Nishimura, Rick

BACKGROUND: Left atrial (LA) stiffening augments the LA V wave, pressurizing the pulmonary artery (PA) out of proportion to left ventricular end-diastolic pressure. We characterized the pathophysiologic, diagnostic, and clinical implications of LA stiffening, as defined by prominent V waves, in heart failure with preserved ejection fraction. METHODS: In this retrospective cohort study, patients with heart failure with preserved ejection fraction and less than moderate mitral regurgitation at rest underwent invasive hemodynamic exercise testing. Patients with heightened operant LA stiffening were defined by the PA wedge pressure (PAWP) V wave exceeding mean PAWP by ≥10 mm Hg. A previously used formula for V wave–corrected PAWP was validated against the PAWP waveform pressure-time-area to explore impact of the V wave on transpulmonary pressure gradients. Clinical, echocardiographic, hemodynamic, and outcome data were compared for patients with and without prominent V waves. RESULTS: Compared with patients without prominent V waves (n=844, 79%), those with prominent V waves (n=225, 21%) were older and more likely to be women, with more severe LA myopathy, evidenced by greater LA volume index (42.2±15.0 versus 32.5±13.0 mL/m 2 , P <0.001), lower LA reservoir strain (16.4±7.5% versus 23.2±8.3%, P <0.001), more atrial fibrillation (61.3% versus 22.9%, P <0.001), and increased operant LA reservoir stiffness (0.59±0.25 versus 0.23±0.24 mm Hg/mL, P <0.001). Patients with prominent V waves had markedly higher PA systolic pressure than those without (54±16 versus 38±12 mm Hg, P <0.001) despite no difference in end-diastolic PAWP-PA pressure gradient (3±5 versus 3±4 mm Hg, P =0.950). Incorporating the V wave into PAWP improved correlation between directly measured PAWP pressure-time integral compared with mid–A wave PAWP (R 2 =0.96 versus R 2 =0.86, P <0.001 for comparison). In patients with prominent V waves, the prevalence of combined pre- and postcapillary pulmonary hypertension decreased from 60.2% to 29.3% after V wave correction for the transpulmonary pressure gradients. Despite similar corrected pulmonary vascular resistances in patients with and without prominent V waves, apparent PA compliance was much lower in patients with prominent V waves (3.03±1.56 versus 4.90±2.27 mL/mm Hg, P <0.001), augmenting right ventricular afterload, and these changes were coupled with more severe right ventricular dysfunction, tricuspid regurgitation, blunted cardiopulmonary exercise reserve, and increased risk of hospitalization for heart failure or death in patients with versus without prominent V waves (adjusted hazard ratio, 2.09 [95% CI, 1.53–2.86]; P <0.001). CONCLUSIONS: More than 1 in 5 patients with heart failure with preserved ejection fraction display prominent V waves in excess of end-diastolic PAWP. This augments right ventricular afterload due to backward transmission of the V wave, contributing to right heart failure that is independent of the pulmonary vasculature. Failure to account for the V wave during hemodynamic assessment overestimates the severity of pulmonary vascular disease present.

BACKGROUND: With evolving therapy for heart failure with reduced ejection fraction, the benefits of adding a defibrillator in patients undergoing cardiac resynchronization therapy (CRT) remain unclear, particularly for nonischemic cardiomyopathy (NICM). This study evaluates long-term survival among patients with NICM treated with CRT defibrillator (CRT-D) versus CRT pacemaker (CRT-P). METHODS: DECIDE-CRT (Cardiac Resynchronization With or Without Defibrillator in Non-Ischemic Cardiomyopathy) is a multicenter cohort study across 170 US Veterans Affairs hospitals. We identified patients with NICM receiving primary-prevention CRT-P or CRT-D between January 1, 2006, and December 31, 2020. Using a propensity score approach, we applied inverse probability of treatment weighting to balance baseline characteristics between the CRT-P and CRT-D groups. An inverse probability of treatment weighting–weighted Cox model estimated hazards for all-cause mortality. Secondary outcomes included generator replacement, device-related infections, hospitalization for heart failure, and ventricular arrhythmias. RESULTS: Of 16 609 CRT recipients, 3965 met NICM primary-prevention criteria (CRT-D=3158; CRT- P =807). At baseline, patients with NICM receiving CRT-P were much older, with more cardiovascular and noncardiovascular comorbidities compared with the CRT-D group. During the median follow-up of 5.2 years, the mortality rate for CRT-P versus CRT-D was 9.46 versus 9.21 per 100 person-years (RR, 0.97 [95% CI, 0.71–1.13]; P =0.66). The adjusted hazard ratio for all-cause mortality using the inverse probability of treatment weighting-Cox model was 0.90 (95% CI, 0.71–1.13; P =0.34). There was no difference in adjusted hazard for heart failure hospitalization (hazard ratio, 1.27 [95% CI, 0.86–1.87]), while the CRT-D group had higher rates of generator replacement and device-related infections. CONCLUSIONS: This nationwide observational study from the Veterans Affairs Health system did not demonstrate a clear survival advantage with the addition of a defibrillator among patients with NICM receiving CRT although residual confounding cannot be excluded. Given the uncertainty surrounding the incremental benefit of the defibrillator in this setting, a randomized trial is needed to test the incremental value of CRT-D over CRT-P in NICM.

BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Abstract Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype–hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype–hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non–Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio ≥0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment. Clinical Perspective What Is New? In the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease Resting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept. A staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification. What Are the Clinical Implications? Pre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold. Intermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield. Exercise pulmonary capillary wedge pressure/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Background Patients with atrial fibrillation (AF) often complain of dyspnea, raising the question that symptoms could be related to unrecognized heart failure (HF) with preserved ejection fraction (HFpEF). Methods We used the HFpEF‐age, body mass index and history of AF algorithm to estimate the probability of undiagnosed HFpEF in CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy), and its interaction with catheter ablation on quality of life (QOL). Probable HFpEF was defined as patient‐reported dyspnea with HFpEF‐age, body mass index and history of AF probability≥75%. Absence of dyspnea or HFpEF‐age, body mass index and history of AF probability<75% was considered to reflect patients without HFpEF. The effect of randomization to catheter ablation on QOL (Mayo Atrial Fibrillation‐Specific Symptom Inventory questionnaire and EuroQol‐5 Dimension‐3 Level score) was assessed using mixed models. Results Of participants without known HF, 70% (n=1225) had probable HFpEF and the remaining 30% (n=522) did not. Those with probable HFpEF had worse New York Heart Association class, EuroQol‐5 Dimension‐3 Level score, Mayo Atrial Fibrillation‐Specific Symptom Inventory severity, and Mayo Atrial Fibrillation‐Specific Symptom Inventory frequency scores ( P <0.0001 for all), with higher risk of HF hospitalization (hazard ratio [HR], 2.19 [95% CI, 1.11–4.31], P =0.01). Ablation resulted in greater improvement in EuroQol‐5 Dimension‐3 Level and Mayo Atrial Fibrillation‐Specific Symptom Inventory severity/frequency scores in probable HFpEF (interactions P =0.005, P =0.05, and P =0.04 respectively). In probable HFpEF, catheter ablation was associated with lower risk of cardiovascular hospitalization (HR, 0.78 [95% CI, 0.66–0.92], P =0.003, interaction P =0.03) but not HF hospitalization (HR, 0.94 [95% CI, 0.55–1.64], P =0.84). Conclusions Nearly three quarters of CABANA participants had potentially undiagnosed HFpEF, with worse QOL and risk of HF hospitalization. Catheter ablation in probable HFpEF resulted in greater improvement in QOL, but residual QOL impairment and HF risk remained elevated despite ablation. These data reinforce the importance of diligent consideration of HFpEF among patients with symptomatic AF to ensure optimal use of foundational treatments for HF.

BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m 2 ) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m 2 (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m 2 (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output ( P <0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P <0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16–3.47]; P =0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10–2.46]; P =0.01) was associated with worse survival. CONCLUSIONS: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

Achieving optimal unloading in patients with left ventricular assist devices (LVADs) is associated with improved outcomes but remains unattainable in some cases. We retrospectively reviewed 33 patients with a HeartMate 3 LVAD who underwent speed optimization with concomitant echocardiography and right heart catheterization for inadequate left ventricular (LV) unloading between January 2016 and December 2023. Patients were stratified based on left ventricular transmural pressure (LVTMP) into two groups: LVTMP ⩽7 mmHg and LVTMP >7 mmHg using a median split approach. Pulmonary capillary wedge pressure (PCWP) decreased in both groups with increased LVAD speed; however, the mean PCWP change per 100 rpm was significantly smaller in patients with LVTMP ⩽7 mmHg (−0.50 vs −0.99 mmHg per 100 rpm, p = 0.003). Comparative analysis demonstrated LVTMP’s superiority over established RV markers, with the strongest interaction effect for predicting speed optimization response. Changes in cardiac output were similar between the two groups. In univariate analysis, multiple hemodynamic parameters were significantly associated with reduced LVTMP, including right atrial pressure (OR = 1.27, p = 0.036), TPG (OR = 1.25, p = 0.037), DPG (OR = 1.69, p = 0.012), and PAPi (OR = 0.35, p = 0.019).LVTMP, as a surrogate for true LV preload, particularly in the context of RV failure, may offer predictive value for the success or failure of LV unloading with LVAD speed optimization.