Clinical performance and exercise hemodynamics in patients with severe secondary tricuspid regurgitation and chronic atrial fibrillation.

OBJECTIVE: The study aimed to investigate the functional capacity and hemodynamics at rest and during exercise in patients with chronic atrial fibrillation and severe functional symptomatic tricuspid regurgitation (AF-FTR). BACKGROUND: Symptoms and clinical performance of severe AF-FTR mimic the population of patients with heart failure with preserved ejection fraction (HFpEF). Severe AF-FTR is known to be associated with an adverse prognosis whereas less is reported about the clinical performance including exercise capacity and hemodynamics in patients symptomatic AF-FTR. METHODS: Right heart catheterization (RHC) at rest and during exercise was conducted in a group of patients with stable chronic AF-TR and compared with a group of patients with HFpEF diagnosed with cardiac amyloid cardiomyopathy (CA). All patients had preserved ejection fraction and no significant left-sided disease. RESULTS: Patients with AF-FTR demonstrated a low exercise capacity that was comparable to CA patients (TR 4.9 ± 1.2 METS vs. CA 4. 7 ± 1.5 METS; P = 0.78) with an average peak maximal oxygen consumption of 15 mL/min/kg. Right atrium pressure increased significantly more in the AF-FTR patients as compared to CA patients at peak exercise (25 ± 8 vs 19 ± 9, p < 0.01) whereas PCWP increased significantly to a similar extent in both groups (31 ± 4 vs 31 ± 8 mmHg, p = 0.88). Cardiac output (CO) was significantly lower among AF-FTR at rest as compared to CA patients (3.6 ± 0.9 vs 4.4 ± 1.3 l/min; p < 0.05) whereas both groups demonstrated a poor but comparable CO reserve at peak exercise (7.3 ± 2.9 vs 7.9 ± 3.8 l/min, p = 0.59). CONCLUSIONS: AF-FTR contributes to the development of advanced heart failure symptoms and poor exercise capacity reflected in increased atrial filling pressures, reduced cardiac output at rest and during exercise sharing common features seen in HFpEF patients with other etiologies.

Right Ventricular and Pulmonary Vascular Function are Influenced by Age and Volume Expansion in Healthy Humans.

BACKGROUND: Patients with heart failure (HF) often show signs of right ventricular (RV) dysfunction. The RV function of coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]/pulmonary arterial systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, but less is known about which factors influence this prognostic marker, and whether those factors can be modified. We sought to obtain normative values and discern the individual effects of age, sex, and fluid overload on RV function. METHODS AND RESULTS: Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest after a rapid saline solution infusion (10 mL/kg, 150 mL/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE/PASP and relevant variables. In healthy persons of all ages, the median (5th-95th percentiles) normative TASPE-PASP ratio was 1.25 (0.81-1.78) mm/mm Hg. The correlation between progressive age and declining TAPSE/PASP was significant (r = -0.35; P = .006). Sex did not influence TAPSE/PASP (P = .30). Rapid fluid expansion increased central venous pressure from 5 ± 2 mm Hg to 11 ± 4 mm Hg after fluid infusion (P < .0001). This resulted in a 32% decrease in the TAPSE-PASP ratio after fluid infusion, compared to baseline (P < .0001). CONCLUSIONS: The TAPSE-PASP ratio was affected by age, but not sex. TAPSE/PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status also dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients.

Layer-specific deformation analysis in severe aortic valve stenosis, primary mitral valve regurgitation, and healthy individuals validated against invasive hemodynamic measurements of heart function.

AIM: Speckle tracking echocardiography is considered valuable in assessing left ventricular (LV) function. The method has been refined to assess deformation in different myocardial layers, but the effect of volume vs pressure overload on this pattern is unknown. The aim was to test whether layer-specific myocardial strain (LSS) obtained by speckle tracking echocardiography exhibits different patterns in conditions with different loading conditions. METHODS AND RESULTS: Forty patients with asymptomatic severe aortic stenosis (AS) (AVA 0.81 ± 0.15 cm2 , LV ejection fraction [LVEF] 66% ± 7%), 43 patients with asymptomatic or mildly symptomatic significant primary mitral regurgitation (MR) (effective regurgitant orifice (ERO) 0.51 (IQR 0.37-0.67) cm2 , LVEF 70% ± 7%), and 23 healthy individuals (LVEF 65% ± 6%) were enrolled. Echocardiography and right heart catheterization were performed in all patients. In MR, strain values in each myocardial layer (endocardial/global longitudinal strain (GLS)/epicardial) were higher (25.0% ± 3.4%/21.6% ± 2.9%/18.8% ± 2.6%) compared to healthy individuals (22.6% ± 3.2%/19.6% ± 2.9%/17.1% ± 2.6%) and AS (20.5% ± 2.8%/17.7% ± 2.5%/14.0% ± 5.6%), P < .001. All 3 groups exhibited a similar LSS pattern with highest values in the endocardial and lowest values in the epicardial layer. The epicardial-endocardial strain ratio was lower in AS (0.72 ± 0.04) than in MR (0.75 ± 0.04, P = .04). Global longitudinal strain (GLS) correlated significantly with LV wall stress (r = .39, P = .0003) but not with LV stroke work or contractility. CONCLUSION: Layer-specific myocardial strain (LSS) patterns differed in patients with severe AS, significant MR, and healthy individuals with highest values in MR. Strain irrespective of layer assessed was associated with LV wall stress but seemed less related to contractility and unrelated to stroke work in the setting of normal LVEF.

Association diastolic function by echo and infarct size by magnetic resonance imaging after STEMI.

OBJECTIVES: Left ventricular (LV) diastolic dysfunction is a predictor of increased morbidity and mortality; however, little is known about diastolic function and the degree of myocardial damage after myocardial infarction (MI). The aim was to assess the association between diastolic dysfunction by echocardiography and myocardial salvage assessed with cardiac magnetic resonance (CMR) imaging in patients with ST-segment elevation MI (STEMI). DESIGN: In a prospective study, echocardiography and CMR were performed in STEMI patients in the early post-MI phase assessing diastolic dysfunction according to E/A and E/e'average and area at risk, and after three months with measurement of final infarct size and salvage index. Linear regression analyses were performed testing the association of diastolic dysfunction with area at risk, final infarct size and salvage index. RESULTS: A total of 193 patients (61 ± 11 years) were included. Median system delay (first medical contact to primary PCI) was 185 min, 123 patients (63%) had TIMI 0/1 flow before intervention and 85 (46%) sustained an anterior MI. In 74 patients (38%), diastolic function was normal. The presence of diastolic dysfunction was associated with larger area at risk of median 6.6% (p < 0.001), larger final infarct size of 4.5% (p < 0.001), and lower salvage index of -5.9% (p = 0.02) compared with patients with normal diastolic function. CONCLUSION: Diastolic dysfunction in the early phase after STEMI is associated with more extensive myocardial damage and significantly poorer myocardial salvage after three months, and the presence of diastolic dysfunction acutely after STEMI may therefore be used as a marker of worse myocardial outcome.

Early diastolic strain rate in relation to systolic and diastolic function and prognosis in acute myocardial infarction: a two-dimensional speckle-tracking study.

AIMS: Diastolic dysfunction in acute myocardial infarction (MI) is associated with adverse outcome. Recently, the ratio of early mitral inflow velocity (E) to global diastolic strain rate (e'sr) has been proposed as a marker of elevated LV filling pressure. However, the prognostic value of this measure has not been demonstrated in a large-scale setting when existing parameters of diastolic function are known. We hypothesized that the E/e'sr ratio would be independently associated with an adverse outcome in patients with MI. METHODS AND RESULTS: We prospectively included patients with MI and performed echocardiography with comprehensive diastolic evaluation including E/e'sr. The relationship between E/e'sr and the primary composite endpoint (all-cause mortality, hospitalization for heart failure (HF), stroke, and new onset atrial fibrillation) was analysed with Cox models. A total of 1048 patients (mean age 63 ± 12, 73% male) were included and 142 patients (13.5%) reached the primary endpoint (median follow-up 29 months). A significant prognostic value was found for E/e'sr [hazard ratio (HR) per 1 unit change: 2.36, 95% confidence interval (CI): 2.02-2.75, P < 0.0001]. After multivariable adjustment E/e'sr remained independently related to the combined endpoint (HR per 1 unit change, 1.50; CI: 1.05-2.13, P = 0.02). The prognostic value of E/e'sr was driven by mortality (HR per 1 unit change, 2.52; CI: 2.09-3.04, P < 0.0001) and HF admissions (HR per 1 unit change, 2.79; CI: 2.23-3.48, P < 0.0001). CONCLUSION: Deformation-based E/e'sr contributes important information about global myocardial relaxation superior to velocity-based analysis and is independently associated with the outcome in acute MI.

Sildenafil and diastolic dysfunction after acute myocardial infarction in patients with preserved ejection fraction: the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (SIDAMI) trial.

BACKGROUND: Diastolic dysfunction is frequently seen after myocardial infarction and is characterized by a disproportionate increase in filling pressure during exercise to maintain stroke volume. We hypothesized that sildenafil would reduce filling pressure during exercise in patients with diastolic dysfunction after myocardial infarction. METHODS AND RESULTS: Seventy patients with diastolic dysfunction and near normal left ventricular ejection fraction on echocardiography were randomly assigned sildenafil 40 mg thrice daily or matching placebo for 9 weeks. Before randomization and after 9 weeks of treatment patients underwent simultaneous echocardiography and right heart catheterization at rest and during exercise. Primary end point was pulmonary capillary wedge pressure, and secondary end points comprised cardiac index and pulmonary arterial pressure at rest and during exercise after 9 weeks. After 9 weeks there were no differences in pulmonary capillary wedge pressure at rest (13±4 versus 13±3 mm Hg, P=0.25) or at peak exercise (35±8 mm Hg versus 31±7 mm Hg, P=0.07). However, with treatment cardiac index increased at rest (P=0.006) and peak exercise (P=0.02) in the sildenafil group, and systemic vascular resistance index (resting, P=0.0002; peak exercise, P=0.007) and diastolic blood pressure (resting, P=0.005; peak exercise, P=0.02) were lower in the sildenafil group. Resting left ventricular end-diastolic volume index increased (P=0.001) within the sildenafil group but was unchanged in the placebo group. CONCLUSIONS: Sildenafil did not decrease filling pressure at rest or during exercise in post-myocardial infarction patients with diastolic dysfunction. However, there were effects on secondary end points, which require further studies.

Relationships between biomarkers and left ventricular filling pressures at rest and during exercise in patients after myocardial infarction.

BACKGROUND: Increased pulmonary capillary wedge pressure (PCWP) is an independent prognostic predictor after myocardial infarction (MI), but PCWP is difficult to assess noninvasively in subjects with preserved ejection fraction (EF). We hypothesized that biomarkers would provide information regarding PCWP at rest and during exercise in subjects with preserved EF after MI. METHODS AND RESULTS: Seventy-four subjects with EF >45% and recent MI underwent right heart catheterization at rest and during a symptom-limited semisupine cycle exercise test with simultaneous echocardiography. Plasma samples were collected at rest for assessment of midregional pro-A-type natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), copeptin, and midregional pro-adrenomedullin (MR-proADM). Plasma levels of MR-proANP and PCWP were associated at rest (r = 0.33; P = .002) and peak exercise (r = 0.35; P = .002) as well as with changes in PCWP (r = 0.26; P = .03). Plasma levels of NT-proBNP and PCWP were weakly associated at rest (r = 0.23; P = .03) and peak exercise (r = 0.28; P = .02) but not with changes in PCWP (r = 0.20; P = .09). In a multivariable analysis, plasma levels of MR-proANP remained associated with rest and exercise PCWP (P < .01), whereas NT-proBNP did not. Plasma levels of Gal-3, copeptin, and MR-proADM were not associated with PCWP at rest or peak exercise. CONCLUSIONS: In subjects recovering from an acute MI with preserved EF, plasma levels of natriuretic peptides, particularly MR-proANP, are associated with filling pressures at rest and during exercise.

Heart failure with preserved ejection fraction: current understandings and challenges.

Heart failure (HF) is the leading cause of hospitalization among older adults and the prevalence is growing with the aging populations in western countries. Approximately one-half of patients with HF have preserved ejection fraction (HFpEF). In contrast to HF with reduced EF (HFrEF), there is no proven effective treatment for HFpEF. The pathophysiology of HFpEF is complex, and the dominant mechanisms leading to symptoms of HF often vary between afflicted patients, confounding efforts to apply "one-size fits all" types of therapeutic approaches. Current treatment strategies focus on control of volume status and comorbidities, but future research aimed at individualized therapies holds promise to improve outcomes in this increasingly prevalent form of cardiac failure.

Invasive hemodynamic characterization of heart failure with preserved ejection fraction.

Recent hemodynamic studies have advanced our understanding of heart failure with preserved ejection fraction (HFpEF). Despite improved pathophysiologic insight, clinical trials have failed to identify an effective treatment for HFpEF. Invasive hemodynamic assessment can diagnose or exclude HFpEF, making it invaluable in understanding the basis of the disease. This article reviews the hemodynamic mechanisms underlying HFpEF and how they manifest clinically, discusses invasive hemodynamic assessment as a diagnostic tool, and explores how invasive hemodynamic profiling may allow understanding of pathophysiological differences and inform the design and entry criteria for future trials.

Metoprolol Improves Left Ventricular Longitudinal Strain at Rest and during Exercise in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with obstructive hypertrophic cardiomyopathy (HCM) often experience symptoms of heart failure upon exertion despite having normal left ventricular (LV) ejection fractions. Longitudinal strain (LS) may be a more sensitive marker of systolic dysfunction in patients with LV hypertrophy. The aims of this study were to characterize LV segmental LS and global LS (GLS) at rest and during exercise and to assess if first-line treatment with ß-blockers improves LV systolic performance. METHODS: Twenty-nine patients with obstructive HCM and New York Heart Association functional class ≥ II symptoms were enrolled in a double-blind, placebo-controlled, randomized crossover trial. Patients received metoprolol 150 mg or placebo for two consecutive 2-week periods in random order. Echocardiographic assessment with speckle-tracking-derived LS was performed at rest and during peak exercise at the end of each treatment period. RESULTS: During placebo treatment, resting values of segmental LS showed an apical-basal difference of -10.3% (95% CI, -12.7% to -7.8%; P < .0001), with a severely abnormal value of the basal segment of -9.3 ± 4.2%. Treatment with metoprolol was associated with more negative LS values of the apical segment (-2.8%; 95% CI, -4.2% to -1.3%; P < .001) and the mid segment (-1.1%; 95% CI, -2.0% to -0.3%; P = .007). During peak exercise there was a deterioration in LV GLS, but treatment with metoprolol was associated with more negative peak exercise LV GLS (-1.3 %; 95% CI, -2.6% to -0.1%; P = .03). CONCLUSIONS: Systolic performance assessed by LV GLS showed impaired values at rest and during exercise, with severely depressed values of the basal and mid segments. Treatment with metoprolol improved LV GLS upon exercise, indicating a beneficial effect of ß-blocker treatment on LV systolic function.

Long-Term Prognostic Impact of Pulmonary Hypertension After Venous Thromboembolism.

Pulmonary embolism is a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prognostic impact of CTEPH on venous thromboembolism (VTE) mortality remains unclear. We examined the impact of CTEPH and other pulmonary hypertension (PH) subtypes on long-term mortality after VTE. We conducted a nationwide, population-based cohort study of all adult Danish patients alive 2 years after incident VTE without previous PH from 1995 to 2020 (n = 129,040). We used inverse probability of treatment weights in a Cox model to calculate standardized mortality rate ratios (SMRs) of the association between receiving a first-time PH diagnosis ≤2 years after incident VTE and mortality (all-cause, cardiovascular, and cancer). We grouped PH as PH associated with left-sided cardiac disease (group II), PH associated with lung diseases and/or hypoxia (group III), CTEPH (group IV), and unclassified (remaining patients). Total follow-up was 858,954 years. The SMR associated with PH overall was 1.99 (95% confidence interval 1.75 to 2.27) for all-cause, 2.48 (1.90 to 3.23) for cardiovascular, and 0.84 (0.60 to 1.17) for cancer mortality. The SMR for all-cause mortality was 2.62 (1.77 to 3.88) for group II, 3.98 (2.85 to 5.56) for group III, 1.88 (1.11 to 3.20) for group IV, and 1.73 (1.47 to 2.04) for unclassified PH. The cardiovascular mortality rate was increased approximately threefold for groups II and III but was not increased for group IV. Only group III was associated with increased cancer mortality. In conclusion, PH diagnosed ≤2 years after incident VTE was associated with an overall twofold increased long-term mortality driven by cardiovascular causes.

Effects of Metoprolol on Exercise Hemodynamics in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The relationship between exercise hemodynamics, loading conditions, and medical treatment in patients with obstructive hypertrophic cardiomyopathy (HCM) is incompletely understood. OBJECTIVES: This study aimed to investigate the effect of metoprolol on invasive hemodynamic parameters at rest and during exercise in patients with obstructive HCM. METHODS: This randomized, double-blind, placebo-controlled crossover trial enrolled 28 patients with obstructive HCM and New York Heart Association functional class ≥II. Patients were randomized to initiate either metoprolol 150 mg or placebo for 2 consecutive 2-week periods. Right-heart catheterization and echocardiography were performed at rest and during exercise at the end of each treatment period. The primary outcome was the difference in pulmonary capillary wedge pressure (ΔPCWP) between peak exercise and rest. RESULTS: No treatment effect on ΔPCWP was observed between metoprolol and placebo treatment (21 ± 9 mm Hg vs 23 ± 9 mm Hg; P = 0.12). At rest, metoprolol lowered heart rate (P < 0.0001), left ventricular outflow tract (LVOT) gradient (P = 0.01), and increased left ventricular end-diastolic volume (P = 0.02) and stroke volume (SV) (+6.4; 95% CI: 0.02-17.7; P = 0.049). During peak exercise, metoprolol was associated with a lower heart rate (P < 0.0001), a lower LVOT gradient (P = 0.0005), lesser degree of mitral regurgitation (P = 0.004), and increased SV (+9 mL; 95% CI: 2-15 mL; P = 0.008). CONCLUSIONS: In patients with obstructive HCM, exercise was associated with an abnormal rise in PCWP, which was unaffected by metoprolol. However, metoprolol increased SV at rest and peak exercise following changes in end-diastolic volume, LVOT gradient, and degree of mitral regurgitation. (The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).

Pressure-flow responses to exercise in aortic stenosis, mitral regurgitation and diastolic dysfunction.

BACKGROUND: Haemodynamic exercise testing is important for evaluating patients with dyspnoea on exertion and preserved ejection fraction. Despite very different pathologies, patients with pressure (aortic stenosis (AS)) and volume (mitral regurgitation (MR)) overload and diastolic dysfunction after recent acute myocardial infarction (AMI) reach similar filling pressure levels with exercise. The pressure-flow relationships (the association between change in cardiac output (∆CO) and change in pulmonary arterial wedge pressure (∆PAWP) may provide insight into haemodynamic adaptation to exercise in these groups. METHODS AND RESULTS: One hundred sixty-eight subjects aged >50 years with a left ventricular ejection fraction of ≥50% underwent invasive exercise testing. They were enrolled in four different studies: AS (40 patients), AMI (52 patients), MR (43 patients) and 33 healthy subjects. Haemodynamic data were measured at rest, at 25 W, 75 W and at peak exercise. In all groups, PAWP increased with exercise. The greatest increase was observed in patients with AMI (from 12.7±3.9 mm Hg to 33.1±8.2 mm Hg, p<0.0001) and patients with AS (from 11.8±3.9 mm Hg to 31.4±6.1 mm Hg, p<0.0001), and the smallest was observed in healthy subjects (from 8.3±2.4 mm Hg to 21.1±7.5 mm Hg, p<0.0001). In all groups, the relative pressure increase was greatest at the beginning of the exercise. CO increased most in healthy patients (from 5.3±1.1 to 16.0±3.0 L/min, p<0.0001) and least in patients with AS (from 5.3±1.2 L/min to 12.4±2.6 L/min, p<0.0001). The pressure-flow relationships (∆PAWP/∆CO) and differed among groups (p=0.02). In all groups, the pressure-flow relationship was steepest in the initial phase of the exercise test. The AMI and AS groups (2.3±1.2 mm Hg/L/min and 3.0±1.3 mm Hg/L/min, AMI and AS, respectively) had the largest overall pressure-flow relationship; the healthy group had the smallest initially and at peak exercise (1.3±1.1 mm Hg/L/min) followed by MR group (1.9±1.4 mm Hg/L/min). CONCLUSION: The pressure-flow relationship was steepest in the initial phase of the exercise test in all groups. The pressure-flow relationship differs between groups. TRIAL REGISTRATION NUMBERS: NCT01974557, NCT01046838, NCT02961647 and NCT02395107.

Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea.

Importance: Diagnosis of heart failure with preserved ejection fraction (HFpEF) among dyspneic patients without overt congestion is challenging. Multiple diagnostic approaches have been proposed but are not well validated against the independent gold standard for HFpEF diagnosis of an elevated pulmonary capillary wedge pressure (PCWP) during exercise. Objective: To evaluate H2FPEF and HFA-PEFF scores and a PCWP/cardiac output (CO) slope of more than 2 mm Hg/L/min to diagnose HFpEF. Design, Setting, and Participants: This retrospective case-control study included patients with unexplained dyspnea from 6 centers in the US, the Netherlands, Denmark, and Australia from March 2016 to October 2020. Diagnosis of HFpEF (cases) was definitively ascertained by the presence of elevated PCWP during exertion; control individuals were those with normal rest and exercise hemodynamics. Main Outcomes and Measures: Logistic regression was used to evaluate the accuracy of HFA-PEFF and H2FPEF scores to discriminate patients with HFpEF from controls. Results: Among 736 patients, 563 (76%) were diagnosed with HFpEF (mean [SD] age, 69 [11] years; 334 [59%] female) and 173 (24%) represented controls (mean [SD] age, 60 [15] years; 109 [63%] female). H2FPEF and HFA-PEFF scores discriminated patients with HFpEF from controls, but the H2FPEF score had greater area under the curve (0.845; 95% CI, 0.810-0.875) compared with the HFA-PEFF score (0.710; 95% CI, 0.659-0.756) (difference, -0.134; 95% CI, -0.177 to -0.094; P < .001). Specificity was robust for both scores, but sensitivity was poorer for HFA-PEFF, with a false-negative rate of 55% for low-probability scores compared with 25% using the H2FPEF score. Use of the PCWP/CO slope to redefine HFpEF rather than exercise PCWP reclassified 20% (117 of 583) of patients, but patients reclassified from HFpEF to control by this metric had clinical, echocardiographic, and hemodynamic features typical of HFpEF, including elevated resting PCWP in 66% (46 of 70) of reclassified patients. Conclusions and Relevance: In this case-control study, despite requiring fewer data, the H2FPEF score had superior diagnostic performance compared with the HFA-PEFF score and PCWP/CO slope in the evaluation of unexplained dyspnea and HFpEF in the outpatient setting.

Randomized Trial of Metoprolol in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: The use of ß-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies. OBJECTIVES: This study aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM. METHODS: This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing. RESULTS: Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg [interquartile range (IQR): 15-58 mm Hg] vs 72 mm Hg [IQR: 28-87 mm Hg]; P = 0.007), at peak exercise (28 mm Hg [IQR: 18-40 mm Hg] vs 62 mm Hg [IQR: 31-113 mm Hg]; P < 0.001), and postexercise (45 mm Hg [IQR: 24-100 mm Hg] vs 115 mm Hg [IQR: 55-171 mm Hg]; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms. CONCLUSIONS: Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).

Felodipine and renal function in lung transplantation: A randomized placebo-controlled trial.

BACKGROUND: Calcium channel blockers may ameliorate the decline in renal function caused by calcineurin inhibitors in lung transplantation (LTX) recipients. We hypothesized that pre-operative and 12-week post-operative treatment with the calcium channel blocker felodipine would reduce the decline in glomerular filtration rate (GFR). METHODS: In this prospective, randomized, double-blind trial, 39 LTX recipients were transplanted and received placebo (n = 19; GFR, 102 ml/min/1.73 m2 [range, 91-113 ml/min/1.73 m2]) or felodipine (n = 20, GFR, 96 ml/min/1.73 m2 [range, 88-104 ml/min/1.73 m2]). Pre-operative treatment was titrated post-operatively to 10 mg or the maximum tolerable dose. The primary end-point was the change in GFR using Cr-51-labeled EDTA from LTX to 12 weeks thereafter, and follow-up was 52 weeks. RESULTS: The treatment group showed an absolute mean decline in GFR of 31 ml/min/1.73 m2 (95% CI: -40 to 22 ml/min/1.73 m2), whereas that of the placebo group was 48 ml/min/1.73 m2 (95% confidence interval [CI]: -56 to 40 ml/min/1.73 m2). Thus, the difference between groups at 12 weeks was 17 ml/min/1.73 m2 (95% CI: 4-29 ml/min/1.73 m2; p = 0.01). Half of the patients were unable to complete the 3-month primary follow-up, and the analysis includes these patients by intention-to-treat. After 52 weeks (40 weeks after termination of treatment), the treatment effect was maintained at 12 ml/min/1.73 m2 (95% CI: 0-24 ml/min/1.73 m2, p = 0.05). The number of days with registered hypotension was significantly higher in the felodipine group than in the placebo group (39 days vs 13 days, rate ratio: 2.9 [95% CI: 1.5-5.3]). CONCLUSIONS: Use of felodipine in select patients was associated with greater preservation in renal function early (90 days) after LTX. The observed benefits were attenuated by 1 year, although trends in better renal function were noted.

Cardiac remodelling and haemodynamic characteristics in primary mitral valve regurgitation.

Objective: To assess the association between cardiac morphology and function assessed with cardiac MRI (CMRI) and haemodynamics at rest and during exercise in patients with primary mitral regurgitation (MR). Methods: In an observational study, subjects with significant primary MR (N = 46) with effective regurgitant orifice ≥ 0.30 cm2 and left ventricular (LV) ejection fraction > 60% were examined with right heart catheterisation during rest and exercise and CMRI at rest. End-diastolic pressure volume relationship (EDPVR) was assessed using a single beat method using pulmonary capillary wedge pressure (PCWP) and end-diastolic volume. Patients were divided according to normal PCWP at rest (> 12 mm Hg) and with exercise (> 28 mm Hg). Results: Resting regurgitant volume correlated positively with resting PCWP, (r = 0.42, p = 0.002). However, with exercise no association between PCWP and regurgitant volume was seen (r = 0.09, p = 0.55). At rest left atrial (LA) maximal, minimal and volume index at atrial contraction correlated positively with PCWP (r = 0.60; r = 0.55; r = 0.58, all p < 0.001); in contrast none of these correlated with exercise PCWP (all p > 0.2). EDPVR in patients with high PCWP at rest was shifted towards higher volumes for the same pressures. The opposite was seen for patients with high PCWP during exercise where estimated volumes were smaller for the same pressure than patients with normal exercise PCWP. Conclusion: In patients with significant MR the degree of regurgitation and LA dilatation is associated with resting PCWP. However, with exercise this association disappears. Estimation of EDPVR suggests lower LV compliance in patients where PCWP is increased with exercise. Clinical trial registration: URL: https://clinicaltrials.gov/ct2/show/NCT02961647?term=HEMI&rank=1. ID: NCT02961647.

The Influence of Age on Hemodynamic Parameters During Rest and Exercise in Healthy Individuals.

OBJECTIVES: In this study, the authors sought to obtain hemodynamic estimates across a wide age span and in both sexes for future reference and compare these estimates with current guideline diagnostic hemodynamic thresholds for abnormal filling pressure and pulmonary hypertension. BACKGROUND: At present, the influence of age on hemodynamic function is largely unknown. Because many diseases with proposed cardiac impact are more prevalent in the older population, it is pivotal to know how hemodynamic parameters are affected by age itself to discern the influence of disease from that of physiological aging. METHODS: Sixty-two healthy participants, evenly distributed with respect to age (20 to 80 years) and sex (32 women/30 men), were prospectively enrolled in the study. Participants were all deemed healthy by medical history, echocardiography, exercise test, spirometry, blood tests, and electrocardiogram. Participants had hemodynamic parameters measured using right heart catheterization during rest, passive leg raise, and incremental exercise. RESULTS: During rest, all hemodynamic parameters were similar between age groups, apart from blood pressure. During leg raise and incremental exercise, there was augmented filling pressure (p < 0.0001) and diminished cardiac output (p = 0.001) and hence a higher pressure:flow ratio (pulmonary artery pressure/capillary wedge pressure to cardiac output) with progressive age, evident from the earliest ages. All indexed hemodynamic measures were similar between sexes. The diagnostic threshold (pulmonary capillary wedge pressure ≥25 mm Hg) currently used during exercise testing to diagnose abnormal left ventricular filling pressure was measured in 30% of our healthy elderly participants. CONCLUSIONS: Cardiac aging was progressive without sex differences in healthy participants. The hemodynamic reference values obtained suggest that the diagnostic threshold for abnormal filling pressure should be individually determined according to age of the patient.

Arterial Stiffening With Exercise in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Aortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This study compared indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive control subjects to examine their relationships to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite. METHODS: A total of 22 hypertensive control subjects and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis to measure oxygen consumption. Invasively measured radial artery pressure waveforms were converted to central aortic waveforms by transfer function to assess integrated measures of pulsatile aortic load, including arterial compliance, resistance, elastance, and wave reflection. RESULTS: Arterial load and wave reflections in HFpEF were similar to those in control subjects at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures in control subjects. This was directly correlated with higher ventricular filling pressures and depressed cardiac output reserve (both p < 0.0001). With peak exercise, increased wave reflections, impaired compliance, and increased resistance and elastance were observed in subjects with HFpEF. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo therapy in a 1:1 double-blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance and elastance and central hemodynamics during exercise. CONCLUSIONS: Abnormal pulsatile aortic loading during exercise occurs in HFpEF independent of hypertension and is correlated with classical hemodynamic derangements that develop with stress. Inorganic nitrite mitigates arterial stiffening with exercise and improves hemodynamics, indicating that arterial stiffening with exercise is at least partially reversible. Further study is required to test effects of agents that target the NO pathway in reducing arterial stiffness in HFpEF. (Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease [EXEC]; NCT01418248. Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606. Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction; NCT02262078).