Behavioural digital biomarkers enable real-time monitoring of patient-reported outcomes: a substudy of the multicenter, prospective observational SafeHeart study.

INTRODUCTION: Patient-reported outcome measures (PROMs) serve multiple purposes, including shared decision-making and patient communication, treatment monitoring and health-technology assessment. Patient monitoring using PROMs is constrained by recall and non-response bias, respondent burden and missing data. We evaluated the potential of behavioural digital biomarkers obtained from a wearable accelerometer to achieve personalised predictions of PROMs. METHODS: Data from the multicenter, prospective SafeHeart study conducted at Amsterdam University Medical Center in the Netherlands and Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark, was used. The study enrolled patients with an implantable cardioverter defibrillator (ICD) between May 2021 and September 2022 who then wore wearable devices with raw acceleration output to capture digital biomarkers reflecting physical behaviour. To collect PROMs, patients received the KCCQ and EQ5D-5 L questionnaire at two instances; baseline and after 6 months. Multivariable Tobit regression models were used to explore associations between digital biomarkers and PROMs, specifically whether digital biomarkers could enable PROM prediction. RESULTS: The study population consisted of 303 patients (mean age 62.9 ± 10.9 years, 81.2% male). Digital biomarkers showed significant correlations to patient-reported physical and social limitations, severity and frequency of symptoms and quality of life. Prospective validation of the Tobit models indicated moderate correlations between the observed and predicted scores for KCCQ (concordance correlation coefficient (CCC) = 0.49, mean difference: 1.07 points) and EQ5D-5 L (CCC = 0.38, mean difference 0.02 points). CONCLUSION: Wearable digital biomarkers correlate with PROMs, and may be leveraged for real-time prediction. These findings hold promise for monitoring of PROMs through wearable accelerometers.

Efficacy on resynchronization and longitudinal contractile function comparing His-bundle pacing with conventional biventricular pacing: a substudy to the His-alternative study.

AIMS: His-bundle pacing has emerged as a novel method to deliver cardiac resynchronization therapy (CRT). However, there are no data comparing conventional biventricular (BiV)-CRT with His-CRT with regard to effects on mechanical dyssynchrony and longitudinal contractile function. METHODS AND RESULTS: Patients with symptomatic heart failure, left ventricular ejection fraction ≤ 35%, and left bundle branch block (LBBB) by strict ECG criteria were randomized 1:1 to His-CRT or BiV-CRT. Two-dimensional strain echocardiography was performed prior to CRT implantation and at 6 months after implantation. Differences in changes in mechanical dyssynchrony (standard deviation of time-to-peak in 12 midventricular and basal segments) and regional longitudinal strain in the six left ventricular walls were compared between the BiV-CRT and His-CRT groups.In the on-treatment analysis, 31 received BiV-CRT and 19 His-CRT. In both groups, mechanical dyssynchrony was significantly reduced after 6 months [BiV group from 120 ms (±45) to 63 ms (±22), P < 0.001, and His group from 116 ms (±54) to 49 ms (±11), P < 0.001] but no significant differences in changes could be demonstrated between groups [-9.0 ms (-36; 18), P = 0.50]. Global longitudinal strain (GLS) improved in both groups [BiV group from -9.1% (±2.7) to -10.7% (±2.6), P = 0.02, and His group from -8.6% (±2.1) to -11.1% (±2.0), P < 0.001], but no significant differences in changes could be demonstrated from baseline to follow-up [-0.9% (-2.4; -0.6), P = 0.25] between groups. There were no regional differences between groups. CONCLUSION: In heart failure, patients with LBBB, BiV-CRT, and His-CRT have comparable effects with regard to improvements in mechanical dyssynchrony and longitudinal contractile function.

Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium-regulating genes. Identification of potential false-positive pathogenic variants was conducted by searching the Exome Aggregation Consortium (ExAC) database (n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics (ACMG) and in silico prediction tools. Of 246 variants 38 (15%) variants previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico predictions showed a reduced probability of disease-causing effect for the variants identified in the exome database (p < 0.001). We have observed a large overrepresentation of previously CPVT-associated variants in a large exome database. Based on the frequency of CPVT in the general population, it is less likely that the previously proposed variants are associated with a highly penetrant monogenic form of the disease.

Assessment of autonomic function after acute spinal cord injury using heart rate variability analyses.

OBJECTIVES: Spinal cord injury (SCI) often results in severe dysfunction of the autonomic nervous system. C1-C8 SCI affects the supraspinal control to the heart, T1-T5 SCI affects the spinal sympathetic outflow to the heart, and T6-T12 SCI leaves sympathetic control to the heart intact. Heart rate variability (HRV) analysis can serve as a surrogate measure of autonomic regulation. The aim of this study was to investigate changes in HRV patterns and alterations in patients with acute traumatic SCI. METHODS: As soon as possible after SCI patients who met the inclusion criteria had 24 h Holter monitoring of their cardiac rhythm, additional Holter monitoring were performed 1, 2, 3 and 4 weeks after SCI. RESULTS: Fifty SCI patients were included. A significant increase in standard deviation of the average normal-to-normal (SDANN) sinus intervals was seen in the first month after injury (P=0.008). The increase was only significant in C1-T5 incomplete patients and in patients who did not experience one or more episodes of cardiac arrest. Significant lower values of Low Frequency Power, Total Power and the Low Frequency over High Frequency ratio were seen in the C1-T5 SCI patients compared with T6-T12 SCI patients. CONCLUSIONS: The rise in SDANN in the incomplete C1-T5 patients could be due to spontaneous functional recovery caused by synaptic plasticity or remodelling of damaged axons. That the autonomic nervous system function differs between C1-C8, T1-T5 and T6-T12 patients suggest that the sympathovagal balance in both the C1-C8 and T1-T5 SCI patients has yet to be reached.

Maximal heart rate does not limit cardiovascular capacity in healthy humans: insight from right atrial pacing during maximal exercise.

In humans, maximal aerobic power (VO2 max ) is associated with a plateau in cardiac output (Q), but the mechanisms regulating the interplay between maximal heart rate (HRmax) and stroke volume (SV) are unclear. To evaluate the effect of tachycardia and elevations in HRmax on cardiovascular function and capacity during maximal exercise in healthy humans, 12 young male cyclists performed incremental cycling and one-legged knee-extensor exercise (KEE) to exhaustion with and without right atrial pacing to increase HR. During control cycling, Q and leg blood flow increased up to 85% of maximal workload (WLmax) and remained unchanged until exhaustion. SV initially increased, plateaued and then decreased before exhaustion (P < 0.05) despite an increase in right atrial pressure (RAP) and a tendency (P = 0.056) for a reduction in left ventricular transmural filling pressure (LVFP). Atrial pacing increased HRmax from 184 ± 2 to 206 ± 3 beats min(-1) (P < 0.05), but Q remained similar to the control condition at all intensities because of a lower SV and LVFP (P < 0.05). No differences in arterial pressure, peripheral haemodynamics, catecholamines or VO2 were observed, but pacing increased the rate pressure product and RAP (P < 0.05). Atrial pacing had a similar effect on haemodynamics during KEE, except that pacing decreased RAP. In conclusion, the human heart can be paced to a higher HR than observed during maximal exercise, suggesting that HRmax and myocardial work capacity do not limit VO2 max in healthy individuals. A limited left ventricular filling and possibly altered contractility reduce SV during atrial pacing, whereas a plateau in LVFP appears to restrict Q close to VO2 max .

Peripheral vasodilatation determines cardiac output in exercising humans: insight from atrial pacing.

In dogs, manipulation of heart rate has no effect on the exercise-induced increase in cardiac output. Whether these findings apply to humans remain uncertain, because of the large differences in cardiovascular anatomy and regulation. To investigate the role of heart rate and peripheral vasodilatation in the regulation of cardiac output during steady-state exercise, we measured central and peripheral haemodynamics in 10 healthy male subjects, with and without atrial pacing (100­150 beats min(−1)) during: (i) resting conditions, (ii) one-legged knee extensor exercise (24 W) and (iii) femoral arterial ATP infusion at rest. Exercise and ATP infusion increased cardiac output, leg blood flow and vascular conductance (P < 0.05), whereas cerebral perfusion remained unchanged. During atrial pacing increasing heart rate by up to 54 beats min(−1), cardiac output did not change in any of the three conditions, because of a parallel decrease in stroke volume (P < 0.01). Atrial pacing increased mean arterial pressure (MAP) at rest and during ATP infusion (P < 0.05), whereas MAP remained unchanged during exercise. Atrial pacing lowered central venous pressure (P < 0.05) and pulmonary capillary wedge pressure (P < 0.05) in all conditions, whereas it did not affect pulmonary mean arterial pressure. Atrial pacing lowered the left ventricular contractility index (dP/dt) (P < 0.05) in all conditions and plasma noradrenaline levels at rest (P < 0.05), but not during exercise and ATP infusion. These results demonstrate that the elevated cardiac output during steady-state exercise is regulated by the increase in skeletal muscle blood flow and venous return to the heart, whereas the increase in heart rate appears to be secondary to the regulation of cardiac output.

Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy.

A single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at performing mutational analysis of the gene and characterizing the associated immunohistochemical features. Sixty-five unrelated patients (55 fulfilling Task Force criteria and 10 borderline cases) were screened for mutations in TMEM43. Immunohistochemistry with anti-TMEM43, anti-plakoglobin, anti-plakophilin-2, anti-connexin-43, and anti-emerin antibodies was performed on myocardium from TMEM43-positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T; in two related patients) and one novel variant (c.705+ 7G> A; in one patient) of unknown significance. All three patients fulfilled Task Force criteria and did not carry mutations in any other ARVC-related gene. Immunostaining with TMEM43 antibody showed intense staining of the sarcolemma. The signal level was reduced in all the three TMEM43-positive patients. Immunostaining with plakoglobin-specific antibody also showed reduced signal levels in the three carriers. All patients displayed a similar immunoreactive signal for plakophilin-2, connexin-43, and emerin. In conclusion, two TMEM43 sequence variants were identified in this Danish ARVC cohort. Evaluation of the expression of TMEM43 showed a unique cardiac localization. The immunoreactive signal for the desmosomal protein plakoglobin was reduced in mutation carriers. The TMEM43 gene underlies a distinctive form of ARVC which may share a final common pathway with desmosome-associated ARVC.

Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins. OBJECTIVE: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status. METHODS: 65 unrelated patients (55 fulfilling current criteria and 10 borderline cases) were screened for mutations in all known desmosome genes (desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP) and plakophilin-2 (PKP2)) and TGFb3. Presence of genomic rearrangements was assessed by multiplex ligation-dependent probe amplification. Results The screening identified 19 different mutations: two mutations in DSG2, four in DSC2, two in DSP (one heterozygous and one homozygous), four in JUP (one patient with compound heterozygous) and seven in PKP2. No genomic rearrangements or mutations in TGFb3 were identified. Ten of the mutations were novel. Seven families carried more than one mutation. Clinical evaluation of these families showed a variable phenotype associated with the double-mutation carrier status. The homozygous desmoplakin mutation (DSP p.G2056R+p.G2056R) carrier came from a consanguineous Danish family and had left ventricular involvement, palmar keratoderma and curly hair consistent with a Carvajal-like syndrome. CONCLUSIONS: 33% of patients in this Danish cohort with ARVC carried desmosomal mutations with a surprisingly wide mutation spectrum. A substantial proportion of patients carried more than one mutation. Our study supports comprehensive desmosomal mutation screening beyond the first encountered mutation, whereas routine screening for genomic rearrangements does not seem indicated.

A nationwide, retrospective analysis of symptoms, comorbidities, medical care and autopsy findings in cases of fatal pulmonary embolism in younger patients.

OBJECTIVE: Our objective was to provide a comprehensive description of fatal pulmonary embolism (PE) in younger persons. Specifically, we recorded information on symptoms, comorbidity, medical contact, if this had been required, and subsequent autopsy findings. METHODS: We reviewed all death certificates from persons aged 0-35 years who had died between 1 January 2000 and 31 December 2006, and retrospectively identified all cases of fatal PE. Additional information was retrieved from the National Patient Registry, autopsy reports, and clinical charts. RESULTS: Sixty-one cases of fatal PE were included; 38% of these were in males. The median age was 29 years. The predominant symptoms were dyspnea, syncope, leg pains, and chest pains. Sixty-three per cent of patients reportedly experienced symptoms for days, weeks, or months. More than half of the patients had sought medical care, and at the time of medical evaluation the majority of the patients were not hemodynamically compromised. In 21% cases, the correct diagnosis was reached before death; however, in only 5% of cases was this accomplished before clinical deterioration. Furthermore, clinical history and subsequent postmortem examinations showed that approximately half of younger persons dying from PE were otherwise healthy, and in no case was occult cancer diagnosed. CONCLUSIONS: Our data show that a substantial proportion of younger victims of fatal PE had experienced symptoms for an extended period of time. Furthermore, the correct diagnosis remained elusive in the majority of cases, even though approximately half of the subjects had sought medical evaluation for symptoms that, in retrospect, were most likely caused by a venothrombotic event.

Quality assessment of pacemaker implantations in Denmark.

AIMS: Quality assessment of therapeutic procedures is essential to insure a cost-effective health care system. Pacemaker implantation is a common procedure with more than 500,000 implantations world-wide per year, but the general complication rate is not well described. We studied procedure related complications for all implantations performed in an entire nation over a 3-year period. METHODS AND RESULTS: A prospective study of complications related to 99% of the 5648 primary pacemaker implantations performed in the 12 Danish pacemaker centres in 1997-1999 was carried out. Overall 76% of the patients received a physiological pacemaker system and 91% received the optimal pacing mode according to international guidelines. Perioperative complications requiring reoperation were: haematoma 0.3%, atrial lead related 1.9%, ventricular lead related 1.7%. Late complications requiring reoperation were: infection 02%, atrial lead related 13%, ventricular lead related 1.2%. The complication rate decreased over the study period, but overall the complication rate was higher than expected and showed considerable variation between centres. CONCLUSIONS: Our results demonstrate that sensitive data such as complications related to pacemaker implantations can be collected on a national basis. We suggest that a reoperation rate higher than 3% for atrial as well as ventricular pacing electrodes in the individual implanting centre should cause the centre to evaluate carefully the procedure as well as the performance of the individual implanter.

Regional myocardial oxygen consumption estimated by carbon-11 acetate and positron emission tomography before and after repetitive ischemia.

BACKGROUND: Preserved myocardial oxygen consumption estimated by carbon 11-acetate and positron emission tomography (PET) in myocardial regions with chronic but reversibly depressed contractile function in patients with ischemic heart disease have been suggested to be caused by repeated short episodes of acute myocardial ischemia. To evaluate this hypothesis myocardial 11C-acetate PET imaging was performed before and after acute repetitive myocardial ischemia. METHODS AND RESULTS: In open chest dogs (n = 8), the left anterior descending coronary artery was occluded 4 times for 5 minutes alternating with 5 minutes of reperfusion. Before and after repetitive coronary occlusions, oxygen 15 water/oxygen 15 carbon monoxide (blood flow), and 11C-acetate (oxygen consumption) PET imaging were performed. Left ventricular regional systolic wall thickening was measured with sonomicrometry. Forty-five minutes after the ischemic episodes, systolic ventricular wall thickening was decreased by 90%, whereas myocardial blood flow was reduced by 21% compared with baseline values (P < .05). Ninety minutes after the ischemic episodes, estimated oxygen consumption was unaltered compared with the baseline level despite a sustained 70% decrease in the regional contractile function (P < .05). CONCLUSIONS: Oxygen consumption estimated by 11C-acetate PET imaging is preserved after repeated episodes of acute myocardial ischemia despite a severe impairment of contractile function.

Tissue temperatures and lesion size during irrigated tip catheter radiofrequency ablation: an in vitro comparison of temperature-controlled irrigated tip ablation, power-controlled irrigated tip ablation, and standard temperature-controlled ablation.

The limited success rate of radiofrequency catheter ablation in patients with ventricular tachycardias related to structural heart disease may be increased by enlarging the lesion size. Irrigated tip catheter ablation is a new method for enlarging the size of the lesion. It was introduced in the power-controlled mode with high power and high infusion rate, and is associated with an increased risk of crater formation, which is related to high tissue temperatures. The present study explored the tissue temperatures during temperature-controlled irrigated tip ablation, comparing it with standard temperature-controlled ablation and power-controlled irrigated tip ablation. In vitro strips of porcine left ventricular myocardium were ablated. Temperature-controlled irrigated tip ablation at target temperatures 60 degrees C, 70 degrees C, and 80 degrees C with infusion of 1 mL saline/min were compared with standard temperature-controlled ablation at 70 degrees C and power-controlled irrigated tip ablation at 40 W, and infusion of 20 mL/min. Lesion size and tissue temperatures were significantly higher during all modes of irrigated tip ablation compared with standard temperature-controlled ablation (P < 0.05). Lesion volume correlated positively with tissue temperature (r = 0.87). The maximum recorded tissue temperature was always 1 mm from the ablation electrode and was 67 +/- 4 degrees C for standard ablation and 93 +/- 6 degrees C, 99 +/- 6 degrees C, and 115 +/- 13 degrees C for temperature-controlled irrigated tip ablation at 60 degrees C, 70 degrees C, and 80 degrees C, respectively, and 112 +/- 12 degrees C for power-controlled irrigated tip ablation, which for irrigated tip ablation was significantly higher than tip temperature (P < 0.0001). Crater formation only occurred at tissue temperatures > 100 degrees C. We conclude that irrigated tip catheter ablation increases lesion size and tissue temperatures compared with standard ablation in the temperature-controlled mode at the same or higher target temperatures and in the power-controlled mode. Furthermore, tissue temperature and delivered power are the best indicators of lesion volume during temperature-controlled ablation.

Temperature-controlled radiofrequency ablation of cardiac tissue: an in vitro study of the impact of electrode orientation, electrode tissue contact pressure and external convective cooling.

BACKGROUND: A variety of basic factors such as electrode tip pressure, flow around the electrode and electrode orientation influence lesion size during radiofrequency ablation, but importantly is dependent on the chosen mode of ablation. However, only little information is available for the frequently used temperature-controlled mode. The purpose of the present experimental study was to evaluate the impact during temperature-controlled radiofrequency ablation of three basic factors regarding electrode-tissue contact and convective cooling on lesion size. METHODS AND RESULTS: In vitro strips of porcine left ventricular myocardium were ablated in a tissue bath. Temperature-controlled ablation at 80 degrees C for 60 s was performed using a 7F 4 mm tip electrode in either perpendicular or parallel contact with the endocardium at a pressure of 10 or 20 g. Increased flow around the electrode was induced by circulating the saline in the tissue bath at a flow-velocity of 0.1 m/s. Lesion volume was determined by cutting lesions in 1 mm thick slices, staining with nitroblue tetrazolium and planimetering. A total of 107 lesions was created. Lesion size was significantly larger for perpendicular electrode orientation compared to parallel for both pressure-settings and both levels of flow around the electrode (p < 0.05). Increased flow around the electrode enlarged lesion size (p < 0.005). Electrode-tissue contact pressure had no significant impact on lesion size. CONCLUSIONS: During temperature-controlled radiofrequency ablation increased external cooling of the electrode tip due to either flow of the surrounding liquid or poor electrode tissue contact, as exemplified by perpendicular versus parallel electrode orientation, increases lesion size significantly. This is in contrast to the impact of these factors during power-controlled ablation due to the lack of increased power-delivery in the latter situation.

Lesion dimensions during temperature-controlled radiofrequency catheter ablation of left ventricular porcine myocardium: impact of ablation site, electrode size, and convective cooling.

BACKGROUND: It is important to increase lesion size to improve the success rate for radiofrequency ablation of ischemic ventricular tachycardia. This study of radiofrequency ablation, with adjustment of power to approach a preset target temperature, ie, temperature-controlled ablation, explores the effect of catheter-tip length, ablation site, and convective cooling on lesion dimensions. METHODS AND RESULTS: In vitro strips of porcine left ventricular myocardium during different levels of convective cooling and in vivo pig hearts at 2 or 3 left ventricular sites were ablated with 2- to 12-mm-tip catheters. We found increased lesion volume for increased catheter-tip length

Temperature-controlled irrigated tip radiofrequency catheter ablation: comparison of in vivo and in vitro lesion dimensions for standard catheter and irrigated tip catheter with minimal infusion rate.

INTRODUCTION: In patients with ventricular tachycardias due to structural heart disease, catheter ablation cures < 60% partly due to the limited lesion size after conventional radiofrequency ablation. Irrigated tip radiofrequency ablation using power control and high infusion rates enlarges lesion size, but has increased risk of cratering. The present study explores irrigated tip catheter ablation in temperature-controlled mode, target temperature 60 degrees C, using an irrigation rate of 1 mL/min, comparing this to conventional catheter technique, target temperature 80 degrees C. METHODS AND RESULTS: In vivo anesthetized pigs were ablated in the left ventricle. In vitro strips of porcine left ventricular myocardium were ablated in a tissue bath. Lesion volume was significantly larger after irrigated tip ablation both in vivo (544 +/- 218 vs 325 +/- 194 mm3, P < 0.01) and in vitro (286 +/- 113 vs 179 +/- 23 mm3, P < 0.001). The incidence of cratering was not significantly different between the two groups. In vivo, no coagulum formation on part of the catheter tip was seen after irrigated tip ablation as opposed to 52% of the applications with conventional ablation (P < 0.05). CONCLUSION: We conclude that temperature-controlled radiofrequency ablation with irrigated tip catheters using low target temperature and low infusion rate enlarges lesion size without increasing the incidence of cratering and reduces coagulum formation of the tip.

Lesion size in relation to ablation site during radiofrequency ablation.

This study was designed to investigate the effect of the convective cooling of the tip of the ablation electrode during temperature controlled radiofrequency ablation. In vivo two different application sites in the left ventricle of anaesthetised pigs were ablated and in vitro ablation was performed during two different flow-velocities in a tissue bath, while electrode contact pressure and position were unchanged. Target temperature was 80 degrees C. Obtained tip temperature, power consumption and lesion dimensions were measured. In vivo lesion volume, depth and width were found significantly larger for septal applications than apical applications (p < 0.01) and more power was used (p < 0.001). Obtained tip temperature was significantly lower in the septal applications (p < 0.001). In vitro increased convective cooling by induction of flow yielded larger lesion volume, depth and width (p < 0.01), and had higher power consumptions (p < 0.01). Obtained tip temperature did not differ significantly. For the given chosen target temperature power consumption was positively related to lesion volume (r = 0.66 in vivo and 0.65 in vitro), whereas obtained tip temperature was not (r = -0.49 in vivo and -0.61 in vitro). We conclude that during temperature controlled radiofrequency ablation lesion size differs for septal and apical left ventricular applications. Differences in convective cooling might play an important role in this respect. This is supported by our in vitro experiments, where increased convective cooling by induction of a flow around the electrode tip increases lesion dimensions and power consumptions. Furthermore we conclude that for the given target temperature the power consumption is positively correlated with lesion volume (p < 0.001), whereas the obtained tip temperature is not.