Cardiovascular Mortality In Heart Failure Research Articles

Non-invasive pressure-volume loops from cardiovascular magnetic resonance predict cardiovascular mortality in heart failure with reduced ejection fraction

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired ventricular energetics secondary to ventricular remodeling. Left ventricular pressure-volume (PV) loop analysis (Figure 1) can now be performed noninvasively using cardiovascular magnetic resonance (CMR) imaging, enabling study of cardiac thermodynamic efficiency without the risk and cost associated with invasive measurements (1–3). Here we investigated whether noninvasive PV loops from CMR can predict cardiovascular death in HFrEF patients. Methods We analyzed 135 datasets (age 60±12 years, 79% male) from HFrEF patients (LVEF≤40%) who underwent clinical CMR examination at our center between 2004-2013. Pressure-volume loop parameters were computed from manually segmented CMR data and same-day brachial blood pressure (Segment 4.0 R11026, Medviso, Lund, Sweden). The primary endpoint was cardiovascular mortality extracted from national registries with a 5-year follow-up. Parameters of interest were selected from univariate Cox regression, and associations with clinical outcome evaluated using multivariate Cox regression. Survival was visualized using Kaplan-Meier analysis. Statistical analysis was performed in R 4.0.3 (R Core Team). Results A total of 19 deaths from cardiovascular causes occurred during follow-up. Univariate Cox regression found stroke work (SW, joule), ventricular efficiency (VE, %), external power (J/s), contractility (mmHg/ml), and energy per ejected volume (mJ/ml) computed from PV loops associated with the primary endpoint alongside age, LVEF, and NT-proBNP level. In multivariate Cox regression adjusted for age, ventricular efficiency remained significant (HR 0.86, p<0.001), while EF did not (p = 0.077). Event-free survival is shown in Figure 2. Conclusion Ventricular efficiency derived from non-invasive pressure-volume loop analysis from standard CMR scans, may outperform LV EF as a predictor of cardiovascular mortality in HFrEF. Figures: Figure 1. Example of left ventricular pressure-volume (PV) loop. The area enclosed by the loop is the stroke work (SW). The area bounded by the PV loop and the end-systolic pressure-volume relationship (ESPVR) is the potential energy (PE). Ventricular efficiency (VE) is calculated as SW/(PE+SW). Figure 2. Kaplan-Meier plots of survival by tertiles of stroke work and ventricular efficiency.Figure 1Figure 2

Predictors and Outcomes of Sudden Cardiac Arrest in Heart Failure With Preserved Ejection Fraction: A Nationwide Inpatient Sample Analysis

Sudden cardiac arrest (SCA) is the leading cause of cardiovascular mortality in heart failure with preserved ejection fraction (HFpEF), contributing to around 25% of deaths observed in pivotal HFpEF trials. However, predictors and outcomes of in-hospital SCA in HFpEF have not been well characterized. We queried the Nationwide Inpatient Sample (2016 to 2017) to identify adult hospitalizations with a diagnosis of HFpEF. Patients with acute or chronic conditions associated with SCA (e.g., acute myocardial infarction, acute pulmonary embolism, sarcoidosis) were excluded. We ascertained whether SCA occurred during these hospitalizations, identified predictors of SCA using multivariate logistic regression, and determined outcomes of SCA in HFpEF. Of 2,909,134 hospitalizations, SCA occurred in 1.48% (43,105). The mean age of the SCA group was 72.3 ± 12.4years, 55.8% were women, and 66.4% were White. Presence of third-degree atrioventricular block (odds ratio [OR] 5.95, 95% confidence interval [CI] 5.31 to 6.67), left bundle branch block (OR 1.96, 95% CI 1.72 to 2.25), and liver disease (OR 1.87, 95% CI 1.73 to 2.02) were the leading predictors of SCA in HFpEF. After excluding patients with do-not-resuscitate status, the SCA group versus those without SCA had higher mortality (25.9% vs 1.6%), major bleeding complications (4.1% vs 1.7%), increased use of percutaneous coronary intervention (2.5% vs 0.7%), and mechanical circulatory assist device (1.2% vs 0.1%). These observational inpatient data suggest identifiable risk factors for SCA in HFpEF including cardiac arrhythmias. Further research is warranted to identify the best tools to risk-stratify patients with HFpEF to implement targeted SCA prevention strategies.

Magnesium Disorders and Prognosis in Heart Failure: A Systematic Review.

Magnesium is an essential mineral for the human body and plays an important role in cardiovascular health. Hypomagnesaemia has been linked with increased cardiovascular mortality in heart failure; however, previous studies have yielded conflicting results. Even fewer studies have addressed the association between hypermagnesemia and prognosis in heart failure. The aim of the present systematic review was to investigate the association of serum magnesium levels with cardiovascular and all-cause mortality in patients with heart failure and reduced ejection fraction (HFrEF). Cardiovascular morbidity, referring to heart failure rehospitalizations and ventricular arrhythmias, was also investigated. Eligible studies were identified by searching PubMed and Scopus. The Quality in Prognosis (QUIPS) tool was used to assess the quality of included studies. Eight studies (total of 13,539 patients with HFrEF) that assessed the effects of serum magnesium levels on cardiovascular mortality, all-cause mortality, and cardiovascular morbidity met inclusion criteria. In half of the studies, hypomagnesemia was found to be an independent risk factor for cardiovascular mortality, including sudden cardiac death. Only 1 study reported that hypermagnesemia (serum magnesium levels above 2.4 mg/dL) is a prognostic factor for noncardiac mortality suggesting that hypermagnesemia is more likely an indicator of comorbidities rather than a true independent prognostic marker. Finally, low serum magnesium levels were not associated with readmissions for heart failure or ventricular arrhythmias in patients with HFrEF.

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

BackgroundSodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.Methods17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable.ResultsSotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition.ConclusionThe SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

Effect of SGLT-1/2 inhibition on mitochondrial dysfunction in left atrial remodeling during HFpEF

Abstract Background In the DAPA-HF trial, SGLT inhibition reduces cardiovascular mortality in heart failure. However, the mechanism and a potential positive effect in HfpEF remain elusive. Introduction LA remodeling is a hallmark feature of HFpEF and commonly associated with LA enlargement and dysfunction. Previous studies of SGLT-2 inhibitor Empagliflozin suggest a utilization of alternative metabolites for energy consumption (i.e. ketone bodies). Additionally, alterations of sodium and calcium ion hemostasis have been reported. We investigated the effect of SGLT inhibition on mitochondrial (dys)function during atrial remodeling in HFpEF. Methods Rats (WT: Wistar Kyoto, HFpEF: ZFS-1 Obese (metabolic syndrome)) were obtained at ∼10w and fed Purina 5008 diet. At 17w, animals were randomized to treatment with either vehicle or Sota (30mg/kg/d) for 5w until primary adult cardiomyocytes were isolated for final experiments. Structural information of mitochondria was obtained with Mitotracker Red in either a glucose starved (1h incubation with mannitol) or saturated state. ROS production was assessed with H2-DCF in a starved and saturated condition. Mitochondrial calcium buffer capacity was imaged with Rhod-2 following perforation of the cellular membrane with saponin. Glycolytic dependency of calcium cycling was assessed upon glycolytic inhibition with 2-deoxyglucose during imaging of cytosolic calcium transients with Fura-2. Results In a glucose saturated state, LA cardiomyocytes in HFpEF showed increased mitochondrial density, which was ameliorated with Sota. Sota increased mitochondrial calcium buffer capacity in HFpEF, indicating a decrease in mitochondrial resting calcium. Differences in mitochondrial fission could not be detected. However, during glucose starvation cardiomyocytes showed a decrease in mitochondrial fission and ROS production with Sota. A difference in ROS production was not visible when cells were abruptly challenged with high glucose concentrations, but Sota decreased mitochondrial fission, indicating long term protective properties towards ROS. Glycolytic inhibition led to an increase of cytosolic diastolic calcium and calcium transient peak height in HFpEF vs. WT, indicating an increased glucose dependency of cytosolic calcium cycling, which was mitigated with Sota. Additionally, Sota negated an increase in diastolic calcium, when cardiomyocytes where challenged with high concentrations of glucose after starvation. Conclusion SGLT1/2 inhibition alters mitochondrial calcium uptake in HFpEF and positively affects mitochondrial structure with subsequent decreases of ROS production and enhanced calcium homeostasis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Else-Kröner-Fresenius-Stiftung, Deutsches Zentrum für Herz-Kreislaufforschung

CRT-400.03 Effects of Angiotensin Receptor Neprilysin Inhibitor on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction

Angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) is well known to be superior over angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARBs) in terms of reducing cardiovascular mortality in heart failure with reduced ejection fraction (HFrEF). However,

Insulin-like Growth Factor Binding Protein 2 predicts mortality risk in heart failure

BackgroundInsulin-like Growth Factor Binding Protein 2 (IGFBP2) showed greater heart failure (HF) diagnostic accuracy than the “grey zone” B-type natriuretic peptides, and may have prognostic utility as well. ObjectivesTo determine if IGFBP2 provides independent information on cardiovascular mortality in HF. MethodsA retrospective study of 870 HF patients from 3 independent international cohorts. Presentation IGFBP2 plasma levels were measured by ELISA, and patients were followed from 1 year (Maastricht, Netherlands) to 6 years (Atlanta, GA, USA and Toulouse, France). Multivariate analysis, Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were performed in the 3 cohorts. The primary outcome was cardiovascular mortality. ResultsIn multivariate Cox proportional hazards analysis, the highest quartile of IGFBP2 was associated with mortality in the Maastricht cohort (adjusted hazard ratio 1.69 (95% CI, 1.18–2.41), p = 0.004) and in the combined Atlanta and Toulouse cohorts (adjusted hazard ratio 2.04 (95%CI, 1.3–3.3), p = 0.003). Adding IGFBP2 to a clinical model allowed a reclassification of adverse outcome risk in the Maastricht cohort (NRI = 18.7% p = 0.03; IDI = 3.9% p = 0.02) and with the Atlanta/Toulouse patients (NRI of 40.4% p = 0.01, 31,2% p = 0.04, 31.5% p = 0,02 and IDI of 2,9% p = 0,0005, 3.1% p = 0,0005 and 4,2%, p = 0.0005, for a follow-up of 1, 2 and 3 years, respectively). ConclusionIn 3 international cohorts, IGFBP2 level is a strong prognostic factor for cardiovascular mortality in HF, adding information to natriuretic monitoring and usual clinical markers, that should be further prospectively evaluated for patients' optimized care.

Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials

BackgroundHeart failure (HF) remains a significant cause of morbidity and mortality. Multiple trials over the past several years have examined the effects of both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet, there is still confusion regarding the relative efficacy of rennin-angiotensin-aldosterone system (RAAS) inhibition. Our study was conducted to assess efficacy of ACEIs and ARBs in reducing all-cause and cardiovascular mortality in heart failure patients.MethodsWe included randomized clinical trials compared ACEIs and ARBs treatment (any dose or type) with placebo treatment, no treatment, or other anti-HF drugs treatment, reporting cardiovascular or total mortality with an observation period of at least 12 months. Data sources included Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials. Dichotomous outcome data from individual trials were analyzed using the risk ratio measure and its 95%CI with random-effects/ fixed-effects models. We performed meta-regression analyses to identify sources of heterogeneity. All-cause mortality and CV mortality were thought to be the main outcomes.ResultsA total of 47,662 subjects were included with a mean/median follow-up ranged from 12 weeks to 4.5 years. Of all 38 studies, 32 compared ACEIs with control therapy (included 13 arms that compared ACEIs with placebo, 10 arms in which the comparator was active treatment and 9 arms that compared ACEIs with ARBs), and six studies compared ARBs with placebo. ACEIs treatment in patients with HF reduced all-cause mortality to 11% (risk ratio (RR): 0.89, 95% confidence interval (CI): 0.83–0.96, p = 0.001) and the corresponding value for cardiovascular mortality was 14% (RR: 0.86, 95% CI: 0.78–0.94, p = 0.001). However, ARBs had no beneficial effect on reducing all-cause and cardiovascular mortality. In head-to-head analysis, ACEIs was not superior to ARBs for all-cause mortality and cardiovascular deaths.ConclusionsIn HF patients, ACEIs, but not ARBs reduced all-cause mortality and cardiovascular deaths. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

Abstract 13999: Elevated Asleep Blood Pressure is Associated With All-cause and Cardiovascular Mortality in Heart Failure With Preserved Left Ventricular Ejection Fraction (HFpEF) -From Nara-HF Study

Introduction: Abnormal circadian blood pressure (BP) rhythms are one of the risks of cardiovascular diseases and death. However, circadian BP rhythms in heart failure (HF) patients are unclear. Therefore, we examined the relationship between circadian BP rhythms for survival in HF patient. Moreover, we valued the difference of circadian BP rhythms between HF with preserved left ventricular ejection fraction (HFpEF) and HF with reduced left ventricular ejection fraction (HFrEF). Methods: Of 810 consecutive patients with acute decompensated HF emergently admitted to our hospital, we studied 228 HF patients performed ambulatory blood pressure monitoring (ABPM) at discharge. We examined the relationship between circadian BP rhythms and survival in HFpEF and HFrEF. Kaplan-Meier survival analysis and Cox proportional hazard model were performed to assess outcomes. Results: During a mean follow-up of 27.9 months, there were 80 deaths from all causes, including 36 deaths from cardiovascular causes. The pattern of circadian BP rhythms was similar between HFpEF and HFrEF. In HFpEF patients, Kaplan-Meier analysis showed that all-cause and cardiovascular death were significantly higher in patients with the pattern of elevated asleep BP (EABP), in which sleep BP exceeded awake BP (log-rank P=0.0298 and P=0.0195, respectively). In a multivariate analysis, EABP pattern was an independent predictor for all-cause and cardiovascular death (HR 2.57; 95% CI 1.09-6.13; P=0.0310 and HR 10.66; 95% CI 1.91-93.9; P=0.0063, respectively) after adjusted by age, hemoglobin and brain natriuretic peptide. However, these findings were not observed in HFrEF. Conclusions: EABP pattern was associated with increasing risk for adverse outcome in HFpEF patients, but not in HFrEF patients. Although further studies are necessary to elucidate the mechanism, we should pay attention to EABP pattern in HFpEF.

Abstract 12221: Impact of Serum Uric Acid on Mortality in Heart Failure With Preserved Ejection Fraction

Background: Serum uric acid is a predictor of cardiovascular mortality in heart failure with reduced ejection fraction. However, the impact of uric acid on heart failure with preserved ejection fraction (HFpEF) remains unclear. Here we investigated the association between hyperuricemia and mortality in HFpEF patients. Methods and Results: Consecutive 424 patients, who admitted to our hospital for decompensated heart failure and diagnosed as HFpEF, were divided into two groups based on presence of hyperuricemia (serum uric acid ≥ 7 mg/dl). We compared patient characteristics, cardio-ankle vascular index and cardio-pulmonary exercise test findings between the two groups. Furthermore, we prospectively followed cardiac and all-cause mortality. The hyperuricemia group (n=254), as compared with non-hyperuricemia group (n=170), had higher prevalence of male gender (55.5 vs. 41.7%, P=0.005), hypertension (79.9 vs. 69.4%, P=0.013), diabetes mellitus (38.5 vs. 26.4%, P=0.010) and use of diuretics (72.4 vs. 41.7%, P<0.001). Furthermore, the hyperuricemia group had higher levels of B-type natriuretic peptide (112.3 vs. 71.4 pg/ml, P<0.001), lower levels of estimated GFR (53.2 vs. 69.7 ml/min/1.73m 2 , P<0.001), higher cardio-ankle vascular index (8.7 vs. 7.5, P<0.001), lower peak VO 2 (14.9 vs. 17.9 ml/kg/min, P<0.001) and higher VE/VCO 2 slope (34.9 vs. 31.9, P=0.02) compared with non-hyperuricemia group. In the follow up period (mean of 897 days), cardiac and all-cause mortalities were significantly higher in those with hyperuricemia (P=0.006 and P=0.004, respectively). In the multivariable Cox proportional hazard analyses after adjusting for confounding factors including chronic kidney disease and use of diuretics, hyperuricemia was an independent predictor of all-cause mortality (hazard ratio 1.98, P=0.039). Conclusion: Hyperuricemia is associated with arterial stiffness, impaired exercise capacity, and high mortality in HFpEF.

Relationship of hyperuricemia with mortality in heart failure patients with preserved ejection fraction.

Serum uric acid is a predictor of cardiovascular mortality in heart failure with reduced ejection fraction. However, the impact of uric acid on heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we investigated the association between hyperuricemia and mortality in HFpEF patients. Consecutive 424 patients, who were admitted to our hospital for decompensated heart failure and diagnosed as having HFpEF, were divided into two groups based on presence of hyperuricemia (serum uric acid ≥7 mg/dl or taking antihyperuricemic agents). We compared patient characteristics, echocardiographic data, cardio-ankle vascular index, and cardiopulmonary exercise test findings between the two groups and prospectively followed cardiac and all-cause mortality. Compared with the non-hyperuricemia group (n = 170), the hyperuricemia group (n = 254) had a higher prevalence of hypertension (P = 0.013), diabetes mellitus (P = 0.01), dyslipidemia (P = 0.038), atrial fibrillation (P = 0.001), and use of diuretics (P < 0.001). Cardio-ankle vascular index (8.7 vs. 7.5, P < 0.001) and V̇e/V̇co2 slope (34.9 vs. 31.9, P = 0.02) were also higher. In addition, peak V̇o2 (14.9 vs. 17.9 ml·kg(-1)·min(-1), P < 0.001) was lower. In the follow-up period (mean 897 days), cardiac and all-cause mortalities were significantly higher in those with hyperuricemia (P = 0.006 and P = 0.004, respectively). In the multivariable Cox proportional hazard analyses after adjustment for several confounding factors including chronic kidney disease and use of diuretics, hyperuricemia was an independent predictor of all-cause mortality (hazard ratio 1.98, 95% confidence interval 1.036-3.793, P = 0.039). Hyperuricemia is associated with arterial stiffness, impaired exercise capacity, and high mortality in HFpEF.

Falling Cardiovascular Mortality in Heart Failure With Reduced Ejection Fraction and Implications for Clinical Trials

ObjectivesThis study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF). BackgroundWith the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing. MethodsIn a systematic review, 2 investigators independently searched online databases to identify clinical trials including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (<33% [low], 33% to 66% [medium], and >66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups. ResultsSixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p < 0.001). ConclusionsIn trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF.

Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure

In chronic heart failure (CHF) patients, the ventilation (Ve) needed to eliminate metabolically produced CO(2) during exercise (i.e. the Ve/Vco(2) slope) is a strong prognosticator. Ve/Vco(2) slope determinants are the dead space-tidal volume (Vd/Vt) ratio and the arterial CO(2) partial pressure (Paco(2)). We aimed at defining the respective prognostic role of these two variables. One hundred and twenty-eight stable CHF patients (average left ventricular ejection fraction 34+/-10%) underwent cardiopulmonary exercise testing and blood gas analysis. The prognostic relevance of the Ve/Vco(2) slope, Vd/Vt, and Paco(2) at peak exercise was evaluated by the Kaplan-Meier approach with log-rank testing and by multivariate Cox regression analysis. During a mean period of 31.3+/-20 months, 24 patients died from cardiac causes. In univariate analysis, predictors of death included the use of anti-aldosterone drugs, low peak Vo(2), peak Ve/Vo(2), peak Paco(2) and high Ve/Vco(2) slope, and peak Vd/Vt. Multivariate analysis identified a low peak Paco(2) (<35 mmHg) as the strongest independent prognostic indicator [hazard ratio 4.65, 95% confidence interval (CI) (1.695-12.751), P=0.003] that primarily accounts for the Ve/Vco(2) slope prognostic power. These findings imply that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.

Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure

Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure