Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications.

AIMS: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.

Pharmacologic Management of Cancer Therapeutics-Induced Cardiomyopathy in Adult Cancer Survivors.

PURPOSE OF REVIEW: The number of cancer survivors is exponentially increasing worldwide, due to both advances in cancer detection and treatment strategies, as well as the aging and growth of the population. This decrease in cancer mortality has brought forth a concurrent increase of non-ischemic (toxic) dilated cardiomyopathy in the survivor population, also known as cancer therapeutics-induced cardiomyopathy (CTIC). The optimal pharmacological management for this condition is still elusive, and hence, the focus of this work. RECENT FINDINGS: Our review of the literature did not identify any prospective randomized clinical trial of CTIC in adult cancer survivors, neither published nor in progress. However, available data seem to suggest that, when managed with standard guideline-derived medical therapy, the outcomes of CTIC are comparable to that of idiopathic dilated cardiomyopathy (IDC). Nonetheless, the evidence behind this strategy is inadequate. Until new information becomes available, pharmacological management of CTIC must parallel that of IDC. However, implementation of such may be hindered by other cancer therapeutics-induced comorbidities and conditioned by the particular effects of heart failure pharmacotherapy on cancer outcomes. This work succinctly reviews these three areas, in the context of adult cancer survivors.

Cardio-Oncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty.

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.

Prognostic Value of Hemodynamic Gain Index in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Assessment of functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) is essential for risk stratification, and it traditionally relied on cardiopulmonary exercise testing (CPET)-derived peak oxygen consumption (peak Vo2). OBJECTIVES: This study sought to investigate the prognostic value of alternative nonmetabolic exercise testing parameters in a contemporary cohort with HFrEF. METHODS: Medical records of 1,067 consecutive patients with chronic HFrEF who underwent CPET from December 2012 to September 2020 were reviewed for a primary outcome that was a composite of all-cause mortality, left ventricular assist device implantation, and/or heart transplantation. Multivariable Cox regression and log-rank testing were used to determine prognostic values of various exercise testing variables. RESULTS: The primary outcome was identified in 331 of 954 patients (34.7%) of the HFrEF cohort (median follow-up time, 946 days). After adjustment for demographics, cardiac parameters, and comorbidities, higher hemodynamic gain index (HGI) and peak rate-pressure product (RPP) were associated with greater event-free survival (adjusted HR per doubling: 0.76 and 0.36; 95% CI: 0.67-0.87 and 0.28-0.47; all P < 0.001, respectively). Moreover, HGI (area under the curve [AUC]: 0.69; 95% CI: 0.65-0.72) and peak RPP (AUC: 0.71; 95% CI: 0.68-0.74) were comparable to the standard peak Vo2 (AUC: 0.70; 95% CI: 0.66-0.73; P for comparison = 0.607 and 0.393, respectively) for primary outcome discrimination. CONCLUSIONS: HGI and peak RPP show good correlation with peak Vo2 in terms of prognostication and outcome discrimination in patients with HFrEF and may serve as suitable alternatives to CPET-derived prognostic variables.

Clinical Implications of Pretest Probability of HFpEF on Outcomes in Precapillary Pulmonary Hypertension.

BACKGROUND: Patients with group 1 pulmonary hypertension (PH) and risk factors for heart failure with preserved ejection fraction (HFpEF) demonstrate worse response to pulmonary vasodilator therapy. The mechanisms and optimal diagnostic approach to identify such patients remain unclear. OBJECTIVES: The purpose of this study was to compare exercise capacity, cardiac function, and hemodynamic responses to provocative maneuvers among patients with group 1 PH based upon pretest probability of HFpEF. METHODS: Pretest probability for HFpEF was determined using the validated HFpEF-ABA algorithm based on age, body mass index, and history of atrial fibrillation among group 1 PH patients recruited to the multicenter PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) study. Functional capacity, quality of life, and dynamic pulmonary capillary wedge pressure (PCWP) responses were compared between those with low (<25%), intermediate (25%-74%), and high (≥75%) ABA score-based HFpEF probability. RESULTS: Among 424 patients with group 1 PH, 54% (n = 228) had intermediate HFpEF probability and 15% (n = 64) had high HFpEF probability. Resting PCWP increased progressively with higher HFpEF probability (P < 0.0001), and patients with group 1 PH and high HFpEF probability had the greatest increases in PCWP with nitric oxide, fluid challenge, and exercise (P < 0.001 for all), changes that were comparable to patients with HFpEF with no pulmonary vascular disease (n = 194), but lower than those with HFpEF and combined precapillary and postcapillary PH. Left ventricular/atrial size, diastolic function, quality of life, 6-minute walk distance, and peak VO2 were most abnormal in patients with group 1 PH and high HFpEF probability compared with those with low or intermediate HFpEF probability (P < 0.0001 for all). Increasing HFpEF probability in group 1 PH was associated with greater risk of death (HR per decile of HFpEF probability 1.09; 95% CI: 1.05-1.13; P < 0.0001). CONCLUSIONS: Quantifying pretest probability for HFpEF in patients with group 1 PH identifies a subset of patients with worse dynamic PCWP response indicative of subclinical left heart disease, with poorer functional status, quality of life, and survival. Further study in this group 1 PH subgroup is indicated to determine whether PH therapies are effective and safe, and also whether HFpEF-specific therapies can improve functional status and outcomes.

Pulmonary hypertension across the spectrum of left heart and lung disease.

AIMS: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized. METHODS AND RESULTS: Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86). CONCLUSIONS: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02980887.

Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation.

BACKGROUND: Several lines of evidence have suggested that maintenance of atrial fibrillation (AF) depends on reentrant mechanisms. Maintenance of reentry necessitates a sufficiently short refractory period and/or delayed conduction, and AF has been associated with both alterations. Fibrosis, cellular dysfunction, and gap junction protein alterations occur in AF and cause conduction delay. We performed this study to test the hypothesis that gap junction protein overexpression would improve conduction and prevent AF. METHODS AND RESULTS: Thirty Yorkshire swine were randomized into 2 groups (sinus rhythm and AF), and each group into 3 subgroups: sham-operated control, gene therapy with adenovirus expressing connexin (Cx) 40, and gene therapy with adenovirus expressing Cx43 (n=5 per subgroup). All animals had epicardial gene painting; the AF group had burst atrial pacing. All animals underwent terminal study 7 days after gene transfer. Sinus rhythm animals had strong transgene expression but no atrial conduction changes. In AF animals, controls had reduced and lateralized Cx43 expression, and Cx43 gene transfer restored expression and cellular location to sinus rhythm control levels. In the AF group, both Cx40 and Cx43 gene transfer improved conduction and reduced AF relative to controls. CONCLUSIONS: Connexin gene therapy preserved atrial conduction and prevented AF.

Distinct Impact of Noncardiac Comorbidities on Exercise Capacity and Functional Status in Chronic Heart Failure.

BACKGROUND: Noncardiac comorbidities (NCCs) are common in patients with heart failure (HF), but how they jointly affect exercise capacity and functional status is relatively unexplored. OBJECTIVES: This study sought to investigate the cumulative effects of NCC on exercise capacity and functional status in chronic HF. METHODS: Baseline NCC-status was assessed in HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), IRONOUT-HF (Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), NEAT-HFpEF (Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction), INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF), and RELAX-HFpEF (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trials, and relations with peak Vo2 and 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), and all-cause death were determined according to HF type (with reduced vs preserved ejection fraction). Cluster analysis of the different NCCs was performed. RESULTS: A total of 2,777 patients were evaluated (mean age: 60 ± 13 years; median NCC burden in HF with preserved vs reduced ejection fraction: 3 [IQR: 2-4] vs 2 [IQR: 1-3]; P < 0.001). Obesity played a more important role in HF with preserved ejection fraction in limiting peak Vo2 and 6MWT. There was a progressive decline in peak Vo2, 6MWT, and KCCQ with increasing NCC burden. Cluster analysis revealed 3 NCC clusters: cluster 1: predominance of stroke and cancer; cluster 2: predominance of chronic kidney disease and peripheral vascular disease; and cluster 3: predominance of obesity and diabetes. Patients in cluster 3 had the worst peak Vo2, 6MWT, and KCCQ despite having the lowest N-terminal pro-B-type natriuretic peptide and exhibited diminished response to aerobic exercise training (peak Vo2Pinteraction = 0.045); however, it had similar risk for all-cause death as cluster 1, whereas cluster 2 had higher risk of death than cluster 1 (HR: 1.60 [95% CI: 1.25-2.04]; P < 0.001). CONCLUSIONS: NCC type and burden have a significant and cumulative effect on exercise capacity, occur in clusters, and are associated with clinical outcomes in patients with chronic HF.

Prognostic Role of Metabolic Exercise Testing in Heart Failure.

Heart failure is a clinical syndrome with significant heterogeneity in presentation and severity. Serial risk-stratification and prognostication can guide management decisions, particularly in advanced heart failure, when progression toward advanced therapies or end-of-life care is warranted. Each currently utilized prognostic marker carries its own set of challenges in acquisition, reproducibility, accuracy, and significance. Left ventricular ejection fraction is foundational for heart failure syndrome classification after clinical diagnosis and remains the primary parameter for inclusion in most clinical trials; however, it does not consistently correlate with symptoms and functional capacity, which are also independently prognostic in this patient population. Utilizing the left ventricular ejection fraction as the sole basis of prognostication provides an incomplete characterization of this condition and is prone to misguide medical decision-making when used in isolation. In this review article, we survey and exposit the important role of metabolic exercise testing across the heart failure spectrum, as a complementary diagnostic and prognostic modality. Metabolic exercise testing, also known as cardiopulmonary exercise testing, provides a comprehensive evaluation of the multisystem (i.e., neurological, respiratory, circulatory, and musculoskeletal) response to exercise performance. These differential responses can help identify the predominant contributors to exercise intolerance and exercise symptoms. Additionally, the aerobic exercise capacity (i.e., oxygen consumption during exercise) is directly correlated with overall life expectancy and prognosis in many disease states. Specifically in heart failure patients, metabolic exercise testing provides an accurate, objective, and reproducible assessment of the overall circulatory sufficiency and circulatory reserve during physical stress, being able to isolate the concurrent chronotropic and stroke volume responses for a reliable depiction of the circulatory flow rate in real time.

Long-term outcomes in nonprogressors to cardiac resynchronization therapy.

BACKGROUND: Among patients with heart failure undergoing cardiac resynchronization therapy (CRT), patients with a minimal change in left ventricular ejection fraction (LVEF) have recently been defined as "nonprogressors" rather than as "nonresponders." Little is known regarding long-term outcomes of nonprogressors. OBJECTIVE: We sought to evaluate outcomes in patients undergoing CRT on the basis of echocardiographically determined response status. METHODS: We reviewed the medical charts of patients with an LVEF of ≤35% and a QRS duration of ≥120 ms undergoing CRT at the Cleveland Clinic, Johns Hopkins Hospital, and Johns Hopkins Bayview Medical Center between 2003 and 2014. Response to CRT was defined on the basis of LVEF change as follows: super-responders ≥20%, responders 6%-19%, nonprogressors 0%-5%, and progressors <0%. Survival free of left ventricular assist device (LVAD) implantation and heart transplantation was compared on the basis of response classification. RESULTS: A total of 1058 patients were included and had a mean follow-up 8.7 ± 5.4 years, over which time there were 606 end points (37 LVAD implants, 32 heart transplants, and 537 deaths). Survival free of LVAD and heart transplant differed significantly between response groups after CRT both in the mid-term (4 years) and in the long-term (8.7 ± 5.4 years), with super-responders achieving the best outcomes and progressors the worst (P < .001). In multivariate analysis, nonprogressors had superior outcomes to progressors (P = .02) at 4 years of follow-up. Over the duration of follow-up (8.7 ± 5.4 years), there was no significant difference in survival between those 2 groups (P = .18). CONCLUSION: Nonprogressors to CRT have superior medium-term outcomes but similar long-term outcomes to progressors and inferior outcomes to responders and super-responders.

Frequency of acute vasodilator response (AVR) in incident and prevalent patients with pulmonary arterial hypertension: Results from the pulmonary vascular disease phenomics study.

The prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease-associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O2 and O2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O2-only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O2 + iNO. IPAH AVR prevalence (4.1%-18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD-PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVR responders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log-rank test p = 0.04 and p = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non-IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation.

Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension.

BACKGROUND: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear. OBJECTIVES: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival. METHODS: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation <90% (T90) per 10-unit increment. Linear models, adjusted for demographics, oxygen, diffusing capacity of the lungs for carbon monoxide, pulmonary hypertension medications, assessed AHI and T90, and RV measures. Log-rank test/Cox proportional hazards models adjusted for demographics, oxygen, and positive airway pressure were constructed for transplantation-free survival analyses. RESULTS: Analysis included 186 participants with group 1 PAH with a mean age of 52.6 ± 14.1 years; 71.5% were women, 80.8% were Caucasian, and there were 43 events (transplantation or death). AHI and T90 were associated with decreased RV ejection fraction (on magnetic resonance imaging), by 2.18% (-2.18; 95% CI: -4.00 to -0.36; P = 0.019) and 0.93% (-0.93; 95% CI: -1.47 to -0.40; P < 0.001), respectively. T90 was associated with increased RV systolic pressure (on echocardiography), by 2.52 mm Hg (2.52; 95% CI: 1.61 to 3.43; P < 0.001); increased mean pulmonary artery pressure (on right heart catheterization), by 0.27 mm Hg (0.27; 95% CI: 0.05 to 0.49; P = 0.019); and RV hypertrophy (on electrocardiography), 1.24 mm (1.24; 95% CI: 1.10 to 1.40; P < 0.001). T90, but not AHI, was associated with a 17% increased 5-year risk for transplantation or death (HR: 1.17; 95% CI: 1.07 to 1.28). In non-CTD-associated PAH, T90 was associated with a 21% increased risk for transplantation or death (HR: 1.21; 95% CI: 1.08 to 1.34). In CTD-associated PAH, T90 was associated with RV dysfunction, but not death or transplantation. CONCLUSIONS: Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplantation overall and in group 1 non-CTD-associated PAH but only with RV dysfunction in CTD-associated PAH. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease.

BACKGROUND: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Invasive Hemodynamic and Metabolic Evaluation of HFpEF.

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous condition of multiple causes, characterized by a clinical syndrome resulting from elevated left ventricular filling pressures, with an apparently unimpaired left ventricular systolic function. Although HFpEF has been long recognized as a distinct entity with significant morbidity for patients, its diagnosis remains challenging to this day. In recent years, few diagnostic algorithms have been postulated to aid in the identification of this condition. Invasive hemodynamic and metabolic evaluation is often warranted for the conclusive diagnosis and risk stratification of HFpEF, in patients presenting with undifferentiated DOE. RECENT FINDINGS: Rest and provoked hemodynamics remain the golden-standard diagnostic tool to unequivocally confirm the diagnosis of both established and incipient HFpEF, respectively. Cycle exercise hemodynamics is the paramount provocative maneuver to unveil this condition. Rapid saline loading does not offer a significant benefit over that of cycle exercise. Vasoactive agents can also uncover and confirm incipient HFpEF disease. The role of metabolic evaluation in patients presenting with idiopathic dyspnea on exertion (DOE) is of unparalleled value for those who have expertise in cardiopulmonary exercise test (CPET) interpretation; however, the average clinician who focuses solely on oxygen consumption will find it underwhelming. Invasive CPET stands alone as the ultimate diagnostic tool to discriminate between pulmonary, cardiovascular, and skeletal muscle disorders, and their respective contribution to DOE and exercise intolerance. SUMMARY: Several hemodynamic and metabolic parameters have demonstrated not only strong diagnostic value, but also predictive power in HFpEF. Additionally, these diagnostic methods have given rise to several therapeutic interventions that are now part of our clinical armamentarium. Regrettably, due to the heterogeneity and multicausality of HFpEF, none of the targeted interventions have been so far successful in decreasing the mortality burden of this prevalent condition.

All-cause mortality predicted by peak oxygen uptake differs depending on spirometry pattern in patients with heart failure and reduced ejection fraction.

AIMS: In patients with heart failure and reduced ejection fraction (HFrEF), it remains unclear how exacerbated impairments in peak exercise oxygen uptake (V̇O2peak ) caused by coexistent obstructive or restrictive ventilatory defects affect mortality risk. We evaluated in patients with HFrEF, whether demonstrating either an obstructive or restrictive-patterned ventilatory defect on spirometry affects V̇O2peak to yield all-cause mortality risk predicted by V̇O2peak that is spirometry pattern specific. METHODS AND RESULTS: We retrospectively analysed resting spirometry and treadmill cardiopulmonary exercise testing data of patients with HFrEF (left ventricular ejection fraction ≤ 40%). The study sample (N = 329) was grouped by spirometry pattern: normal [Group 1: N = 101; forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) ≥ 0.70; FVC ≥ 80% predicted], restrictive without airflow obstruction (Group 2: N = 104; FEV1 /FVC ≥ 0.70; FVC < 80% predicted), or obstructive (Group 3: N = 124; FEV1 /FVC < 0.70). Patients were followed up to 1 year for the endpoint of all-cause mortality. V̇O2peak was higher in Group 1 versus Groups 2 and 3 (13.4 ± 4.0 vs. 12.1 ± 3.7 and 12.2 ± 3.3 mL/kg/min, respectively; P = 0.014). Over the 1 year follow-up, n = 9, n = 16, and n = 12 deaths occurred in Groups 1-3, respectively, with corresponding crude survival rates of 88%, 81%, and 92%, respectively (log-rank; P = 0.352). V̇O2peak was associated with all-cause mortality (crude hazard ratio = 0.77; P < 0.001). In multivariate analyses, a significant V̇O2peak -by-spirometry group interaction yielded 1.99 (95% confidence interval, 1.14-3.46) and 2.43 (95% confidence interval, 1.44-4.11) higher mortality risk associated with V̇O2peak in Group 2 versus Groups 1 and 3, respectively. CONCLUSIONS: Demonstrating a restrictive pattern on spirometry yields the severest mortality risk associated with V̇O2peak . Using spirometry to screen patients with HFrEF for ventilatory defects has a potential role in improving risk stratification based on V̇O2peak .

Temporal Trends of Cardiac Outcomes and Impact on Survival in Patients With Cancer.

To evaluate the temporal relations of cardiovascular disease in oncology patients referred to cardio-oncology and describe the impact of cardiovascular disease and cardiovascular risk factors on outcomes. All adult oncology patients referred to the cardio-oncology service at the Cleveland Clinic from January 2011 to June 2018 were included in the study. Comprehensive clinical information were collected. The impact on survival of temporal trends of cardiovascular disease in oncology patients were assessed with a Cox proportional hazards model and time-varying covariate adjustment for confounders. In total, 6,754 patients were included in the study (median age, 57 years; [interquartile range, 47 to 65 years]; 3,898 women [58%]; oncology history [60% - breast cancer, lymphoma, and leukemia]). Mortality and diagnosis of clinical cardiac disease peaked around the time of chemotherapy. 2,293 patients (34%) were diagnosed with a new cardiovascular risk factor after chemotherapy, over half of which were identified in the first year after cancer diagnosis. Patients with preexisting and post-chemotherapy cardiovascular disease had significantly worse outcomes than patients that did not develop any cardiovascular disease (p < 0.0001). The highest 1-year hazard ratios (HR) of post-chemotherapy cardiovascular disease were significantly associated with male (HR 1.81; 95% confidence interval 1.55 to 2.11; p < 0.001] and diabetes [HR 1.51; 95% confidence interval 1.26 to 1.81; p < 0.001]. In conclusion, patients referred to cardio-oncology, first diagnosis of cardiac events peaked around the time of chemotherapy. Those with preexisting or post-chemotherapy cardiovascular disease had worse survival. In addition to a high rate of cardiovascular risk factors at baseline, risk factor profile worsened over course of follow-up.

Calcium/calmodulin-dependent protein kinase II causes atrial structural remodeling associated with atrial fibrillation and heart failure.

BACKGROUND: Atrial fibrillation (AF) is sustained by reentrant mechanisms that depend, in part, on atrial structural remodeling. Increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity occurs in persistent AF. A general consensus has been that electrophysiological actions of CaMKII must be the contributing factor, but electrical remodeling in AF differs considerably with electrophysiological effects of CaMKII. CaMKII has been associated with structural remodeling in several tissues, but not the cardiac atria. The role of CaMKII in sustaining AF remains undefined. OBJECTIVE: The purpose of this study was to assess the effects of CaMKII on AF-related structural remodeling. METHODS: We evaluated the objective in a porcine AF-heart failure model using atrial gene transfer of the CaMKII inhibitory peptide CaMKIIn. We used conventional methods including in vivo electrophysiological study, telemetry, western blot, echocardiography, and histology to quantify rhythm, function, microstructure, and signaling pathways relevant to CaMKII and structural remodeling. RESULTS: CaMKII levels and activity increased progressively in the early stages of AF-heart failure. Inhibiting CaMKII preserved atrial contractile function and attenuated atrial hypertrophy, fibrosis, and apoptosis but did not affect inflammation or myolysis. These effects were accompanied by significantly decreased phosphorylation of HDAC4, decreased expression of p38MAP-kinase, and alterations in the phosphorylation pattern and relative ratios of JNK isoforms. CONCLUSION: Our findings suggest that CaMKII mediates signaling pathways related to atrial contractile function and structural remodeling in AF. CaMKII inhibition is potentially a novel therapy for AF. These findings are of importance because no clinically relevant mediators of either atrial contractile function or structural remodeling have yet been identified.

Protecting the heart in cancer therapy.

Recent advances in cancer prevention and management have led to an exponential increase of cancer survivors worldwide. Regrettably, cardiovascular disease has risen in the aftermath as one of the most devastating consequences of cancer therapies. In this work, we define cancer therapeutics-induced cardiotoxicity as the direct or indirect cardiovascular injury or injurious effect caused by cancer therapies. We describe four progressive stages of this condition and four corresponding levels of prevention, each having a specific goal, focus, and means of action. We subsequently unfold this didactic framework, surveying mechanisms of cardiotoxicity, risk factors, cardioprotectants, biomarkers, and diagnostic imaging modalities. Finally, we outline the most current evidence-based recommendations in this area according to multidisciplinary expert consensus guidelines.

Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer.

AAV-mediated gene therapy has become a promising therapeutic strategy for chronic diseases. Its clinical utilization, however, is limited by the potential risk of off-target effects. In this work we attempt to overcome this challenge, hypothesizing that cardiac ion channel-specific ligands could be fused onto the AAV capsid, and narrow its tropism to cardiac myocytes. We successfully fused the cardiac sodium channel (Nav1.5)-binding toxin Anthopleurin-B onto the AAV2 capsid without compromising virus integrity, and demonstrated increased specificity of cardiomyocyte attachment. Although virus attachment to Nav1.5 did not supersede the natural heparan-mediated virus binding, heparan-binding ablated vectors carrying Anthopleurin-B eliminated hepatic and other extracardiac gene transfer, while preserving cardiac myocyte gene transfer. Virus binding to the cardiac sodium channel transiently decreased sodium current density, but did not cause any arrhythmias. Our findings expand the knowledge of attachment, infectivity, and intracellular processing of AAV vectors, and present an alternative strategy for vector retargeting.