dysfunction; the possible ways of their medical correction are also presented.

The main clinical manifestation of heart failure with preserved ejection fraction is poor exercise tolerance. In addi-tion to the dysfunction of the left heart chambers, which were presented in the first part of this review, many other disorders are involved in poor exercise tolerance in such patients: impairments of the right heart, vascular system and skeletal muscle. The second part of this review presents the mechanisms for the development of these disorders, as well as possible ways to correct them.