In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) and right ventricular (RV) dysfunction are frequent and have important impact on disease progression, morbidity, and mortality, and therefore warrant clinical attention. Pulmonary hypertension related to left heart disease (LHD) by far represents the most common form of PH, accounting for 65-80% of cases. The proper distinction between pulmonary arterial hypertension and PH-LHD may be challenging, yet it has direct therapeutic consequences. Despite recent advances in the pathophysiological understanding and clinical assessment, and adjustments in the haemodynamic definitions and classification of PH-LHD, the haemodynamic interrelations in combined post- and pre-capillary PH are complex, definitions and prognostic significance of haemodynamic variables characterizing the degree of pre-capillary PH in LHD remain suboptimal, and there are currently no evidence-based recommendations for the management of PH-LHD. Here, we highlight the prevalence and significance of PH and RV dysfunction in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), and provide insights into the complex pathophysiology of cardiopulmonary interaction in LHD, which may lead to the evolution from a 'left ventricular phenotype' to a 'right ventricular phenotype' across the natural history of HF. Furthermore, we propose to better define the individual phenotype of PH by integrating the clinical context, non-invasive assessment, and invasive haemodynamic variables in a structured diagnostic work-up. Finally, we challenge current definitions and diagnostic short falls, and discuss gaps in evidence, therapeutic options and the necessity for future developments in this context.

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Left ventricular heart failure and pulmonary hypertension.

Heart failure with preserved ejection fraction

Pulmonary hypertension due to left heart disease.

Background —In non-randomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), less symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and mid-range or preserved ejection fraction (EF ≥ 40%). We conducted the first randomized, sham-controlled trial to evaluate the IASD in HF with EF ≥ 40%. Methods —REDUCE LAP-HF I was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, EF ≥ 40%, exercise PCWP ≥ 25 mmHg, and PCWP-right atrial pressure gradient ≥ 5 mmHg. Participants were randomized (1:1) to the IASD vs. a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. PCWP during exercise was compared between treatment groups using a mixed effects repeated measures model analysis of covariance that included data from all available stages of exercise. Results —A total of 94 patients were enrolled, of which n=44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared to sham-control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mmHg in the treatment group vs. 0.5±5.0 mmHg in the control group (P=0.14). There were no peri-procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). Conclusions —In patients with HF and EF ≥ 40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. Clinical Trial Registration —URL: http://clinicaltrials.gov. Unique identifier: NCT02600234

Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial.

As part of this series devoted to heart failure (HF), we review the epidemiology, diagnosis, pathophysiology, and treatment of HF with preserved ejection fraction (HFpEF). Gaps in knowledge and needed future research are discussed.

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Cardiac remodeling is a fundamental part of the heart failure (HF) syndrome, representing a common response to various pathological stimuli that result in changes in the structural and functional properties of the heart. To date, most studies in HF have focused on ventricular remodeling, and much less emphasis has been placed on atrial structural and functional changes. Specifically, in the context of HF with preserved ejection fraction (HFpEF), more attention has recently been placed on the left atrial (LA) remodeling, which is now considered a potential therapeutic target and an end point for evaluation of novel therapies. In this review, we discuss the pathophysiologic and clinical implication of LA remodeling in HFpEF.

Left atrium is a thin-walled structure located in the inflow path from the pulmonary veins to the left ventricle (LV) and is characterized by (a) main body with smooth walls that embryologically is developed from the outgrowth of the pulmonary veins and (b) by a finger-like trabeculated appendage, which is a remnant of the original embryonic left atrium.1 Distribution of atrial myocyte fibers is highly variable, but some components are relatively constant. In particular, the Bachmann’s bundle is the most superficial group of circumferential myofibers located close to the atrioventricular groove. In this bundle, the electric conduction from right to LA preferentially occurs. Other myocardial longitudinal fibres are likely responsible for upward motion of mitral annulus during atrial contraction.

### Mechanical Function

The mechanical function of LA is usually defined by 3 phases of LA volume variations during the cardiac cycle. The reservoir phase takes place during ventricular systole when the LA collects blood coming from the pulmonary veins. This phase is mechanistically determined by LA relaxation and by LV contraction, which moves the mitral annulus toward the apex, resulting in increased LA volume.2 Atrial compliance allows chamber volume …

Andrea Rossi

Papers

Left atrium in heart failure with preserved ejection fraction: structure, function, and significance