Nishimura, Rick

Abstract Background and Aims Decrease in pulmonary vascular resistance (PVR) during exercise confers favourable prognosis in biventricular physiology, but its role in Fontan circulation remains unknown. This study aimed to evaluate the prognostic value of PVR index (PVRI) response to exercise in adults post-Fontan palliation. Methods Retrospective cohort of 88 adults (age ≥18 years) post-Fontan undergoing exercise (supine cycling) cardiac catheterization. Patients were categorized into absence (n = 23) or presence (n = 65) of exercise-induced reduction in PVRI. The clinical endpoint was a composite of death or transplantation. Results Age at catheterization was 32.2 ± 8.8 years, and 45.5% were female. Resting and exercise PVRI were 1.9 ± 0.9 and 1.2 (interquartile range [IQR] 0.8–2.1) WU·m2, respectively. Clinical, biochemical and echocardiographic parameters were not associated with PVRI response to exercise. During a follow-up of 2.2 ± 1.4 (IQR 1.2–2.6) years, resting PVRI was not associated with the clinical endpoint (hazard ratio [HR] 0.95 per WU·m2, 95% confidence interval [CI] 0.52–1.74; P = 0.86), whereas exercise PVRI was (HR 2.15 per WU·m2, 95% CI 1.24–3.73; P = .007). Exercise PVRI remained predictive of outcomes after adjusting for exercise pulmonary artery wedge pressure (HR 2.08 per WU·m2, 95% CI 1.19–3.62; P = .01) or clinical risk factors individually. Two-year event-free survival was lower in the no PVRI reduction than in the reduction group (67% vs 95%; P < .001). Conclusions In adults post-Fontan, PVRI response to exercise is a robust predictor of clinical outcomes and offers additive prognostic information beyond resting invasive haemodynamic data and clinical risk factors, underscoring the importance of invasive exercise testing in this population.

Background Exercise cardiac catheterization is the gold standard for diagnosing diastolic dysfunction and impaired pulmonary reserve in patients with Fontan circulation. The diagnostic value of noninvasive parameters is unclear. Methods Patients who underwent simultaneous exercise hemodynamic evaluation and peripheral venous pressure (PVP) measurement were included. Echocardiographic surrogates for ventricular filling pressure were compared with invasive measures. Diastolic dysfunction was defined invasively as either resting pulmonary artery wedge pressure ≥12 mm Hg or exercise pulmonary artery wedge pressure >20 mm Hg. Results Twenty‐nine patients were included. Age at catheterization was 34±9 years. Atrioventricular valve systole‐to‐diastole duration ratio (S/D) and resting PVP were significant predictors of resting pulmonary artery wedge pressure (S/D: β=0.71 per 0.1 S/D [95% CI, 0.16–1.25]; P =0.01; PVP: β=0.68 per mm Hg [95% CI, 0.41–0.96]; P <0.001). By contrast, resting PVP was a predictor of diastolic dysfunction, whereas S/D was not. Based on these data, we proposed a 2‐tier assessment algorithm with the first tier considering resting PVP ≤15 mm Hg and S/D ≤1.1 and the second tier considering exercise PVP ≤25 mm Hg in those with 1 elevated resting parameter. This algorithm showed a positive predictive value of 88% (95% CI, 47%–100%), a negative predictive value of 90% (95% CI, 70%–99%), a sensitivity of 78% (95% CI, 40%–97%), and a specificity of 95% (95% CI, 75%–100%). Exercise PVP indexed to peak oxygen consumption also predicted invasively measured exercise pulmonary vascular resistance index (β=0.36 WU·m 2 per mm Hg/100 mL per min [95% CI, 0.08–0.64]; P =0.01). Conclusions This study presents a simple, noninvasive approach for evaluating diastolic function and pulmonary vascular reserve in patients with a Fontan circulation.

Background: Group 1 pulmonary artery hypertension (PAH) is treated with three main drug classes: prostacyclin analogs (PCAs), endothelin receptor antagonists, and nitric oxide pathway drugs. PCAs may be administered via parenteral (intravenous (IV), subcutaneous (SQ)) or oral/inhaled routes. The role of parenteral versus non-parenteral PCAs in contemporary PH practice remains unclear. Objectives: To compare contemporary hemodynamic and survival outcomes between parenteral and non-parenteral PCA use. Methods: This retrospective study included patients with WHO Group 1 PAH, who underwent a right heart catheterization (RHC) at Mayo Clinic. Diagnosis required mPAP was ≥25 mm Hg, documented chart diagnosis and initiation of PAH therapy. Echocardiographic and repeat RHC parameters were collected and only patients started on PCA therapy were included. Patients were grouped based on intiiated PCA route: parenteral (IV/SQ) vs non-parenteral routes (oral/inhaled). Hemodynamic changes (post-pretreatment) were compared using t-tests and ANOVA for parenteral vs non-parenteral PCA. Survival was assessed using Kaplan-Meier curves, and Cox proportional hazards models. Results: Of 144 patients initiated on PCA after the first RHC, 89 (62%) received parenteral and 55 (38%) non-parenteral PCA.. At baseline, patients who started on parenteral PCA had more severe disease with higher mean PAP, RAP and PVR. On follow-up, parenteral PCAs led to greater reductions in mean PAP and RAP, with no differences in PVR, TPR, or CO changes. Survival was worse with parenteral PCA use even after adjusting for comorbidities and baseline hemodynamics (HR 1.93; 95% CI 1.17-3.18; p=0.009). Discussion: Parenteral PCAs were more often used in patients with more severe pulmonary vascular disease. Despite greater hemodynamic improvements, parenteral PCAs were associated with worse survival, likely due to more severe disease at baseline. Further research is needed to understand the role of PCA route in guiding treatment strategies.

Background: Heart failure (HF) is the leading cause of mortality in adults with congenital heart disease (CHD) after transcatheter pulmonary valve replacement (TPVR), likely due to preexisting myocardial dysfunction and suboptimal reverse remodeling. Left ventricular (LV) diastolic dysfunction, unmasked by an acute increase in preload post-TPVR, may elevate left-sided filling pressures and precipitate pulmonary edema. However, the prognostic implications of elevated left-sided filling pressures prior to TPVR are currently unknown. Objective: To evaluate the prognostic value of pre-TPVR pulmonary artery wedge pressure (PAWP) and the heart failure with preserved ejection fraction – Age, Body mass index (BMI), Atrial fibrillation (HFpEF-ABA) score in patients undergoing TPVR. Methods: Adults with congenital heart disease (CHD) undergoing TPVR were stratified by pre-implant PAWP (<15 vs ≥15 mmHg) and HFpEF-ABA score (low <25%, intermediate 25–75%, high >75%). The composite endpoint was all-cause mortality, heart transplantation, heart failure (HF) hospitalization, or sustained ventricular arrhythmia. Kaplan-Meier and Cox regression analyses assessed associations with clinical outcomes. Results: Out of 150 patients, 37 (24.7%) had PAWP ≥15 mmHg. Elevated PAWP was associated with older age (36 [31;53] vs. 26 [19; 37] years, p<0.01), BMI (27.9 [24.5; 35.1] vs. 24.2 [20.6; 29.7] kg/m 2 , p<0.01), and higher HFpEF-ABA score (42.8 [9.5;63.6] vs. 6.4 [2.5;18.1]%, p<0.001) compared to normal PAWP. Over a median follow-up of 38 [13; 83] months, 26 events (17.3%) occurred. Kaplan-Meier analysis demonstrated a significant difference in event-free survival based on pre-TPVR PAWP categories (log-rank p=0.002) and HFpEF-ABA score categories (log-rank p<0.001). Elevated PAWP was associated with adverse outcomes (hazard ratio [HR] 4.27, 95% CI 1.61–11.31, p=0.003) (Figure 1), but this was no longer significant after age adjustment. HFpEF-ABA ≥25% was associated with adverse outcomes (HR 10.6, 95% CI 3.8–30.0, p<0.001) (Figure 2), independent of N-terminal prohormone of brain natriuretic peptide levels and left ventricular ejection fraction. Conclusion: Albeit confounded by demographics, pre-TPVR PAWP correlated with adverse long-term outcomes, and patients with this hemodynamic profile may require closer post-procedural surveillance. HFpEF-ABA was independently associated with incident events, representing an inexpensive, novel prognostic tool in patients undergoing TPVR.

Introduction: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema, hypoxia and systemic inflammation. The presence and clinical implications of a high cardiac output state in patients with ARDS remain unknown given the lack of invasive hemodynamic monitoring in most patients with ARDS. Hypothesis: A subset of patients with ARDS will have high output heart failure with high cardiac output and elevated pulmonary capillary wedge pressure (PAWP) representing a unique subphenotype of ARDS. Methods: Patients from the Comparison of Two Fluid-Management Strategies in Acute Lung Injury (FACTT) Trial were stratified according to baseline cardiac output states and filling pressures: HOLHF (high-output with left heart failure) was defined as cardiac index (CI) ≥ 4 L/min/m 2 and PAWP ≥ 15 mmHg; HOnoLHF (high-output without left heart failure) as CI ≥ 4 L/min/m 2 and PAWP < 15 mmHg; and NOHO (non-high-output) as CI < 4 L/min/m 2 . Hemodynamics, oxygenation, metabolic demand (VO 2 ) and clinical outcomes were compared across groups. Results: Of the 399 patients included, high-output states were present in 52% of all patients (Figure 1). High-output cohorts demonstrated higher myocardial workload, lower systemic vascular resistance (SVR), lower pulsatile arterial load, higher VO 2 and more impaired systemic O 2 utilization despite the highest peripheral O 2 delivery compared to NOHO (Table). Among the high-output cohorts, the HOLHF cohort demonstrated higher right ventricular stroke work (25.2 ± 12.1 vs. 20.3 ± 12.3, P<0.001), worse A-a gradient (326.0 ± 136.5 vs. 276.1 ± 114.7, P=0.048) and higher VO 2 (382.3 ± 234.2 vs. 289.8 ± 171.7, P<0.001) compared to HOnoLHF. Increasing cardiac output was individually related to decreasing SVR (r=-0.742, P<0.001) and increasing VO 2 (r=0.565, P<0.001) (Figure 2). When adjusted, both variables remained strongly related to increasing cardiac output (P<0.001). There were no significant differences among the cohorts with respect to refractory hypoxia and mortality. Conclusions: High-output states in ARDS are prevalent and underrecognized. Such states appear to be driven by arterial vasodilatation and heightened VO 2 with additional manifestations of increased myocardial workload and inefficient peripheral utilization with impaired systemic O 2 utilization. Whether specific strategies to mitigate the high output state might improve gas exchange, hypoxia and outcomes in patients with HOLHF and ARDS requires further study.

Background: Fontan circulation is characterized by the absence of a subpulmonary ventricle with resultant systemic venous hypertension. Despite exercise intolerance being nearly universal in this population, the determinants of exercise capacity in this population are still poorly understood. Research Question: We investigated the prevalence of peripheral impairment and assessed the contribution of peripheral O 2 extraction versus central hemodynamics to peak O 2 consumption (pVO 2 ) post-Fontan palliation. Methods: This single-center retrospective cross-sectional study compared 52 consecutive adults post-Fontan procedure who underwent exercise catheterization to patients with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnea (NCD) at 1:1 ratio. Several previously reported measures for peripheral O 2 extraction were evaluated in the absence of a golden standard. Correlates of pVO 2 were identified by multivariate linear regression analyses using the backward selection method. Results: Patients with Fontan circulation were younger [age 32 (24;36) years] and tended to have a lower body mass index [26 (23; 29) kg/m 2 ] compared to patients with HFpEF [70 (57; 75) years, p<0.001 and 33 (27; 39) kg/m 2 , p<0.001] and NCD [48 (38; 61) years, p<0.001 and 27 (24; 35) kg/m 2 , p=0.08]. Peak heart rate [108 (85;126) vs 108 (95;125) bpm] and indexed stroke volume [46 (39;54) vs 45 (40;53) ml/m 2 ] were similar in the Fontan and HFpEF groups but lower compared to NCD [126 (108;141) bpm, p<0.001 and 51 (45;59) ml/m 2 , p<0.001]. Peak mean pulmonary artery pressures were highest in HFpEF [45 (41;50) mmHg, p<0.001], followed by Fontan and NCD [26 (22;31) vs 23 (19;25) mmHg, p=0.03]. Median peak O 2 extraction post-Fontan was comparable to HFpEF [12 (10;14) vs 11 (10;13) ml/dl, p=0.17] but higher than in NCD [10 (9;12) ml/dl, p<0.001]. It was <14 ml/dl in 73% compared to 94% and 98% of patients with HFpEF and NCD [p<0.001]. O 2 extraction ratio was <70% in 62% compared to 60% in HFpEF and 96% in NCD [p<0.001]. Correlates of pVO 2 post-Fontan were peak O 2 extraction [β 0.5±0.1 per ml/dl; p<0.001], mean pulmonary artery pressures [β -0.2±0.05 per mmHg; p=0.002], heart rate [β 0.03±0.01 per bpm; p=0.01], and systolic arterial blood pressure [β 0.03±0.01 per mmHg; p=0.02]. Conclusion: Impaired O 2 extraction is prevalent amongst adults post-Fontan. Whether exercise can modulate this important determinant of exercise capacity post-Fontan merits further investigation.

Abstract Aims The efficacy and safety of vericiguat in patients with chronic heart failure with reduced ejection fraction (HFrEF) on contemporary heart failure (HF) therapies and without recent worsening was investigated in the VICTOR trial, yet some subgroups may be more susceptible to symptomatic hypotension. Methods and results Among VICTOR trial participants that received at least one dose of study drug or placebo, we describe the systolic blood pressure (SBP) trajectories over time (mean change from baseline), symptomatic hypotension events and efficacy of vericiguat in potentially vulnerable patient subgroups: lower baseline blood pressure (SBP ≤110 mmHg), older patients (&gt;75 years) and those taking angiotensin receptor–neprilysin inhibitors (ARNI) or sodium–glucose co-transporter 2 inhibitors (SGLT2i) at baseline. The efficacy outcomes of cardiovascular death and HF hospitalization and cardiovascular death alone across baseline SBP were examined using Cox proportional hazards models. Overall SBP trajectories showed a small initial decline from baseline in vericiguat-treated patients compared with placebo (placebo-corrected differences of −1.17 [−1.84, −0.50], p = 0.0007) that was relatively stable throughout follow-up. This trajectory was similar in those &gt;75 years (vs. younger) as well as those receiving ARNI or SGLT2i (as compared with those not receiving these) or those with SBP ≤110 mmHg at baseline (compared with &gt;110 mmHg). Symptomatic hypotension occurred in 11.3% of vericiguat-treated patients compared with 9.2% of placebo-treated patients with an adjusted hazard ratio of 1.24 (95% confidence interval 1.06–1.46), which was similar across age, SBP, SGLT2i and ARNI groups (all interaction p &gt;0.05). The treatment effect of vericiguat compared with placebo on the efficacy outcomes was similar across the spectrum of baseline SBP (both interaction p &gt;0.15). Conclusions Vericiguat showed a slight adjusted decrease in SBP and resulted in more symptomatic hypotension compared with placebo but was overall well-tolerated in a broad population with HFrEF on contemporary therapy even among those predisposed to hypotension. Treatment effects on efficacy outcomes were consistent regardless of baseline SBP.

Abstract Aims The pathophysiology of tricuspid regurgitation (TR) during exercise in heart failure with preserved ejection fraction (HFpEF) is not well understood. Methods and results We investigated dynamic changes in TR severity during exercise in patients with HFpEF and associated relationships with haemodynamics, cardiopulmonary reserve, and prognosis using invasive haemodynamic exercise testing with simultaneous echocardiography and expired gas analysis. Among 169 patients with HFpEF (91 no TR, 44 mild TR, 34 ≥ moderate TR), older age and atrial fibrillation were more common in patients with greater TR severity. Right heart remodelling and dysfunction were more frequently observed with greater TR severity, particularly in the right atrium, along with stepwise increases in right atrial (RA) pressure and interventricular septal flattening, and decreases in cardiac output (CO). During exercise, TR severity frequently worsened, and over half of the patients with moderate TR at rest displayed severe TR during exercise, accompanied by profound RA dilatation, reduced RA reservoir strain, increased septal flattening, and more severely impaired CO reserve. Abnormalities in tricuspid annular motion and ventricular interaction were amplified by exercise with greater TR, but exercise pulmonary vascular pressures did not differ across groups. Patients with ≥ moderate TR during exercise displayed higher event rates (hazard ratio 2.85, 95% confidence interval 1.18–6.85), but patients with mild TR had similar prognosis as those without TR in adjusted models. Conclusions Tricuspid regurgitation in HFpEF is related to advanced RA myopathy and often worsens during exercise leading to dynamic right-sided heart failure, exaggerated ventricular interaction, impaired CO reserve, and increased risk for adverse outcomes. These data emphasize the clinical importance of exercise evaluation and call for further study of novel treatments in those with significant resting and provocable TR.

BACKGROUND: The purpose of this study was to assess the feasibility and prognostic value of cardiac output (CO) reserve assessment using exercise echocardiography in Fontan patients. We hypothesized that adults with Fontan palliation had lower CO reserve compared with controls, and impaired CO reserve was associated with greater congestion (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) and cardiovascular events (death/transplant/heart failure hospitalization) in Fontan patients. METHODS: Thirty-seven Fontan patients and 61 controls underwent exercise echocardiography using a supine cycle ergometer. Doppler-derived CO and oxygen consumption (VO 2 ) were assessed at rest and every stage of exercise. CO reserve was calculated as ∆CO/Watt (∆CO/W) and ∆CO/∆VO 2 . RESULTS: Assessment of CO reserve was feasible in 95% of the Fontan group with modest reproducibility. Although both groups had similar CO at rest, the Fontan group had lower CO reserve with exercise as evidenced by lower ∆CO/W ratio (46±17 versus 57±19 mL/W; P <0.001) and lower ∆CO/∆VO 2 ratio (4.48±1.02 versus 5.37±2.18 mL/mL; P =0.03). There was a correlation between ∆CO/W ratio and log NT-proBNP (r=0.65; P <0.001), and between ∆CO/∆VO 2 ratio and log NT-proBNP (r=0.53; P =0.009). Impaired CO reserve was associated with congestion and cardiovascular events and provided improved prognostication (higher area under the curve and C statistics) above conventional echocardiographic indices and treadmill peak VO 2 . CONCLUSIONS: Patients with Fontan palliation had lower CO reserve, and impaired CO reserve was associated with congestion and cardiovascular events. Further studies are required to determine whether cardiac interventions can improve CO reserve and whether changes in CO reserve can be used as a surrogate end point for therapeutic response.