Cardiopulmonary Exercise Testing in Heart Failure With Preserved Ejection Fraction: Technique Principles, Current Evidence, and Future Perspectives.

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial clinical syndrome involving a rather complex pathophysiologic substrate and quite a challenging diagnosis. Exercise intolerance is a major feature of HFpEF, and in many cases, diagnosis is suspected in subjects presenting with exertional dyspnea. Cardiopulmonary exercise testing (CPET) is a noninvasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, hematopoietic, neuropsychological, and metabolic functions during maximal or submaximal exercise. The assessment is based on the principle that system failure typically occurs when the system is under stress, and thus, CPET is currently considered to be the gold standard for identifying exercise intolerance, allowing the differential diagnosis of underlying causes. CPET is used in observational studies and clinical trials in HFpEF; however, in most cases, only a few from a wide variety of CPET parameters are examined, while the technique is largely underused in everyday cardiology practice. This article discusses the basic principles and methodology of CPET and studies that utilized CPET in patients with HFpEF, in an effort to increase awareness of CPET capabilities among practicing cardiologists.

Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.

Syncope without prodromes is associated with excessive plasma release of adenosine at the time of syncope during head-up tilt table test.

BACKGROUND: In syncopal patients without underlying structural disease, we sought to investigate the association of Adenosine Plasma Levels (ADP) with the clinical presentation of neurally mediated syncope (NMS) and the outcomes of Head-Up Tilt Table Test (HUTT) and Adenosine test (ADT). METHODS: We studied 124 patients with different clinical types of NMS, i.e., Vasovagal (VVS, n=58), non-prodromes (NPS, n=18), or situational syncope (SS, n=48), using a standard protocol including HUTT and ADT. During HUTT, ADP was measured in the supine position, at table tilting and in syncope. RESULTS: Baseline ADP did not differ among groups. ADP at syncope were higher in NPS (n=5) compared to VVS (n=20): 0.23 vs. 0.12 µΜ, p=0.03, and SS (n=22): 0.04 µΜ, p=0.02. In NPS, ADP increased from supine to syncope (n=5): 0.15 vs. 0.23 µΜ, p=0.04. In VVS, ADP increased only from supine to tilt position: 0.11 vs. 0.14 µΜ, p=0.02. In SS, ADP did not change during HUTT. In positive vasodepressor HUTT, ADP increased from supine to tilt position (p=0.002) and at syncope (p=0.01). In SS, 20.0% exhibited cardioinhibitory HUTT vs. 6.8% in other forms of syncope (p=0.04). In SS, 22.9% manifested positive ADT vs 6.6% in other types of syncope (p=0.012). CONCLUSION: The subset of NPS patients with positive HUTT, show excessive ADP release at the time of syncope. This may explain the lack of prodromes in this form of syncope. Such observations contribute to the understanding of distinct profiles of clinical forms of syncope and may differentiate the management approach accordingly.

Effects of different exercise programs on the cardiorespiratory reserve in HFpEF patients: a systematic review and meta-analysis.

HFpEF represents a heterogeneous syndrome with complex pathophysiological substrates and multiple clinical manifestations. Recently, much attention has been focused on cardiac rehabilitation programs for HFpEF patients, and several studies have examined the effects of exercise training on this specific population. This systematic review and meta-analysis included studies on adult patients with HFpEF and evaluated the impact of exercise on the cardiorespiratory fitness variables measured during CPET. The primary outcome was the difference in the change in the peak oxygen uptake (Δpeak VO2) between the groups. Literature search involved PubMed/MEDLINE, Cochrane/CENTRAL and Scopus databases. From an initial 5,143 literature records, we identified 18 studies fulfilling the inclusion criteria; 11 studies with 515 patients were finally included in the primary outcome analysis. Δpeak VO2 between baseline and study end was significantly higher in the groups of exercise training versus control (WMD 2.25 ml/kg/min, 95% CI 1.81-2.70). Exercise training resulted in greater change in the 6-minute walking test (6MWT) distance (WMD 2.25 m, 95% CI 1.81-2.70). Health-related quality of life (HRQoL) (WMD: -3.36, 95% CI -9.42 to 2.70, I2 = 14%, p = 0.33) and echocardiographic indices of diastolic function showed no differences between exercise and control groups at study end. In the subgroup analysis, no difference between resistance versus aerobic exercise was noted in Δpeak VO2, but high-intensity interval training showed a greater increase in peak VO2 versus aerobic exercise (WMD 1.62 ml/kg/min, 95% CI 0.96-2.29, I2 = 0%, p = 0.82). Exercise training in HFpEF results in significant improvements in peak VO2 and 6MWT distance as compared to those for controls. High-intensity interval training may offer greater enhancement of the exercise capacity of these patients than standard aerobic exercise.

Lung ultrasound-guided dry-weight reduction and echocardiographic changes in clinically euvolemic hypertensive hemodialysis patients: 12-month results of a randomized controlled trial.

OBJECTIVE: Left ventricular hypertrophy (LVH) and dysfunction are highly prevalent in hemodialysis patients and are independently associated with adverse outcomes. This study examines the long-term effects of dry-weight reduction with a standardized lung ultrasound (LUS)-guided strategy on echocardiographic indexes of left ventricular (LV) mass and function in hemodialysis patients. METHODS: Seventy-one clinically euvolemic hemodialysis patients with hypertension were randomized to dry-weight reduction guided by pre-hemodialysis LUS (n = 35) or standard-of-care treatment (n = 36) and were followed-up for 12 months. Two-dimensional and tissue-Doppler echocardiographies (TDI) were performed at the baseline and 12-month evaluations. RESULTS: During follow-up, dry-weight reduction took place in more patients in the active arm than in the control arm of the trial (71.4% vs 22.2%; p < 0.001). Left atrial (LA) surface (-1.37 ± 4.50 vs 1.28 ± 5.00 cm2; P = 0.006) and LA volume index (-3.22 ± 11.82 vs 4.76 ± 12.83 ml/m2; P = 0.009) decreased in the active and increased in the control group. LV end-diastolic volume (-0.94 ± 11.45 vs 6.58 ± 13.92 ml/m2; P = 0.015) decreased only in the active group. The LV mass index was unchanged in the active (134.21 ± 44.75 vs 133.57 ± 45.51; P = 0.844) and marginally increased in the control group (134.21 ± 40.96 vs 143.77 ± 50.04 g/m2; P = 0.089). The LV E/e' wave ratio was unchanged in the active (12.45 ± 4.69 vs 12.56 ± 4.89; P = 0.521) and increased in the usual-care group (10.91 ± 4.97 vs12.36 ± 6.43; P = 0.003). LV systolic function did not differ between the two study arms across the trial. CONCLUSION: Over 12 months, LUS-guided dry-weight reduction is associated with reverse LV and LA remodeling, myocardial hypertrophy regression, and improved LV diastolic filling properties.

5-Fluorouracil, capecitabine and vasospasm: a scoping review of pathogenesis, management options and future research considerations.

BACKGROUND: 5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that can cause cardiotoxicity manifesting, among others, as chest pain. Capecitabine is an oral prodrug of 5-FU, with reported preferential activation in malignant cells that may also cause cardiotoxic reactions. Standard treatment of 5-FU and capecitabine induced chest pain with vasodilators is mostly effective, but there are several cases of patients unresponsive to these agents. METHODS: We performed a PubMed search on 31st May 2020. We used a three keyword search strategy using Boolean search operators. More specifically, we included fluorouracil or 5-FU or capecitabine and chest pain or angina and mechanism or treatment or management. We included primary reports of clinical and non-clinical data, as well as systematic reviews. Narrative reviews, expert opinions, letters to the editor and other forms of non-primary literature were excluded. RESULTS: Our search yielded a total of 1595 reports. Of these, 1460 were narrative reviews or irrelevant to the topic and were excluded. A total of 135 reports were used for our review. We used 81 reports for data extraction, which included 13 clinical trials, 4 retrospective reports, 61 case reports, and 3 systematic reviews. CONCLUSION: We report the incidence and predisposing factors, the value of available diagnostic procedures, and standard medical and invasive treatments. We also speculate on the potential benefit of arginine as a promising option both in prevention as well as treatment of 5-FU-induced chest pain. Finally, gaps of evidence are identified and proposals are made in terms of future research.

The impact of atrial mechanical function on age-dependent presentation of neurocardiogenic syncope.

BACKGROUND: The contribution of atrial and ventricular function in neurocardiogenic syncope (NCS) pathophysiology is elusive. HYPOTHESIS: We assessed the influence of echocardiographic properties to the age of presentation and NCS recurrences. METHODS: We assigned 124 patients with symptoms suggesting NCS, to those with syncope initiation at age <35 (group A, n = 56) and >35 years (group B, n = 68). Echocardiographic indices were measured before head-up tilt test (HUTT). RESULTS: A total of 55 had positive HUTT (44%) with a trend favoring group A (p = .08). Group A exhibited lower left atrial (LA) volume index (17 ± 6 vs. 22 ± 11 ml/m2 , p = .015), higher LA ejection fraction (69 ± 10 vs. 63 ± 11%, p = .008), LA peak strain (reservoir phase 41 ± 13 vs. 31 ± 14%, p = .001, contraction phase 27 ± 11 vs. 15 ± 10%, p < .001) and LA peak strain rate (reservoir phase 1.83 ± 1.04 vs. 1.36 ± 0.96 1/s, p = .012, conduit phase 2.36 ± 1.25 vs. 1.36 ± 0.78 1/s, p = .001). Group A showed smaller minimum right atrial (RA) volume, better RA systolic function, superior left ventricular diastolic indices, and lower filling pressures. Group A patients were more likely to have >3 recurrences (82.0% vs. 50.1%, p < .05). CONCLUSIONS: Patients with younger age of NCS onset and more syncopal recurrences manifest smaller LA and RA dimensions with distinct patterns of systolic and diastolic function and better LA reservoir and contraction properties. These findings may indicate an increased susceptibility to preload reduction, thereby triggering the NCS mechanism.

Spontaneous Epidural Hematoma of the Cervical Spine Following Thrombolysis in a Patient with STEMI-Two Medical Specialties Facing a Rare Dilemma.

Spontaneous spinal epidural hematoma (SSEH) is a rare, albeit well-documented complication following thrombolysis treatment in ST elevation myocardial infarction (STEMI). A SSEH usually manifests with cervical pain and neurologic deficits and may require surgical intervention. In this case report, we present the first reported SSEH to occur following thrombolysis with reteplase. In this case, the SSEH manifested with cervical pain shortly after the patient emerged from his rescue percutaneous coronary intervention (PCI). Although magnetic resonance imaging reported spinal cord compression, the lack of neurologic symptoms prompted the treating clinicians to delay surgery. A dangerous dilemma emerged, as the usual antithrombotic regimen that was necessary to avoid stent thrombosis post-PCI, was also likely to exacerbate the bleeding. As a compromise, the patient only received aspirin as a single antiplatelet therapy. Ultimately, the patient responded well to conservative treatment, with the hematoma stabilizing a week later, without residual neurologic deficits. In conclusion, the conservative treatment of SSEH appears to be an acceptable option for carefully selected patients, but the risks of permanent neurologic deficits and stent thrombosis have to be weighted for each patient.

Left atrial deformation as a potent predictor for paroxysmal atrial fibrillation in patients with end-stage renal disease.

It is widely known that various factors contribute to left atrial (LA) mechanical dysfunction in patients with end stage renal disease (ESRD). However, the connection between atrial dysfunction and arrhythmic events such as paroxysmal atrial fibrillation (PAF), in this group of patients, remains unclear. The purpose of our study was to evaluate prospectively the association between LA deformation indices and PAF in ESRD patients. 79 patients (41 men, mean age 57 ± 17) with ESRD and preserved left ventricular systolic function comprised the study population. All patients underwent a baseline comprehensive echocardiography study and were followed for a mean period of 16 ± 5 months. PAF episodes, first and the following events, were reported. LA longitudinal strain reflecting LA reservoir function and LA longitudinal strain rate reflecting LA pump function were specifically evaluated as LA deformation indices of interest, using 2D speckle tracking echocardiography. At the end of follow up period nine patients died. 15 of the rest 70 reported one or more episodes of PAF. LA indexed volumes were significantly higher in patients with PAF (32 ± 26 vs. 21.5 ± 9 ml/m2, p = 0.002), mean LA strain was significantly reduced (17 ± 7 vs. 27 ± 9%, p < 0.001) as well as mean LA stain rate (- 1.19 ± 0.5 vs. - 1.95 ± 0.5 1/s, p < 0.001). Multivariate analysis showed that LA strain rate when adjusted with age together with PAF history remained the single most significant echocardiographic parameter for PAF prediction. Impaired LA strain and LA strain rate are associated with PAF in ESRD patients. LA strain rate might be a better independent predictor of PAF, compared to standard echocardiographic indices. Further prospective studies are needed to validate its relevance in routine clinical practice.

A Rare Case of Lipomatous Hypertrophy of the Interventricular Septum.

Asymmetrical left ventricular hypertrophy secondary to interventricular septum hypertrophy is usually considered a typical phenotype of hypertrophic cardiomyopathy. In rare cases other conditions such as tumors or lipomatous hypertrophy of the interventricular septum may have a similar presentation. We present a case of a male patient who presented for routine cardiology work up and was diagnosed of having ventricular septal hypertrophy secondary to localized lipomatous hypertrophy.

Beneficial effect of ischemic preconditioning on post-infarction left ventricular remodeling and global left ventricular function.

BACKGROUND: Preinfarction angina (PA) is a clinical analogue of ischemic preconditioning that improves postinfarct prognosis. Data concerning the association of PA with post infarction left ventricular (LV) remodeling and LV diastolic function are limited. We aimed to evaluate this association in patients with acute myocardial infarction (AMI) in the modern clinical era of widespread use of revascularization and antiremodeling medical treatment. METHODS: We studied 53 patients with anterior AMI who underwent complete reperfusion and received up to date antiremodeling medical treatment. LV remodeling, systolic and diastolic function were assessed using 2D echocardiography at baseline and 6 at months follow-up. Patients were divided into two groups regarding the presence or absence of PA. RESULTS: LV remodeling at follow-up was less frequent in the PA group (25 vs. 55 %, P<.05). Patients with PA had lower end-systolic volume index at baseline and follow up (24.1±6 vs. 30.1±14 ml/m(2), P<.001 and 25.3±8 vs. 35.6±2 ml/m(2), P=.001 respectively). Additionally at 6 months, they had better LV ejection fraction (52.1±9 vs. 42.9±10 %, P=.002) and exhibited improved diastolic filling as reflected by mitral E/e' (14.6±5 vs. 18.8±8, P=.05). CONCLUSIONS: Ischemic preconditioning in the form of PA promotes better LV systolic and diastolic function in the mid-term and is associated with less postinfarct LV remodeling in this specific study population. The results of the study underline the possible need for further risk stratification of AMI patients regarding the absence of PA.

QT dispersion is determined by the relative extent of normal, hibernating, and scarred myocardium in patients with chronic ischemic cardiomyopathy. A dobutamine stress echocardiography study before and after surgical revascularization.

INTRODUCTION: The aim of the present study was to evaluate a possible association between QT dispersion (QTd) and the amount of viable and scarred myocardial tissue after revascularization in patients with coronary artery disease and impaired left ventricular (LV) function. METHODS: Twenty-two patients with ischemic LV dysfunction underwent dobutamine stress echocardiography (DSE) before and 6 months after surgical revascularization. Mean corrected QT-interval value and QTd were calculated at baseline and follow-up. Segments consisting of transmural scar were determined as the segments that remained akinetic in all stages of DSE despite reperfusion. Patients were divided into 2 groups according to the number of definitive segments consisting of transmural scar (minor scar group, < or =2 scarred segments; major scar group, >2 scarred segments). RESULTS: QTd was significantly lower in the minor compared with the major scar group at baseline and follow-up (mean [SD], 61 [22] vs 98 [33] milliseconds, P = .008, and 45 [18] vs 68 [21] milliseconds, P = .01, respectively). Segments consisting of transmural scar positively correlated to QTd at baseline (r = 0.53, P = .01) and follow-up (r = 0.62, P = .002). CONCLUSIONS: QTd is positively correlated with the extent of scarred myocardial tissue assessed by DSE. Surgical revascularization results in reduction of QTd in all patients with hibernating myocardium and LV dysfunction.

Association between plasma homocysteine levels and coronary artery disease: a population-based study in northern Greece.

OBJECTIVE: Elevated plasma total homocysteine (tHcy) levels constitute a risk factor for coronary artery disease (CAD). We prospectively examined the association of fasting tHcy levels in patients in Northern Greece who had established CAD. PATIENTS AND METHODS: Plasma fasting tHcy levels were measured in 42 patients with angiographically documented CAD and compared to 42 age-, sex-, BMI- and smoking habit-matched control subjects. We also determined the plasma vitamin B(12), folic acid and lipoprotein levels in all patients and controls. Conventional risk factors for CAD were also estimated. RESULTS: In a univariate analysis, tHcy (micromol/l) levels were higher in patients compared to controls almost reaching statistical significance (13 (7-41) vs 11.3 (4-39); p= 0.07). Multivariate analysis of conventional risk factors showed that tHcy levels were not an independent risk factor for CAD. However, tHcy levels were significantly higher in patients with a previous history of myocardial infarction compared to patients without such a history and to controls (15 (8.8-29) vs 11.7 (7-41); p = 0.007 and 15 (8.8-29) vs 11.3 (4-39); p = 0.002, respectively). Hyperhomocysteinaemia (> 15 micromol/l) was detected in 35.7% of patients and 11.9% of controls (p < 0.05). CONCLUSIONS: In Northern Greece, plasma tHcy levels may not be an independent risk factor for CAD in patients with angiographically documented CAD. However, patients with CAD have a trend towards higher tHcy levels. Additionally, plasma tHcy levels may be associated with the development of myocardial infarction.

Preconditioning reduces QTc value in patients with first non-ST-segment elevation myocardial infarction (NSTEMI).

BACKGROUND: Preinfarction angina (PA) consists a strong clinical correlate to ischemic preconditioning (PC) and seems to occur in a bimodal time course. The aim of the study is to evaluate the impact of both forms of PC on QTc value representing myocardial electric stability, in patients with a first NSTEMI. METHODS: Forty-eight patients, with first NSTEMI and poor or no collateral development were enrolled in the study. QTc at admission and discharge were recorded. All patients had comparable admission QTc values and were divided into three groups according to the absence or presence and exact timing of preinfarction angina. The first group consisted of 20 patients who did not report PA (PA-, representing no PC effect); the second group of 12 patients with reported PA within 12 hours prior to admission (12h PA+, representing the classic form of PC); and the third group of 16 patients reporting PA within 12 to 48 hours prior to admission (48-hour PA+, representing the delayed form of PC). The primary outcome was determined as the effect of PA on QTc value at discharge. RESULTS: Discharge QTc values were significantly reduced in both (PA+) groups compared to (PA-) group (412 +/- 50 vs. 455 +/- 53 ms, p = 0.015 and 417 +/- 29 vs. 455 +/- 53 ms, P = 0.033, respectively). Both groups of (PA+) patients compared to (PA-) patients suffered no arrhythmic events during their hospitalization (0/12 vs. 6/20, P = 0.04 and 0/16 vs. 6/20, P = 0.02). CONCLUSIONS: Both forms of preconditioning, similarly and significantly reduce QTc value at discharge in patients experiencing a first NSTEMI, suggesting possible protection from future arrhythmic events.