Angiotensin receptor-neprilysin inhibition and improved ventricular-arterial coupling in heart failure with reduced ejection fraction.

Sacubitril/valsartan improves outcome in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LV-EF ≤ 40% were enrolled prospectively. Non-invasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance (Ees; a measure of LV contractility), effective arterial elastance (Ea; a measure of afterload), and the ventricular-arterial coupling ratio (Ea/Ees). Mean age was 65±13 years, 30% were female, and 54.7% had ischemic heart disease. During six months of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. 102 patients were included in pressure-volume analyses. After six months of sacubitril/valsartan treatment, Ees increased (0.66mmHg/ml [IQR 0.45-0.94] vs. 0.78mmHg/ml [IQR 0.57-1.10], p=0.001), Ea decreased (1.76mmHg/ml [IQR 1.48-2.13] vs. 1.62mmHg/ml [IQR 1.36-1.96], p=0.014), and the Ea/Ees ratio improved (2.52 [IQR 1.88-4.05] vs. 1.93 [IQR 1.50-2.63], p<0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both p<0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-minute walking distance. Change in LVEF correlated with change in Ees (r=0.33, p=0.0008), while change in NT-proBNP was associated with change in LVEDP (r=0.42, p<0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF.

On the importance of the innervation of the human cervical longitudinal ligaments at vertebral level.

PURPOSE: In our aging society, the prevalence of degenerative spinal diseases rose drastically within the last years. However, up till now, the origin of cervical pain is incompletely understood. While animal and small cadaver studies indicate that a complex system of sensory and nociceptive nerve fibers in the anterior (ALL) and posterior longitudinal ligament (PLL) at the level of the intervertebral disc might be involved, there is a lack of data exploring whether such a network exists and is equally distributed within the cervical vertebrae (VB). We, therefore, aimed to investigate the spatial distribution of the mentioned nerve networks in human tissue. METHODS: We performed macroscopic (Sihler staining, Spalteholz technique, and Plastination) and microscopic (immunohistochemistry for PGP 9.5 and CGRP) studies to characterize spatial differences in sensory and nociceptive innervation patterns. Therefore, 23 human body donors were dissected from level C3-C6. RESULTS: We could show that there is a focal increase in sensory and nociceptive nerve fibers at the level of C4 and C5 for both ALL and PLL, while we observed less nerve fiber density at the level of C3 and C6. An anatomical vicinity between nerve and vessels was observed. CONCLUSION: To our knowledge, these findings for the first time report spatial differences in sensory and nociceptive nerve fibers in the human cervical spine at VB level. The interconnection between nerves and vessels supports the importance of the perivascular plexus. These findings might be of special interest for clinical practice as many patients suffer from pain after cervical spine surgery.

Early detection of atrial fibrillation in patients with heart failure reduces the risk of subsequent hospitalization: a subanalysis of the randomized TIM-HF2 trial.

Aims: To evaluate the rate of new-onset atrial fibrillation (AF) and the potential improved outcome in heart failure (HF) patients using non-invasive remote patient management (RPM) compared with usual care (UC). Methods and results: This analysis assessed a subgroup of 1538 patients of the TIM-HF2 trial with chronic HF, New York Heart Association Class II or III, admission to hospital for HF within 12 months before randomization, and a left ventricular ejection fraction (LVEF) of 45% or lower. Patients with AF in the baseline electrocardiogram (ECG), with an implanted cardiac device, a history of ablation therapy, and recent anticoagulation were excluded, leaving 347 patients for final analysis (RPM = 175; UC = 172). The percentage of days lost due to unplanned cardiovascular hospitalization or death of any cause (primary endpoint of TIM-HF2), the rate of newly detected AF, and the hospitalization rate due to AF were analysed. For patients with new AF, there was a significant reduction for the primary endpoint in the RPM group [5.5%, 95% confidence interval (CI) 0-11.6 vs. UC: 14.6%, 95% CI 8.0-21.2; P < 0.001]. Within the first 3 months, the detection rate of new AF was significantly higher in the RPM group (5.1%) compared with UC (1.2%), P = 0.035. After 1 year, 23 patients (13.1%) assigned to RPM and 12 patients (7.0%) assigned to UC had newly detected AF, P = 0.056. Unplanned hospitalizations related to AF were significantly lower in the RPM group (2 out of 23 patients vs. UC: 10 out of 12 patients; P < 0.001). Conclusion: In this subgroup of HF patients in the TIM-HF2 trial, non-invasive daily ECG transmission leads to a four times higher detection rate of new AF compared with UC. This was associated with a significant reduction of days lost due to unplanned cardiovascular hospitalizations, especially hospitalizations related to AF.

Event dependent overall survival in the population-based LIFE-Adult-Study.

BACKROUND: Information about the direct comparability of big data of epidemiological cohort studies and the general population still is lacking, especially regarding all-cause mortality rates. The aim of this study was to investigate the overall survival and the influence of several diagnoses in the medical history on survival time, adjusted to common risk factors in a populations-based cohort. METHODS: From 10,000 subjects of the population-based cohort LIFE-Adult-Study (Leipzig Research Centre for Civilization Diseases), the medical history and typical risk factors such as age, smoking status and body-mass-index (BMI) were assessed. The survival status was identified from the saxonian population register. Univariate and multivariate analyses were used to determine the influence of the medical history and risk factors on overall survival. To develope an optimal model, the method by Collet [1] was used. RESULTS: The mortality rate of the participants is approximately half the mortality rate expected for the german population. The selection bias in epidemiological studies needs to be considered whenever interpreting results of epidemiological cohort studies. Nevertheless we have shown that several diagnoses proved to have a negative influence on overall survival time even in this relatively healthy cohort. This study showed the significantly increased mortality risk if the following diseases are reported in medical history of the participants in a large population-based cohort study including adults aged 18 and over: diabetes mellitus (HR 1.533, p = 0.002), hypertension (HR 1.447, p = 0.005), liver cirrhosis (HR 4.251, p < 0.001), osteoporosis (HR 2.165, p = 0.011), chronic bronchitis (HR 2.179, p < 0.001), peptic ulcer disease (HR 1.531, p = 0.024) and cancer (HR 1.797, p < 0.001). Surprisingly, asthma has the opposite effect on survival time (HR 0.574, p = 0.024), but we believe this may be due to an overrepresentation of mild to moderate asthma and its management, which includes educating patients about a healthy lifestyle. CONCLUSION: In the LIFE-Adult-Study, common risk factors and several diseases had relevant effect on overall survival. However, selection bias in epidemiological studies needs to be considered whenever interpreting results of epidemiological cohort studies. Nevertheless it was shown that the general cause-and-effect principles also apply in this relatively healthy cohort.

Signs of left atrial disease and 10-year risk of atrial fibrillation.

BACKGROUND: The contribution of left atrial disease and excessive supraventricular ectopic activity (ESVEA) to the risk for incident atrial fibrillation (AF) is incompletely understood. OBJECTIVE: To analyse the ten-year risk to develop AF in patients with cardiovascular risk factors and to define the impact of parameters of left atrial disease and ESVEA on AF risk. METHODS: 148 patients from the Diast-CHF trial with at least one cardiovascular risk factor and free of AF at baseline were followed for 10 years. Left atrial disease was defined as left atrial volume index (LAVI) >35 ml/m2, P-terminal force in lead V1 (PTFV1) >4000 ms*µV or elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/ml. We analyzed the association of these parameters and ESVEA (either >720 premature atrial contractions (PAC) or one atrial run >20 beats per day) on AF-free survival. RESULTS: After ten years, AF was newly detected in twelve patients (13.4%) with signs of left atrial disease and two patients (3.4%) without signs of left atrial disease (p = 0.04). LAVI (p = 0.005), ESVEA (p = 0.016) and NT-proBNP (p = 0.010) were significantly associated with AF-free survival in univariate analysis. A combined Cox model of left atrial disease parameters showed associations for NT-proBNP (HR 3.56; 95%CI 1.33-5.31; p = 0.04) and PAC (HR 2.66; 95%CI 1.25-10.15; p = 0.01) but not for LAVI or PTFV1 with AF-free survival. CONCLUSION: The risk for AF is higher in patients with cardiovascular risk factors and signs of left atrial disease. NT-proBNP and premature atrial contractions independently predict AF-free survival. The role of excessive supraventricular ectopic activity for the assessment of AF risk may be underestimated and requires further study.

Patients' attitude towards a sham-controlled trial on pulmonary vein isolation in atrial fibrillation.

BACKGROUND: The interpretation of recent trials on pulmonary vein ablation (PVI) for the treatment of atrial fibrillation (AF) is hampered by the lack of blinding and sham controls. The feasibility of a sham-controlled trial has been questioned. We aimed to assess the attitude of potential participants regarding a sham-controlled trial in a common AF-patient population planned for PVI. METHODS: Patients in two tertiary care centres planned for PVI were asked for their current AF symptoms using the Atrial Fibrillation Effect on QualiTy of Life (AFEQT) questionnaire 1 day before catheter ablation. Subsequently, the study design of a hypothetical sham-controlled PVI-study was introduced, and patients were asked for their agreement in participation. Telephone follow-up of the AFEQT questionnaire was conducted 3 months after PVI. RESULTS: One hundred and ninety-six patients (mean age 64 ± 11 years, 63% male) were included. Seventy-nine (40%) patients expressed their agreement to participate in the hypothetical sham-controlled trial. An additional 7% agreed to participate if a cross-over option after three months was offered. Agreement rate was similar in patients with first and Redo-PVI and minimal, moderate or severe symptoms. Mean overall AFEQT at baseline was 55 ± 19 and improved by 25 ± 20 points after 3 months (p < 0.001 versus baseline). CONCLUSION: With a participation rate of 40% in potential study participants, a sham-controlled trial for pulmonary vein isolation seems feasible. Patient-reported symptom relief after pulmonary vein isolation is in accordance with previous randomized open studies. The benefit of PVI should be rigorously evaluated in a sham-controlled trial.

Effects of surgical and FFP2 masks on cardiopulmonary exercise capacity in patients with heart failure.

AIMS: Surgical and FFP2 masks are recommended to reduce transmission of SARS-CoV-2. The cardiopulmonary effects of facemasks in patients with chronic heart failure are unknown. This prospective, cross-over study quantified the effects of wearing no mask (nm), surgical mask (sm), and FFP2 mask (ffpm) in patients with stable heart failure. METHODS: 12 patients with clinically stable chronic heart failure (HF) (age 63.8±12 years, left ventricular ejection fraction (LVEF) 43.8±11%, NTProBNP 573±567 pg/ml) underwent spiroergometry with and without masks in a randomized sequence. Comfort/discomfort was assessed using a standardized questionnaire. RESULTS: Maximum power was reduced with both types of masks (nm: 108.3 W vs. sm: 101.2 W vs. ffpm: 95.6 W, p<0.01). Maximum respiratory oxygen uptake (1499ml/min vs. 1481 ml/min vs. 1300 ml/min, p = 0.95 and <0.01), peak ventilation (62.1 l/min vs. 56.4 l/min vs. 50.3 l/min, p = 0.15 and p<0.05) and O2-pulse (11.6 ml/beat vs. 11.8 ml/beat vs. 10.6 ml/beat, p = 0.87 and p<0.01) were significantly changed with ffpm but not sm. Discomfort was moderately but significantly increased (nm: 1.6 vs. sm: 3.4 vs. ffpm: 4.4, p<0.05). CONCLUSION: Both surgical and FFP masks reduce exercise capacity in heart failure patients, while FFP2 masks reduce oxygen uptake and peak ventilation. This reduction in cardiopulmonary performance should be considered in heart failure patients whose daily life activities are often just as challenging as exercise is for healthy adults.

Long-term clinical and haemodynamic results after transcatheter annuloplasty for secondary mitral regurgitation.

AIMS: The study sought to investigate the long-term outcome after transcatheter mitral valve annuloplasty for secondary mitral regurgitation (MR). METHODS AND RESULTS: Consecutive patients with symptomatic secondary MR undergoing transcatheter mitral valve annuloplasty with the Carillon device at Leipzig University Hospital between 2012 and 2018 were studied prospectively. Left ventricular (LV) function and MR severity were quantified by standardized echocardiography. 33 patients were included. Mean age was 75 ± 10 years, and 20 patients were women. A Society of Thoracic Surgeons score of 8.1 ± 7.2% indicated high-risk status. In 24 patients, MR resulted from LV remodelling and dysfunction, eight suffered from left atrial dilatation, and one patient had MR due to combined primary and secondary aetiology. LV ejection fraction at baseline was (median) 38% [inter-quartile range (IQR) 30-49%]. During the mean follow-up time of 45 ± 20 months, 17 patients died, two patients withdraw consent, and four patients were lost. Of the remaining patients, four were hospitalized for decompensated heart failure. Two of these patients underwent additional transcatheter edge-to-edge mitral valve repair. At follow-up, New York Heart Association (NYHA) functional class improved from 95% in Class III/IV at baseline to 70% in Class I/II with no patients in NYHA Class IV (P < 0.0001). Mitral regurgitant volume was reduced from 27 mL (IQR 25-42 mL) to 8 mL (IQR 3-17 mL) (P = 0.018) and regurgitant fraction from 42% (IQR 34-54%) to 11% (IQR 8-24%) (P = 0.014). LV end-diastolic volume index [92 mL/m2 (IQR 74-107 mL/m2 ) vs. 67 mL/m2 (IQR 46-101 mL/m2 ), P = 0.065] and end-systolic volume index [50 mL/m2 (IQR 44-69 mL/m2 ) vs. 32 mL/m2 (IQR 20-53 mL/m2 ), P = 0.037] decreased. Total stroke volume remained unchanged [38 mL/m2 (IQR 33-43 mL/m2 ) vs. 33 mL/m2 (IQR 26-44 mL/m2 ), P = 0.695], while LV ejection fraction increased [43% (IQR 35-49%) vs. 54% (IQR 46-57%), P = 0.014]. Forward stroke volume, heart rate, and forward cardiac output were not significantly altered. CONCLUSIONS: Among high-risk patients undergoing transcatheter mitral valve annuloplasty for symptomatic secondary MR, mortality was ~50% at 4 years. In the surviving patients, reduced MR severity was associated with reduced NYHA functional class, reverse LV remodelling, and improved LV function.

Heart failure is independently associated with white matter lesions: insights from the population-based LIFE-Adult Study.

AIMS: White matter lesions (WML) are common structural alterations in the white matter of the brain and their prevalence increases with age. They are associated with cerebral ischaemia and cognitive dysfunction. Patients with heart failure (HF) are at risk for cognitive decline. We hypothesized that the presence and duration of HF are associated with WML. METHODS AND RESULTS: The LIFE-Adult Study is a population-based study of 10 000 residents of Leipzig, Germany. WML were quantitated in 2490 participants who additionally underwent cerebral MRI using the Fazekas score. Mean age was 64 years, and 46% were female; 2156 (86.6%) subjects had Fazekas score of 0-1, and 334 (13.4%) had Fazekas score of 2-3. Thirty participants had a medical history of HF, 1019 had hypertension, and 51 had a history of stroke. Median left ventricular ejection fraction of the participants with HF was 57% (interquartile ranges 54-62). Age, troponin T, NT-proBNP, body mass index, history of acute myocardial infarction, stroke, HF, and diabetes were positively associated with WML in univariate analysis. On multivariate analysis, age, hypertension, stroke, and HF were independently associated with WML. The odd's ratio for the association of WML (Fazekas 2-3) with HF was 2.8 (95% CI 1.2-6.5; P = 0.019). WML increased with longer duration of HF (P = 0.036 for trend). CONCLUSIONS: In addition to age, hypertension, and stroke, the prevalence and duration of HF are independently associated with WML. This observation sets the stage to investigate the prognostic value of WML in HF and the impact of HF therapies on WML.

Heart failure patients with atrial fibrillation benefit from remote patient management: insights from the TIM-HF2 trial.

AIMS: Atrial fibrillation (AF) is a frequent comorbidity in patients with heart failure (HF). HF patients with AF are characterized by high morbidity and increased risk of hospitalizations. We assessed the effects of remote patient management (RPM) in HF patients with AF compared with usual care (UC) in the TIM-HF2 trial. METHODS AND RESULTS: For this post-hoc analysis, AF status at randomization was assessed in 1537 patients with HF. The primary outcome was the percentage of days lost due to unplanned cardiovascular hospital admissions or death of any cause. Around 966 patients had sinus rhythm (SR) and 571 had AF. The analysis showed a significant interaction between heart rhythm and all-cause mortality (P for interaction = 0.001). AF patients had more days lost due to unplanned cardiovascular hospitalization than SR patients (7.53%, CI 6.01-9.05 vs. 4.90%, CI 3.98-5.82, ratio 1.54, P = 0.004) and higher all-cause mortality (11.9%, CI 9.4-14.9 vs. 8.5%, CI 6.8-10.4, HR 0.66, CI 0.47-0.94, P = 0.029). Patients with AF randomized to RPM had significantly less days lost due to unplanned cardiovascular hospital admissions or all-cause death (5.64%, CI 3.81-7.48) than patients with AF randomized to UC (9.37%, CI 6.98-11.76, ratio 0.60, P = 0.015). No difference was seen in SR patients (UC: 5.25%, CI 3.93-6.58, RPM: 4.55%, CI 3.27-5.83, ratio 0.87, P = 0.452). All-cause mortality in AF patients was reduced with 9.2% (CI 6.1-13.2) in the RPM group compared with 14.5% (CI 10.7-18.1) in the UC group (HR 0.60, CI 0.36-1.00, P = 0.050). CONCLUSIONS: For patients with atrial fibrillation at study entry, RPM was associated with increased days alive out of hospital. Our results identify HF patients with atrial fibrillation as a promising target population for RPM.