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Purpose The relevance of repetitive [ 99m Tc]Tc-DPD scintigraphy in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remains unclear. We investigated the impact of tafamidis on cardiac [ 99m Tc]Tc-DPD uptake, clinical, and laboratory markers at 6 and 12 months, and correlated 12 months [ 99m Tc]Tc-DPD uptake regression with survival. Methods This single-center study enrolled 39 ATTRwt-CM patients. Upon treatment initiation with tafamidis, patients underwent follow-up [ 99m Tc]Tc-DPD scintigraphy, and clinical and laboratory evaluations at 6 months ( n  = 6) and 12 months ( n  = 13), or both ( n  = 20). Results Tafamidis resulted in a significant decline in Perugini score (6 months p  = 0.008, 12 months p  < 0.001), and (semi-)quantitative [ 99m Tc]Tc-DPD uptake (total cardiac uptake: baseline 816 [522–933] cps, vs. 6 months 634 [502–734] cps, p  = 0.003, vs. 12 months 523 [108–754] cps, p  = 0.001). Clinical and laboratory improvements were observed (NYHA: 6 months p  = 0.007, 12 months p  = 0.033; NT-proBNP: baseline 2586 [1271–5561] ng/L, vs. 6 months 2526 [1109–4786] ng/L, p  = 0.016, vs. 12 months 2340 [1411–4749] ng/L, p  = 0.012). In Kaplan–Meier analysis, a decrease in right ventricular [ 99m Tc]Tc-DPD tracer uptake equal to or greater than the median value at 12 months (-30%) was associated with improved survival (log-rank p  = 0.021). Conclusions Tafamidis in ATTRwt-CM resulted in significant reductions of cardiac [ 99m Tc]Tc-DPD uptake, NYHA class, and cardiac biomarkers at 6 and 12 months. Regression of right ventricular [ 99m Tc]Tc-DPD uptake at 12 months was associated with improved survival.

PurposeCaffeinated beverages are consumed daily throughout the world. Caffeine consumption has been linked to dysfunction of the autonomic nervous system. However, the exact effects are still insufficiently understood.MethodsSixteen healthy individuals were included in the present non-randomized cross-over interventional study. All study subjects consumed a commercial energy drink (containing 240 mg caffeine), and in a second independent session coffee (containing 240 mg caffeine). High-resolution digital ECGs in Frank-lead configuration were recorded at baseline before consumption, and 45 min after consumption of the respective beverage. Using customized software, we assessed ECG-based biomarker periodic repolarization dynamics (PRD), which mirrors the effect of efferent cardiac sympathetic activity on the ventricular myocardium.ResultsThe consumption of energy drinks resulted in an increase in PRD levels (3.64 vs. 5.85 deg2; p < 0.001). In contrast, coffee consumption did not alter PRD levels (3.47 vs 3.16 deg2, p = 0.63). The heart rates remained unchanged both after coffee and after energy drink consumption. Spearman analysis showed no significant correlation between PRD changes and heart rate changes (R = 0.34, p = 0.31 for coffee, R = 0.31, p = 0.24 for energy drink).ConclusionOur data suggests that sympathetic activation after consumption of caffeinated beverages is independent from caffeine and might be mediated by other substances.Trial Number: NCT04886869, 13 May 2021, retrospectively registered

Decreased vagal activity after myocardial infarction results in reduced heart-rate variability and increased risk of death. To distinguish between vagal and sympathetic factors that affect heart-rate variability, we used a signal-processing algorithm to separately characterise deceleration and acceleration of heart rate. We postulated that diminished deceleration-related modulation of heart rate is an important prognostic marker. Our prospective hypotheses were that deceleration capacity is a better predictor of risk than left-ventricular ejection fraction (LVEF) and standard deviation of normal-to-normal intervals (SDNN). We quantified heart rate deceleration capacity by assessing 24-h Holter recordings from a post-infarction cohort in Munich (n=1455). We blindly validated the prognostic power of deceleration capacity in post-infarction populations in London, UK (n=656), and Oulu, Finland (n=600). We tested our hypotheses by assessment of the area under the receiver-operator characteristics curve (AUC). During a median follow-up of 24 months, 70 people died in the Munich cohort and 66 in the London cohort. The Oulu cohort was followed-up for 38 months and 77 people died. In the London cohort, mean AUC of deceleration capacity was 0·80 (SD 0·03) compared with 0·67 (0·04) for LVEF and 0·69 (0·04) for SDNN. In the Oulu cohort, mean AUC of deceleration capacity was 0·74 (0·03) compared with 0·60 (0·04) for LVEF and 0·64 (0·03) for SDNN (p<0·0001 for all comparisons). Stratification by dichotomised deceleration capacity was especially powerful in patients with preserved LVEF (p<0·0001 in all cohorts). Impaired heart rate deceleration capacity is a powerful predictor of mortality after myocardial infarction and is more accurate than LVEF and the conventional measures of heart-rate variability.

Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor ( Igf1r ) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration.

Acute alcohol consumption may facilitate cardiac arrhythmias underlying the ‘Holiday Heart Syndrome’. Autonomic imbalance is promoting atrial arrhythmias. We analyzed the effects of alcohol on measures of the cardiac autonomic nervous system and their relation to arrhythmias. In 15 healthy individuals, alcohol was administered parenterally until a breath alcohol concentration of 0.50 mg/l. High-resolution digital 30-min ECGs were recorded at baseline, at the time of maximum alcohol concentration, and after alcohol concentration returned to near baseline. Using customized software, we assessed periodic repolarization dynamics (PRD), deceleration capacity (DC), standard measures of heart rate variability (SDNN; RMSSD; LF; HF), and standard ECG parameters (mean heart rate; PQ; QRS; QTc interval). At the maximum alcohol concentration, PRD levels were significantly increased compared to baseline [1.92 (IQR 1.14–3.33) deg 2 vs. 0.85 (0.69–1.48) deg 2 ; p = 0.001]. PRD levels remained slightly increased when alcohol concentrations returned to baseline. DC levels were significantly decreased at the maximum alcohol concentration compared to baseline [7.79 (5.89–9.62) ms vs. 9.97 (8.20–10.99) ms; p = 0.030], and returned to baseline levels upon reaching baseline levels of alcohol. Standard HRV measures were reduced at maximum alcohol concentration. The mean heart rate increased significantly during alcohol administration. QRS and QTc duration were significantly prolonged, whereas PQ interval showed no change. Our findings revealed an increase of sympathetic activity and a reduction of parasympathetic activity under the influence of alcohol administration, resulting in autonomic imbalance. This imbalance might ultimately trigger arrhythmias underlying the ‘Holiday Heart Syndrome’.

Enhanced sympathetic activity at the ventricular myocardium can destabilize repolarization, increasing the risk of death. Sympathetic activity is known to cluster in low-frequency bursts; therefore, we hypothesized that sympathetic activity induces periodic low-frequency changes of repolarization. We developed a technique to assess the sympathetic effect on repolarization and identified periodic components in the low-frequency spectral range (≤0.1 Hz), which we termed periodic repolarization dynamics (PRD). We investigated the physiological properties of PRD in multiple experimental studies, including a swine model of steady-state ventilation (n=7) and human studies involving fixed atrial pacing (n=10), passive head-up tilt testing (n=11), low-intensity exercise testing (n=11), and beta blockade (n=10). We tested the prognostic power of PRD in 908 survivors of acute myocardial infarction (MI). Finally, we tested the predictive values of PRD and T-wave alternans (TWA) in 2,965 patients undergoing clinically indicated exercise testing. PRD was not related to underlying respiratory activity (P<0.001) or heart-rate variability (P=0.002). Furthermore, PRD was enhanced by activation of the sympathetic nervous system, and pharmacological blockade of sympathetic nervous system activity suppressed PRD (P≤0.005 for both). Increased PRD was the strongest single risk predictor of 5-year total mortality (hazard ratio 4.75, 95% CI 2.94-7.66; P<0.001) after acute MI. In patients undergoing exercise testing, the predictive value of PRD was strong and complementary to that of TWA. We have described and identified low-frequency rhythmic modulations of repolarization that are associated with sympathetic activity. Increased PRD can be used as a predictor of mortality in survivors of acute MI and patients undergoing exercise testing. ClinicalTrials.gov NCT00196274. This study was funded by Angewandte Klinische Forschung, University of Tübingen (252-1-0).

Introduction Sympathetic activity plays an important role in the pathogenesis of ventricular tachyarrhythmia. Catheter-based renal sympathetic denervation (RDN) is a novel treatment option for patients with resistant hypertension, proved to reduce local and whole-body sympathetic activity. Methods Two patients with chronic heart failure (CHF) (non-obstructive hypertrophic and dilated cardiomyopathy, NYHA III) suffering from therapy resistant electrical storm underwent therapeutic renal denervation. In both patients, RDN was conducted with agreement of the local ethics committee and after obtaining informed consent. Results The patient with hypertrophic cardiomyopathy had recurrent monomorphic ventricular tachycardia despite extensive antiarrhythmic therapy, following repeated endocardial and epicardial electrophysiological ablation attempts to destroy an arrhythmogenic intramural focus in the left ventricle. The second patient, with dilated nonischemic cardiomyopathy, suffered from recurrent episodes of polymorphic ventricular tachycardia and ventricular fibrillation. The patient declined catheter ablation of these tachycardias. In both patients, RDN was performed without procedure-related complications. Following RDN, ventricular tachyarrhythmias were significantly reduced in both patients. Blood pressure and clinical status remained stable during the procedure and follow-up in these patients with CHF. Conclusion Our findings suggest that RDN is feasible even in cardiac unstable patients. Randomized controlled trials are urgently needed to study the effects of RD in patients with electrical storm and CHF.

A novel in-vitro test (T 50 -test) assesses ex-vivo serum calcification propensity which predicts mortality in HD patients. The association of longitudinal changes of T 50 with all-cause and cardiovascular mortality has not been investigated. We assessed T 50 in paired sera collected at baseline and at 24 months in 188 prevalent European HD patients from the ISAR cohort, most of whom were Caucasians. Patients were followed for another 19 [interquartile range: 11–37] months. Serum T 50 exhibited a significant decline between baseline and 24 months (246 ± 64 to 190 ± 68 minutes; p < 0.001). With serum Δ-phosphate showing the strongest independent association with declining T 50 (r = −0.39; p < 0.001) in multivariable linear regression. The rate of decline of T 50 over 24 months was a significant predictor of all-cause (HR = 1.51 per 1SD decline, 95% CI: 1.04 to 2.2; p = 0.03) and cardiovascular mortality (HR = 2.15; 95% CI: 1.15 to 3.97; p = 0.02) in Kaplan Meier and multivariable Cox-regression analysis, while cross-sectional T 50 at inclusion and 24 months were not. Worsening serum calcification propensity was an independent predictor of mortality in this small cohort of prevalent HD patients. Prospective larger scaled studies are needed to assess the value of calcification propensity as a longitudinal parameter for risk stratification and monitoring of therapeutic interventions.

Transthoracic echocardiography (TTE) is the diagnostic routine standard for assessing aortic stenosis (AS). However, its inaccuracies in determining stroke volume (SV) and aortic valve area (AVA) call for a more precise and dependable method. Phase-contrast cardiovascular magnetic resonance imaging (PC-CMR) is a promising tool to push these boundaries. Thus, the aim of this study was to validate a novel approach based on PC-CMR against the gold-standard of invasive determination of AVA in AS compared to TTE. A total of 50 patients with moderate or severe AS underwent TTE, cardiac catheterization and CMR. AVA via PC-CMR was determined by plotting momentary flow across the valve against flow-velocity. SV by CMR was measured directly via PC-CMR and volumetrically using cine-images. Invasive SV and AVA were determined via Fick-principle and Gorlin-formula, respectively. TTE yielded SV and AVA using continuity equation. Gradients were calculated via the modified Bernoulli-equation. SV by PC-CMR (85 ± 31 ml) correlated strongly (r: 0.73, p < 0.001) with cine-CMR (85 ± 19 ml) without significant bias (lower and upper limits of agreement (LLoA and ULoA): − 41 ml and 44 ml, p = 0.83). In PC-CMR, mean pressure gradient correlated significantly with invasive determination (r: 0.36, p = 0.011). Mean AVA, as determined by PC-CMR during systole (0.78 ± 0.25 cm2), correlated moderately (r: 0.54, p < 0.001) with invasive AVA (0.70 ± 0.23 cm2), resulting in a small bias of 0.08 cm2 (LLoA and ULoA: − 0.36 cm2 and 0.55 cm2, p = 0.017). Inter-methodically, AVA by TTE (0.81 ± 0.23 cm2) compared to invasive determination showed similar correlations (r: 0.58, p < 0.001 with a bias of 0.11 cm2, LLoA and ULoA: − 0.30 and 0.52, p < 0.001) to PC-CMR. Intra- and interobserver reproducibility were excellent for AVA (intraclass-correlation-coefficients of 0.939 and 0.827, respectively). Our novel approach using continuous determination of flow-volumes and velocities with PC-CMR enables simple AVA measurement with no bias to invasive assessment. This approach highlights non-invasive AS grading through CMR, especially when TTE findings are inconclusive.

Hemodynamic assessment of coronary artery stenosis has impact on arterial graft patency. Quantitative flow ratio (QFR) obtains hemodynamic information of coronary artery stenosis. Patients with history of isolated coronary artery bypass grafting (with ≥1 arterial graft) and at least one postoperative coronary re-assessment were retrospectively investigated. The preoperative angiography was used for retrospective QFR analysis of the native coronary target vessel, to which the arterial bypass graft was anastomosed. Analysis was performed by certified investigators, who were blinded towards postoperative arterial graft patency status. Coronary targets with QFR values of ≤0.80 were defined as hemodynamically relevant, whereas values of >0.80 were defined as hemodynamically irrelevant. Out of 5,692 patients, 596 patients had a postoperative coronary assessment and were therefore eligible for inclusion. In 196 arterial target vessels QFR analysis was possible. Kaplan-Meier analysis revealed higher graft patency rates for arterial grafts anastomosed to coronary branches with QFR values ≤0.80 (log-rank:  = 0.017). In multivariable Cox regression analysis, QFR ≤ 0.80 remained an independent predictor for arterial graft patency (HR: 0.475, 95% CI: 0.261-0.867;  = 0.015), while visually estimated stenosis from preoperative coronary angiography did not (  = 0.160). With an area under the curve of 0.595, 95% CI (0.503-0.688), the performance of the model was poor to at most moderate. Most target vessels [546 (80.22%)] were not analysable in retrospective fashion. Though target vessel QFR ≤ 0.80 was associated with higher arterial graft patency, our trial observed low feasibility (high drop out rates) and poor diagnostic performance of QFR used in retrospective fashion. Caution is warranted for retrospective use of QFR in datasets with similar constraints.