Clinical impact of the pathological quantification of myocardial fibrosis and infiltrating T lymphocytes using an endomyocardial biopsy in patients with hypertrophic cardiomyopathy.

BACKGROUND: The impact of quantitative pathological findings derived from endomyocardial biopsies (EMB) on clinical prognosis in patients with hypertrophic cardiomyopathy (HCM) remains unclear. METHODS: We retrospectively studied 55 consecutive HCM patients who underwent EMB. We quantified the collagen area fraction (CAF), the cardiomyocyte diameter, the nuclear area and circularity, and the number of myocardial infiltrating CD3+ cells using EMB samples by image analyzing software. The primary clinical endpoint was defined as a composite including cardiovascular death, admission due to heart failure and ventricular arrhythmia. RESULTS: During the median follow-up of 37.2 months, the primary endpoint was found in 12 patients. No significant difference in the risk score of 5-year sudden cardiac death was observed between the event-occurrence group and the event-free group. In the multivariable Cox proportional-hazard analysis, CAF [hazard ratio (HR) per 10% increase: 1.555, 95% CI: 1.014-2.367, p = 0.044] and the number of infiltrating CD3+ cells (HR per 10% increase: 1.231, 95% CI: 1.011-1.453, p = 0.041) were the independent predictors of the primary endpoint, while the myocardial diameter and the nuclear irregularity had no significant prognostic impact. Kaplan-Meier survival curves demonstrated that patients with both higher CAF and higher number of CD3+ cells had the worst prognosis (log-rank, P < 0.001). CONCLUSIONS: The higher CAF and the higher number of infiltrating CD3+ cells quantified using EMB samples were the independent predictors of poor clinical outcomes in patients with HCM. Cardiomyocyte diameter and nuclear irregularity did not significantly impact the clinical prognosis.

Ventricular Sigmoid Septum as a Risk Factor for Anthracycline-Induced Cancer Therapeutics-Related Cardiac Dysfunction in Patients With Malignant Lymphoma.

Background: Identifying risk factors for cancer therapeutics-related cardiac dysfunction (CTRCD) is essential for the early detection and prompt initiation of medial therapy for CTRCD. No study has investigated whether the sigmoid septum is a risk factor for anthracycline-induced CTRCD. Methods and Results: We enrolled 167 patients with malignant lymphoma who received a CHOP-like regimen from January 2008 to December 2017 and underwent both baseline and follow-up echocardiography. Patients with left ventricular ejection fraction (LVEF) ≤50% were excluded. CTRCD was defined as a ≥10% decline in LVEF and LVEF <50% after chemotherapy. The angle between the anterior wall of the aorta and the ventricular septal surface (ASA) was measured to quantify the sigmoid septum. CTRCD was observed in 36 patients (22%). Mean LVEF and global longitudinal strain (GLS) were lower, left ventricular mass index was higher, and ASA was smaller in patients with CTRCD. In a multivariable Cox proportional hazard analysis, GLS (hazard ratio [HR] per 1% decrease 1.20; 95% confidence interval [CI] 1.07-1.35) and ASA (HR per 1° increase 0.97; 95% CI 0.95-0.99) were identified as independent determinants of CTRCD. An integrated discrimination improvement evaluation confirmed the significant incremental value of ASA for developing CTRCD. Conclusions: Smaller ASA was an independent risk factor and had significant incremental value for CTRCD in patients with malignant lymphoma who received the CHOP-like regimen.

Early detection and progression of sepsis-related myocardial calcification with subsequent left ventricular systolic dysfunction: a case report.

Sepsis-related myocardial calcification (SRMC) is a life-threatening complication. However, it is a rare entity and its clinical course is not well-understood. A 54-year-old man after bone graft surgery presented with septic shock due to surgical site infection. The initial computed tomography (CT) showed no deposit of calcium in the left ventricle (LV), and echocardiography demonstrated preserved left ventricular ejection fraction (LVEF) of 61%. On the 10th day of admission, CT detected new-onset LV myocardial calcification with preserved LVEF of 60% in echocardiography. On the 63rd day, follow-up CT revealed an increased density of the calcified lesion in the LV, and echocardiography showed a significantly reduced LVEF of 30%. This case report clarified a clinical course of SRMC that the calcium deposit began early after the onset of sepsis and LV systolic function declined subsequently along with the progression of the LV calcification. A serial assessment of CT and echocardiography from the initial stage in sepsis could be helpful for early detection and appropriate management of SRMC patients. Learning objective:Sepsis-related myocardial calcification (SRMC) is under-diagnosed in daily clinical practice because most cases progress silently. By serially assessing computed tomography and echocardiography in patients with sepsis from the initial stage, we can detect SRMC early and follow a change in the calcium in the left ventricle (LV) and LV function.>.

Multimorbidity, polypharmacy, and mortality in older patients with pacemakers.

BACKGROUND: The prevalence of multimorbidity and polypharmacy and its association with all-cause mortality in older patients with pacemakers are largely unknown. We aimed to clarify the prevalence of multimorbidity and polypharmacy, and its association with all-cause mortality in patients ≥75 years of age with pacemakers. METHODS: We retrospectively investigated 256 patients aged ≥75 years (mean age 84.0 ± 5.3 years; 45.7% male) with newly implanted pacemakers. The study endpoint was all-cause mortality ("with events"). Multimorbidity was defined as a Charlson Comorbidity Index ≥3. Polypharmacy was defined as the use of ≥5 medications. RESULTS: During the follow-up period (median, 3.1 years), 60 all-cause deaths were reported. The Charlson Comorbidity Index (2.9 ± 1.9 vs. 1.7 ± 1.7, p < .001) and prevalence of multimorbidity (56.7% vs. 26.0%, p < .001) were significantly higher in deceased patients than in survivors. The number of drugs (6.9 ± 3.0 vs. 5.9 ± 3.3, p = .03) and the prevalence of polypharmacy (78.3% vs. 63.8%, p = .04) were significantly higher in patients with events than in those without events. The event-free survival rate was significantly higher among patients without multimorbidity than in those with multimorbidity (log-rank, p < .001), and was also significantly higher among patients without polypharmacy than in those with polypharmacy (log-rank, p < .001). Multimorbidity (hazard ratio [HR]: 3.21; 95% confidence interval [CI]: 1.85-5.58; p < .001) and polypharmacy (HR: 1.97; 95% CI: 1.03-3.77; p = .04) were independent predictors of all-cause mortality. CONCLUSIONS: Multimorbidity and its associated polypharmacy, which are common in the older population, are prevalent in patients with pacemakers and are independent predictors of poor prognosis.

Effects of catheter-based renal denervation on heart failure with reduced ejection fraction: a meta-analysis of randomized controlled trials.

Despite the major progress in the treatment of heart failure, the burden of heart failure is steadily increasing in the Western world. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Recent studies have shown that catheter-based renal denervation (RDN) presents a safe and minimally invasive treatment option for uncontrolled hypertension, a condition that is driven by increased sympathetic activity. Although randomized controlled trials (RCTs) have examined the effect of RDN in heart failure patients, results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs on the effect of RDN in heart failure patients with reduced left ventricular (LV) ejection fraction (EF). Electronic search identified 5 RCTs including 177 patients. In the pooled analysis, RDN increased LVEF (weighted mean difference (WMD) [95% CI] = 6.289 [1.883, 10.695]%) and 6-min walk distance (61.063 [24.313, 97.813] m) and decreased B-type natriuretic peptide levels (standardized mean difference [95% CI] = - 1.139 [- 1.824, - 0.454]) compared with control. In contrast, RDN did not significantly change estimated glomerular filtration rate (WMD [95% CI] = 5.969 [- 2.595, 14.533] ml/min/1.73 m2) and systolic (- 1.991 [- 15.639, 11.655] mmHg) or diastolic (- 0.003 [- 10.325, 10.320] mmHg) blood pressure compared with control. Our meta-analysis suggests that RDN may improve LV function and exercise capacity in heart failure patients with reduced EF, providing the rationale to conduct large-scale multicenter trials to confirm the observed potential benefits of RDN.

Non-Invasive Estimation of Left Ventricular Filling Pressure Based on Left Atrial Area Strain Measured With Transthoracic 3-Dimensional Speckle Tracking Echocardiography in Patients With Coronary Artery Disease.

Background: Chronic elevation of left ventricular (LV) diastolic pressure (DP) or chronic elevation of left atrial (LA) pressure, which is required to maintain LV filling, may determine LA wall deformation. We investigated this issue using transthoracic 3-dimensional speckle tracking echocardiography (3D-STE). Methods and Results: We retrospectively enrolled 75 consecutive patients with sinus rhythm and suspected stable coronary artery disease who underwent diagnostic cardiac catheterization and 3D-STE on the same day. We computed the global LA wall area change ratio, termed the global LA area strain (GLAS), during both the reservoir phase (GLAS-r) and contraction phase (GLAS-ct). The LVDP at end-diastole (LVEDP) and mean LVDP (mLVDP) were measured with a catheter-tipped micromanometer in each patient. GLAS-r and GLAS-ct were significantly correlated with both mLVDP (r=-0.70 [P<0.001] and r=0.71 [P<0.001], respectively) and LVEDP (r=-0.63 [P<0.001] and r=0.65 [P<0.001], respectively). In receiver operating characteristic curve analysis, the optimal cut-off values for diagnosing elevated LVEDP (≥16 mmHg) were 75.7% (sensitivity 83.3%, specificity 77.8%) for GLAS-r and -43.1% (sensitivity 90.0%, specificity 80.0%) for GLAS-ct. Similarly, for diagnosing elevated mLVDP (≥12 mmHg), the cut-off values were 63.6% (sensitivity 88.9%, specificity 80.3%) for GLAS-r and -26.2% (sensitivity 66.7%, specificity 97.0%) for GLAS-ct. Conclusions: We showed that 3D-STE-derived GLAS values could be used to non-invasively diagnose elevated LV filling pressure.

Correlation Between Longitudinal Strain in the Apical Segments of the Left Ventricle at End-Systole Obtained by 2-Dimensional Speckle-Tracking Echocardiography and Left Ventricular Relaxation.

BACKGROUND: It is well acknowledged that left ventricular (LV) contractile performance affects LV relaxation via LV elastic recoil. Accordingly, we aimed to investigate whether global longitudinal strain (GLS), particularly longitudinal strain at LV apical segments at end-systole (ALS), obtained by 2-dimensional speckle-tracking echocardiography could be used to assess LV relaxation.Methods and Results:We enrolled 121 patients with suspected or definite coronary artery disease in whom echocardiography and diagnostic cardiac catheterization were performed on the same day. We obtained conventional echo-Doppler parameters and GLS, as well as ALS prior to catheterization. LV functional parameters were obtained from the LV pressure recorded using a catheter-tipped micromanometer. In all patients, GLS and ALS were significantly correlated with the time constant τ of LV pressure decay during isovolumetric relaxation (r=0.63 [P<0.001] and r=0.66 [P<0.001], respectively). Receiver operating characteristic curve analysis for identifying impaired LV relaxation (τ ≥48 ms) revealed that ALS greater than -22.3% was an optimal cut-off value, with 81.7% sensitivity and 82.4% specificity. Even in patients with preserved LV ejection fraction, the same ALS cut-off value enabled the identification of impaired LV relaxation with 70% sensitivity and 87.5% specificity. CONCLUSIONS: The findings indicate that contractile dysfunction at LV apical segments slows LV relaxation via loss of LV elastic recoil, even in patients with preserved LVEF.

Effect of renin-angiotensin system inhibition on cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials.

Targeting the renin-angiotensin system (RAS) pathways has been considered a logical intervention for patients with heart failure with preserved ejection fraction (HFpEF), due to its hypothesized link to left ventricular (LV) remodeling. Although the effects of RAS inhibitors including angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) on LV structure and function and exercise capacity in HFpEF patients have been examined in multiple randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We conducted a meta-analysis of RCTs on the effects of RAS inhibitors on LV structure and function as well as exercise capacity in HFpEF patients. The search of electronic databases identified 7 trials including 569 patients; 4 trials were on ACE-Is; 2 on ARBs; and 1 on DRIs. Follow-up duration ranged across trials from 12 to 52 weeks. The pooled analysis showed that RAS inhibitors significantly increased EF compared with control (weighted mean difference [95% CI] = 2.182 [0.462, 3.901] %). In contrast, RAS inhibitors did not significantly change the ratio of peak early to late diastolic mitral inflow velocities (weighted mean difference [95% CI] = 0.046 [- 0.012, 0.105]), early diastolic mitral annular velocity (0.327 [- 0.07, 0.725] cm/s), the ratio of early diastolic mitral inflow to annular velocities (0.291 [- 0.937, 1.518]), LV mass (- 6.254 [- 15.165, 2.656] g), or 6-min walk distance (1.972 [- 14.22, 18.163] m) compared with control. The present meta-analysis suggests that RAS inhibitors may increase LVEF in HFpEF patients.

Effect of beta-blockers on heart failure severity in patients with heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials.

Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and likely to have cardiac comorbidities such as coronary artery disease (CAD) and atrial fibrillation (AF). The primary chronic symptom of HFpEF patients is severe exercise intolerance. The inability to adequately increase heart rate during exercise is commonly present in HFpEF patients and contributes to their exercise intolerance. Although beta-blockers are frequently used for the treatment of myocardial ischemia and tachycardia in HFpEF patients, there is a concern that slowing heart rate by beta-blockers may worsen chronotropic incompetence and further exacerbate their symptoms. Although the effect of beta-blockers on heart failure severity in HFpEF patients has been examined in randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effect of beta-blockers on heart failure severity in HFpEF patients. The search of electronic databases identified 5 RCTs including 538 patients. In pooled analyses, beta-blockers did not significantly change the New York Heart Association (NYHA) class, exercise capacity expressed as metabolic equivalents, or plasma B-type natriuretic peptide (BNP) levels compared with control but with substantial heterogeneity across trials. In meta-regression analyses, the higher proportion of CAD or AF in the included trials was associated with a decrease in NYHA class and BNP levels and with an increase in exercise capacity. Thus, we found no clear beneficial effect of beta-blockers on heart failure severity in HFpEF patients. However, beta-blockers may be beneficial in HFpEF patients with CAD or AF.

Left ventricular contractile performance and heart failure in patients with left ventricular ejection fraction more than 40.

Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF < 50%, which is the upper threshold of LVEF for HFmrEF, is thought to represent a mild decrease in LV contractile performance. We aimed to consider an LVEF threshold value to be taken as a surrogate for impairment of LV contractile performance, resulting in new-onset HF. We enrolled 398 patients with LVEF ≥ 40% that underwent cardiac catheterization. Using the LV pressure recording with a catheter-tipped micromanometer, we calculated the inertia force of late systolic aortic flow (IFLSAF), which was sensitive to the slight impairment in LV contractile performance. We evaluated the utility of the IFLSAF for predicting future cardiovascular death or hospitalization for HF. We performed a receiver operating characteristic (ROC) curve analysis to determine the best LVEF threshold value for distinguishing whether the LV maintained the IFLSAF. A multivariate Cox proportional-hazards model revealed that the loss of IFLSAF was significantly associated with the future adverse events (HR: 7.798, 95%CI 2.174-27.969, p = 0.002). According to the ROC curve analysis, an LVEF ≥ 58% indicated that the LV could maintain the IFLSAF. We concluded that the loss of IFLSAF, which could reflect even slight impairment in LV contractile performance, was a reliable indicator for new-onset HF in patients with LVEF ≥ 40%. LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance; this threshold could be useful for risk stratification of new-onset HF in patients with preserved LVEF.

Clinical features of anthracycline-induced cardiotoxicity in patients with malignant lymphoma who received a CHOP regimen with or without rituximab: A single-center, retrospective observational study.

We investigated the incidence of cardiotoxicity, its risk factors, and the clinical course of cardiac function in patients with malignant lymphoma (ML) who received a cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen. Among all ML patients who received a CHOP regimen with or without rituximab from January 2008 to December 2017 in Nagoya City University hospital, 229 patients who underwent both baseline and follow-up echocardiography and had baseline left ventricular ejection fraction (LVEF) ≥50% were analyzed, retrospectively. Cardiotoxicity was defined as a ≥10% decline in LVEF and LVEF < 50%; recovery from cardiotoxicity was defined as a ≥5% increase in LVEF and LVEF ≥50%. Re-cardiotoxicity was defined as meeting the criteria of cardiotoxicity again. With a median follow-up of 1132 days, cardiotoxicity, symptomatic heart failure, and cardiovascular death were observed in 48 (21%), 30 (13%), and 5 (2%) patients, respectively. Multivariate analysis demonstrated that history of ischemic heart disease (hazard ratio (HR), 3.15; 95% CI, 1.17-8.47, P = .023) and decreased baseline LVEF (HR per 10% increase, 2.55; 95% CI, 1.49-4.06; P < .001) were independent risk factors for cardiotoxicity. Recovery from cardiotoxicity and re-cardiotoxicity were observed in 21 of 48, and six of 21, respectively. Cardiac condition before chemotherapy seemed to be most relevant for developing cardiotoxicity. Furthermore, Continuous management must be required in patients with cardiotoxicity, even after LVEF recovery.

Transmission Rate of Remote Monitoring and Mortality in Patients With Pacemaker.

Background: Remote monitoring of cardiac implantable electronic devices improves clinical outcomes, but data on the association between the transmission rate (TR) of the remote monitoring, calculated in percentage as the ratio between days of transmission and days of follow-up after remote monitoring introduction, and death in patients with a pacemaker are limited. Methods and Results: In this single-center retrospective observational study, we investigated 180 patients with a newly implanted pacemaker capable of using a specific remote monitoring system with daily transmission (79.5±8.8 years, men 50.6%). The study endpoint was all-cause death. During the follow-up period (median 2.7 years), 33 all-cause deaths were reported, and the TR was significantly lower in the deceased patients than in the survivors (89.6±9.6% vs. 95.4±7.0%, P<0.001). The area under the receiver-operating characteristic curve for TR to predict all-cause death was 0.72 (95% confidence interval [CI] 0.62-0.81, P<0.001). A TR of 95% had sensitivity of 74.1% and specificity of 63.6% for predicting all-cause death. In the multivariate Cox regression analysis, TR <95% was selected as a predictor of all-cause death (hazard ratio 3.43, 95% CI 1.61-7.27, P=0.001). Conclusions: Low TR is a predictor of all-cause death in patients with a pacemaker. Patients with TR ≥95% may experience a lower incidence of death, and should have a good prognosis.

Physical activity and mortality in older patients with a pacemaker.

AIM: With increasing lifespans, patients requiring a pacemaker are older than they were in the past. Data regarding all-cause mortality in older patients implanted with a pacemaker are scarce. As physical activity is associated with a decrease in all-cause mortality, we investigated whether daily physical activity time, expressed as the activity rate determined by pacemakers, can predict all-cause mortality in older patients (aged ≥75 years) with a pacemaker. METHODS: We retrospectively investigated the baseline characteristics, echocardiographic indices, laboratory data and pacemaker parameters of 107 consecutive older patients with a newly implanted pacemaker at our hospital (age 83.8 ± 5.0 years; 54.2% men). The study end-point was all-cause mortality. RESULTS: During the follow-up period (mean 3.0 years), 21 cases of all-cause death were reported. The area under the receiver operating characteristic curve for activity rate to predict all-cause mortality was 0.82 (95% confidence interval 0.72-0.92, P < 0.001). An activity rate of 3.4% (50 min/day) had a sensitivity of 86.0% and a specificity of 66.7% for predicting all-cause mortality. The survival rate was significantly higher among patients with an activity rate ≥3.4% than among those with an activity rate <3.4% (log-rank, P < 0.001). A multivariate Cox regression analysis identified low activity rates as a predictor of all-cause mortality (hazard ratio 15.0, 95% confidence interval 4.29-52.6; P < 0.001). CONCLUSIONS: Low activity rates appear to be a strong predictor of all-cause mortality in older patients with a pacemaker. Geriatr Gerontol Int 2020; 20: 106-111.

Effects of exercise training on cardiac function, exercise capacity, and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials.

Left ventricular (LV) diastolic dysfunction is associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and contributes importantly to exercise intolerance that results in a reduced quality of life (QOL) in HFpEF patients. Although the effects of exercise training on LV diastolic function, exercise capacity, or QOL in HFpEF patients have been examined in randomized clinical trials (RCTs), results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs examining the effects of exercise training on LV diastolic function and exercise capacity as well as QOL in HFpEF patients. The search of electronic databases identified 8 RCTs with 436 patients. The duration of exercise training ranged from 12 to 24 weeks. In the pooled analysis, exercise training improved peak exercise oxygen uptake (weighted mean difference [95% CI], 1.660 [0.973, 2.348] ml/min/kg), 6-min walk distance (33.883 [12.384 55.381] m), and Minnesota Living With Heart Failure Questionnaire total score (9.059 [3.083, 15.035] point) compared with control. In contrast, exercise training did not significantly change early diastolic mitral annular velocity (weighted mean difference [95% CI], 0.317 [- 0.952, 1.587] cm/s), the ratio of early diastolic mitral inflow to annular velocities (- 1.203 [- 4.065, 1.658]), or LV ejection fraction (0.850 [- 0.128, 1.828] %) compared with control. In conclusion, the present meta-analysis suggests that exercise training improves exercise capacity and QOL without significant change in LV systolic or diastolic function in HFpEF patients.

Verification of Echocardiographic Assessment of Left Ventricular Diastolic Dysfunction in Patients With Preserved Left Ventricular Ejection Fraction Using the American Society of Echocardiography and European Association of Cardiovascular Imaging 2016 Recommendations.

Background: Non-invasive evaluation of left ventricular (LV) diastolic dysfunction (DD) and elevated LV filling pressure are crucial for diagnosing heart failure. The 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) recommendations for evaluating elevated LV filling pressure (algorithm B) have acceptable diagnostic accuracy, including in patients with reduced LV ejection fraction (EF). No prior study, however, has assessed the diagnostic accuracy of algorithm A of the ASE/EACVI recommendations for evaluating LVDD in patients with normal LVEF. Methods and Results: We evaluated the clinical relevance of algorithm A in 94 patients who underwent invasive LV pressure measurement. Algorithm A identified invasively defined LVDD (time constant τ≥48 ms and/or LV end-diastolic pressure ≥16 mmHg) with low sensitivity (22.4%) but high specificity (90.7%). Algorithm A also identified elevated LV filling pressure with low sensitivity (41.7%) but high specificity (87.5%), and with a high negative predictive value (90.9%). Conclusions: Algorithm A may not be useful for screening LVDD in patients with normal LVEF. Negative findings using algorithm A, however, may identify a patient with normal LVDD with high specificity, and most of such patients will have LV pre-A pressure in the normal range.

Effects of mineralocorticoid receptor antagonists on left ventricular diastolic function, exercise capacity, and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials.

Left ventricular (LV) diastolic dysfunction is associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and contributes importantly to exercise intolerance that results in a reduced quality of life (QOL) in HFpEF patients. Experimental studies have shown that aldosterone plays a role in the genesis of myocardial hypertrophy and fibrosis, thereby enhancing LV diastolic dysfunction, and that aldosterone antagonists (mineralocorticoid receptor antagonists [MRAs]) prevents myocardial hypertrophy and fibrosis. Although the effects of MRAs on LV diastolic function, exercise capacity, and QOL in HFpEF patients have been examined in randomized clinical trials (RCTs), results are inconsistent due partly to limited power with small sample sizes. We aimed to conduct a meta-analysis of RCTs on the effects of MRAs on LV diastolic function, exercise capacity, and QOL in HFpEF patients. The search of electronic databases identified 6 studies including 755 HFpEF patients. In the pooled analysis, MRAs increased early diastolic mitral annular velocity (weighted mean difference [95% CI] = 0.455 [0.232-0.679] cm/s; Pfix < 0.001) and decreased the ratio of early diastolic mitral inflow to annular velocities (- 1.474 [- 2.073 to - 0.875]; Pfix < 0.001) compared with control. There was no significant difference in change of peak exercise oxygen uptake, 6-minute walking distance, or QOL questionnaire scores between MRA and control group. In conclusion, our meta-analysis showed that MRAs improved LV diastolic function in HFpEF patients. However, the observed improvement in LV diastolic function with the use of MRAs did not translate into improved exercise capacity or QOL in these patients.

The effect of influenza vaccination on mortality and hospitalization in patients with heart failure: a systematic review and meta-analysis.

Influenza infection is associated with increased risk for mortality and hospitalization in heart failure patients. Although there are no published randomized controlled trials examining the effect of influenza vaccination on clinical outcomes in heart failure patients, the effect has been examined in observational cohort studies. Nevertheless, results are inconsistent due partly to limited power with small sample sizes and use of different definitions of outcomes. We therefore aimed to conduct a systematic review and meta-analysis of the effect of influenza vaccination on mortality and hospitalization in heart failure patients. The search of electronic databases identified 6 observational cohort studies with 22,486 patients examining the effect of influenza vaccination on mortality and hospitalization in heart failure patients. Pooled analysis of confounder-adjusted hazard ratio showed that influenza vaccination was associated with reduced risk of mortality during 1-year follow-up (risk ratio [95% CI] = 0.76 [0.63-0.92], Pfix < 0.01) and during long-term (up to 4 years) follow-up (0.80 [0.71-0.90], Pfix < 0.001). Furthermore, influenza vaccination was associated with reduced risk of mortality during influenza season (risk ratio [95% CI] = 0.52 [0.39-0.69], Prandom < 0.001) and during non-influenza season (0.79 [0.69-0.90], Pfix < 0.001). Only a few studies reported the effect of influenza vaccination on hospitalization, which did not permit us to perform pooled analysis. In conclusion, our meta-analysis showed that influenza vaccination was associated with reduced risk of mortality in heart failure patients. Large-scale and adequately powered randomized controlled trials should be planned to confirm our observed potential survival benefit of influenza vaccination in these patients.

Compensatory Increase in Heart Rate Is Responsible for Exercise Tolerance among Male Patients with Permanent Atrial Fibrillation.

Atrial fibrillation (AF) is an exacerbating factor for exercise tolerance due to the loss of atrial kick. However, many patients with permanent AF, which lasts for at least a year without interruption, and preserved left ventricular ejection fraction (LVEF ≥ 50%) are asymptomatic and have good exercise tolerance. In such cases, the possible mechanism that compensates for the decrease in cardiac output accompanying the loss of atrial kick is a sufficient increase in heart rate (HR) during exercise. We investigated the relationship between exercise tolerance and peak HR during exercise using cardiopulmonary exercise testing in 242 male patients with preserved LVEF, 214 with sinus rhythm (SR) and 28 with permanent AF. Peak HR was significantly higher in the AF group than the SR group (148.9 ± 41.9 vs. 132.0 ± 22.0 beats/min, p = 0.001). However, oxygen uptake at peak exercise did not differ between the AF and SR groups (19.4 ± 5.7 vs. 21.6 ± 6.0 mL/kg/min, p = 0.17). In multiple regression analysis, peak HR (ß, 0.091; p < 0.001) and the interaction term constructed by peak HR and presence of permanent AF (ß, 0.05; p = 0.04) were selected as determinants for peak VO2; however, presence of permanent AF was not selected (ß, -0.38; p = 0.31). Therefore, the impact of peak HR on exercise tolerance differed between the AF and SR groups, suggesting that a sufficient increase in HR during exercise is an important factor to preserve exercise tolerance among patients with AF.

Left Ventricular Mass Influences Relationship Between Filling Pressure and Early-Diastolic Ratio of Inflow Velocity to Mitral Annular Velocity (E/e').

BACKGROUND: Early-diastolic mitral annular velocity (e') and the ratio of early-diastolic left ventricular (LV) inflow velocity (E) to e' (E/e') have been widely used as indexes of LV relaxation and filling pressure, respectively. However, many recent studies have demonstrated that they are not reliable in various clinical settings. We thus investigated the factors influencing these echocardiographic parameters in a multicenter study.Methods and Results:The study group comprised 69 patients, referred for cardiac catheterization, and enrolled in 5 university hospitals. Time constant (τ) and LV mean diastolic pressure (LVMDP) were measured using a micromanometer-tipped catheter. Although e' only weakly correlated with τ (r=-0.35, P<0.01), E/e' modestly correlated with LVMDP (r=0.48, P<0.001). Multivariable analysis revealed that hypertension (ß=-0.33, P<0.01) and LV ejection fraction (LVEF) (ß=0.44, P<0.001) were the independent determinants of e', and LV mass index (LVMI) (ß=0.37, P<0.001) and LVMDP (ß=0.47, P<0.001) were those of E/e'. Additionally, E/e' significantly correlated with LVMDP in patients with normal LVMI (r=0.74, P<0.001) but not in those with increased LVMI. CONCLUSIONS: The coincidence of hypertension and LVEF affected the relationship between LV relaxation and e', whereas LVMI altered the relationship between LV filling pressure and E/e'. Thus, clinical conditions associated with an increase in LVMI, such as LV hypertrophy and LV dilatation, should be considered when estimating the filling pressure from E/e'.

Effect of renin-angiotensin system inhibitors on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies.

Despite the high mortality rate, there is no therapy to improve survival in heart failure with preserved ejection fraction (HFpEF). Large randomized controlled trials (RCTs) did not show clear mortality benefit of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in HFpEF. However, because of the strict enrollment criteria, the patients who participated in these trials might represent a selected group of patients that is poorly representative of patients treated in routine clinical practice. In contrast, clinical characteristics of real-world patients are similar to those of patients enrolled in observational cohort studies (OCSs). Although many OCSs have examined the prognostic effect of RAS inhibitors in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or inadequate adjustment for known prognostic factors. We aimed to conduct a meta-analysis of OCSs with and those without propensity score (PS) analysis and RCTs on the effect of RAS inhibitors on mortality in HFpEF patients. The search of electronic databases identified 4 OCSs with PS analysis (10,164 patients), 8 OCSs without PS analysis (16,393 patients), and 3 RCTs (8001 patients). Use of RAS inhibitors was associated with reduced mortality in the pooled analysis of OCSs with PS analysis (RR [95% CI] = 0.90 [0.81-1.00]) and in that of OCSs without PS analysis (0.81 [0.68-0.96]) but not in that of RCTs (0.99 [0.87-1.12]). In conclusion, the present meta-analysis suggests the potential mortality benefit of RAS inhibitors in HFpEF, emphasizing the importance of conducting new well-designed RCTs.