Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Nolte, Ilja M.; Muñoz, M. Loretto; Tragante, Vinicius; Amare, Azmeraw T.; Jansen, Rick; Vaez, Ahmad; Heyde, Benedikt von der; Avery, Christy L.; Bis, Joshua C.; Dierckx, Bram; Dongen, Jenny van; Gogarten, Stephanie M.; Goyette, Philippe; Hernesniemi, Jussi; Huikari, Ville; Hwang, Shih‐Jen; Jaju, Deepali; Kerr, Kathleen F.; Kluttig, Alexander; Krijthe, Bouwe P.; Kumar, Jitender; Laan, Sander W. van der; Lyytikäinen, Leo-Pekka; Maihofer, Adam X.; Minassian, Arpi; Most, Peter J. van der; Mueller-Nurasyid, Martina; Nivard, Michel G.; Salvi, Erika; Stewart, James D.; Thayer, Julian F.; Verweij, Niek; Wong, Andrew; Zabaneh, Delilah; Zafarmand, Mohammad Hadi; Abdellaoui, Abdel; Albarwani, Sulayma; Albert, Christine M.; Alonso, Álvaro; Ashar, Foram N.; Auvinen, Juha; Axelsson, Tomas; Baker, Dewleen G.; Bakker, Paul I. W. de; Barcella, Matteo; Bayoumi, Riad; Bieringa, Rob J.; Boomsma, Dorret I.; Boucher, Gabrielle; Britton, Annie; Christophersen, Ingrid E.; Dietrich, Andrea; Ehret, G.; Ellinor, Patrick T.; Eskola, Markku; Felix, Janine F.; Floras, John S.; Franco, Oscar H.; Friberg, Peter; Gademan, Maaike G.J.; Geyer, Mark A.; Giedraitis, Vilmantas; Hartman, Catharina A.; Hemerich, Daiane; Hofman, Albert; Hottenga, Jouke‐Jan; Huikuri, Heikki V.; Hutri‐Kähönen, Nina; Jouven, Xavier; Junttila, Juhani; Juonala, Markus; Kiviniemi, Antti M.; Kors, Jan A.; Kumari, Meena; Kuznetsova, T.; Laurie, Cathy C.; Lefrandt, Joop D.; Li, Yong; Li, Yun; Liao, Duanping; Limacher, Marian C.; Lin, Henry J.; Lindgren, Cecilia M.; Lubitz, Steven A.; Mahajan, Anubha; McKnight, Barbara; Schwabedissen, Henriette Meyer zu; Milaneschi, Yuri; Mononen, Nina; Morris, Andrew P.; Nalls, Mike A.; Navis, Gerjan; Neijts, Melanie; Nikus, Kjell; North, Kari E.; O’Connor, Daniel T.; Ormel, Johan; Perz, Siegfried; Peters, Annette; Psaty, Bruce M.; Raitakari, Olli T.; Risbrough, Victoria B.; Sinner, Moritz F.; Siscovick, David S.; Smit, Johannes H.; Smith, Nicholas L.; Soliman, Elsayed Z; Sotoodehnia, Nona; Staessen, Jan A.; Stein, Phyllis K.; Stilp, Adrienne M.; Stolarz‐Skrzypek, Katarzyna; Strauch, Konstantin; Sundström, Johan; Swenne, Cees A.; Syvänen, Ann‐Christine; Tardif, Jean‐Claude; Taylor, Kent D.; Teumer, Alexander; Thornton, Timothy A.; Tinker, Lesley; Uitterlinden, André G.; Setten, Jessica van; Voß, Andreas; Waldenberger, Mélanie; Wilhelmsen, Kirk C.; Willemsen, Gonneke; Wong, Quenna; Zhang, Zhu-Ming; Zonderman, Alan B.; Cusi, Daniele; Evans, Michele K.; Greiser, Halina; Harst, Pim van der; Hassan, Mohammed O.; Ingelsson, Erik; Järvelin, Marjo‐Riitta; Kääb, Stefan; Kähönen, Mika; Kivimäki, Mika; Kooperberg, Charles; Kuh, Diana; Lehtimäki, Terho; Lind, Lars; Nievergelt, Caroline M.; O’Donnell, Chris; Oldehinkel, Albertine J.; Penninx, Brenda; Reiner, Alexander P.; Riese, Harriëtte; Roon, Arie M. van; Rioux, John D.; Rotter, Jerome I.; Sofer, Tamar; Stricker, Bruno H.; Tiemeier, Henning; Vrijkotte, Tanja G. M.; Asselbergs, Folkert W.; Brundel, Bianca J. J. M.; Heckbert, Susan R.; Whitsel, Eric A.; Hoed, Marcel den; Snieder, Harold; Geus, Eco J. C. de

doi:10.1038/ncomms16140

Cited by 6 publications

(6 citation statements)

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“…This confirms our hypothesis that shared genetic factors might also explain the negative associations between HRV and BP. In agreement with this, the genetic correlations using bivariate linkage disequilibrium score regression on genome-wide association study summary statistics for HRV 27 and BP 28 – 30 show largely consistent estimates. On the contrary, the Oman Family study 10 recently reported a nonsignificant genetic correlation.…”

Section: Discussionsupporting

confidence: 76%

“…This implies the need for more studies in the future to identify more genetic variants as the variance explained by known common single-nucleotide polymorphisms discovered in previous genome-wide association studies is still low (0.9%–2.3% for HRV measures and 2.9%–5.7% for BP measures). 27 , 30 The negative genetic correlations between HRV and BP are in line with a causal effect of cardiac vagal control in the development of hypertension. However, some more discussion is warranted what the results may mean: (1) pleotropic genes, (2) causal effect, or (3) reverse causation, meaning an increase in BP causes compensatory changes in cardiac autonomic nervous system activity that lead to reduced HRV.…”

Section: Perspectivesmentioning

confidence: 67%

“…We additionally estimated the genetic correlations using bivariate linkage disequilibrium score regression 26 on the latest publicly available genome-wide association study summary statistics for HRV 27 and BP. 28 – 30 …”

Section: Methodsmentioning

confidence: 99%

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Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families

et al. 2020

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Dysregulation of the cardiac autonomic nervous system, as indexed by reduced heart rate variability (HRV), has been associated with the development of high blood pressure (BP). However, the underlying pathological mechanisms are not yet fully understood. This study aimed to estimate heritability of HRV and BP and to determine their genetic overlap. We used baseline data of the 3-generation Lifelines population-based cohort study (n=149 067; mean age, 44.5). In-house software was used to calculate root mean square of successive differences and SD of normal-to-normal intervals as indices of HRV based on 10-second resting ECGs. BP was recorded with an automatic BP monitor. We estimated heritabilities and genetic correlations with variance components methods in ASReml software. We additionally estimated genetic correlations with bivariate linkage disequilibrium score regression using publicly available genome-wide association study data. The heritability (SE) estimates were 15.6% (0.90%) for SD of normal-to-normal intervals and 17.9% (0.90%) for root mean square of successive differences. For BP measures, they ranged from 24.4% (0.90%) for pulse pressure to 30.3% (0.90%) for diastolic BP. Significant negative genetic correlations (all P <0.0001) of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (−0.20/−0.16) and with diastolic BP (−0.15/−0.13) were observed. LD score regression showed largely consistent genetic correlation estimates of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (range, −0.08 to −0.23) and diastolic BP (range, −0.20 to −0.27). Our study shows a substantial contribution of genetic factors in explaining the variance of HRV and BP measures in the general population. The significant negative genetic correlations between HRV and BP indicate that genetic pathways for HRV and BP partially overlap.

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Section: Discussionsupporting

confidence: 76%

Section: Perspectivesmentioning

confidence: 67%

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Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families

et al. 2020

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“…Hereto, 1-pixel width lines were drawn across the heart wall, followed by determination of Plot-Z axis profile (based on contrast changes) to generate heart wall traces or kymographs (via the kymograph plugin of Image J) for M-mode cardiography. To determine the heart rate and arrhythmicity index (defined as the standard deviation of the heart period normalized to the median heart period of each fly followed by averaging across flies) 55 , the heart wall traces were further analyzed with the use of Drosan software, which was modified from the software originally developed to determine human heart rate and arrhythmicity 56 , 57 . The detailed algorithm of the Drosan software is described in the Supplementary Methods section and overview of the outcome parameters is presented in Supplementary Table 2 .…”

Section: Methodsmentioning

confidence: 99%

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

Zhang

et al. 2019

Nat Commun

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Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction. Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.

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“…Arrhythmia index was obtained from a 2 min/100 frames per second high-speed movie with a 203 lens of spontaneous heart wall contractions in whole pre-pupae and analyzed by via software as described before. 22…”

Section: Drosophila Stocks and Cardiac Physiological Measurementsmentioning

confidence: 99%

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

Iuso

Wiersma²,

Schüller

et al. 2018

The American Journal of Human Genetics

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Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

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Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Cited by 6 publications

References 0 publications

Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families

Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

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