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CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus

Cardiac conduction disease and sudden cardiac death by heart block in cardiomyocyte-specific knockouts.(a) survival of cardiomyocyte-specific knockout mice. (b) Left, plot of average heart rate in control littermate mice (top) cardiomyocyte-specific CAP2- (bottom) over the 12 days prior to sudden death of the CAP2- mice. Note that about 5 days prior to death, the average heart rate begins to drop in the CAP2- mice but remains stable in the control mice. (c) Loss of CAP2 leads to heart block and sudden death. Representative ECG recordings at the time of death from ambulatory mice using a telemetry recording system. The top trace is from a littermate control mouse recorded at exactly the same time while the bottom trace is from a cardiomyocyte-specific CAP2- mouse at the time of its death. Note that at this time the initial p-wave to p-wave intervals (arrowheads) is longer in the CAP2- mouse, as is the QRS-complex to QRS-complex intervals (arrows). The rhythm then degenerates to high-grade AV block in the CAP2- mouse (several consecutive p-waves with no conducted QRS-complexes) while it remains normal in the control mouse. (d) Representative surface ECG and intracardiac tracings from CAP2- mice. Shown are surface ECGs leads (I through aVF), along with the intracardiac electrogram from the RA (RAE) and His bundle region (HBE) from an 81 week old female, cap2+/cap2+mouse (lefthand), a 19 week old male Myh6Cre-cap2loxp/cap2loxp mouse (middle), and an 81 week old female cap2−/cap2−mouse (righthand). Note the p-wave morphology (P), QRS-complex (QRS), PR-interval and T-wave morphology (T) are similar between the cap2+/cap2+ and Myh6Cre-cap2loxp/cap2loxp mice, but these are both significantly different from the ECG of the cap2−/cap2− mouse. In addition, the HV-interval is prolonged in both CAP2 mutant mice, compared to the control mouse, and these intervals are highlighted by the light blue vertical line at the bottom of each HBE.
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f6: Cardiac conduction disease and sudden cardiac death by heart block in cardiomyocyte-specific knockouts.(a) survival of cardiomyocyte-specific knockout mice. (b) Left, plot of average heart rate in control littermate mice (top) cardiomyocyte-specific CAP2- (bottom) over the 12 days prior to sudden death of the CAP2- mice. Note that about 5 days prior to death, the average heart rate begins to drop in the CAP2- mice but remains stable in the control mice. (c) Loss of CAP2 leads to heart block and sudden death. Representative ECG recordings at the time of death from ambulatory mice using a telemetry recording system. The top trace is from a littermate control mouse recorded at exactly the same time while the bottom trace is from a cardiomyocyte-specific CAP2- mouse at the time of its death. Note that at this time the initial p-wave to p-wave intervals (arrowheads) is longer in the CAP2- mouse, as is the QRS-complex to QRS-complex intervals (arrows). The rhythm then degenerates to high-grade AV block in the CAP2- mouse (several consecutive p-waves with no conducted QRS-complexes) while it remains normal in the control mouse. (d) Representative surface ECG and intracardiac tracings from CAP2- mice. Shown are surface ECGs leads (I through aVF), along with the intracardiac electrogram from the RA (RAE) and His bundle region (HBE) from an 81 week old female, cap2+/cap2+mouse (lefthand), a 19 week old male Myh6Cre-cap2loxp/cap2loxp mouse (middle), and an 81 week old female cap2−/cap2−mouse (righthand). Note the p-wave morphology (P), QRS-complex (QRS), PR-interval and T-wave morphology (T) are similar between the cap2+/cap2+ and Myh6Cre-cap2loxp/cap2loxp mice, but these are both significantly different from the ECG of the cap2−/cap2− mouse. In addition, the HV-interval is prolonged in both CAP2 mutant mice, compared to the control mouse, and these intervals are highlighted by the light blue vertical line at the bottom of each HBE.

Mentions: Next, because histological analysis suggested the hearts of cap2−/cap2− mice were abnormal, we used transthoracic echocardiography to study heart function in mice as they age. In female cap2−/cap2− mice ranging from 9 to 109 weeks we found that left ventricular chamber size, function and wall thickness were unchanged compared to age-matched control mice (Supplementary Table S2). In male cap2−/cap2− mice, on the other hand, while at 10-weeks and 21-weeks of age, we did not observe changes in left ventricular chamber size, function and wall thickness (Supplementary Table S1), we did find changes in older males. At 55-weeks of age, the cap2−/cap2− males showed increased left ventricular diameter during systole (LVIDs/BW) and reduced LV ejection fraction (Supplementary Tables S1& S2). We also noted several anomalies on the surface ECGs including a prolonged QT interval and increased QRS duration in both male and female cap2−/cap2− mice as they aged. However, the rate corrected QT-intervals (QTm) were not significantly different for both male and female cap2−/cap2− mice compared to control mice (Supplementary Tables S3& S4; Fig. 6). Interestingly, all ECG parameters were normal in male and female cap2−/cap2− mice that were ~30-weeks old and younger. Taken together these data suggest that CAP2 mutant mice initially have normal cardiac function and conduction that degenerates later in life with ventricular conduction system disease and mild, dilated cardiomyopathy that is more pronounced in males versus females.


CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

Cardiac conduction disease and sudden cardiac death by heart block in cardiomyocyte-specific knockouts.(a) survival of cardiomyocyte-specific knockout mice. (b) Left, plot of average heart rate in control littermate mice (top) cardiomyocyte-specific CAP2- (bottom) over the 12 days prior to sudden death of the CAP2- mice. Note that about 5 days prior to death, the average heart rate begins to drop in the CAP2- mice but remains stable in the control mice. (c) Loss of CAP2 leads to heart block and sudden death. Representative ECG recordings at the time of death from ambulatory mice using a telemetry recording system. The top trace is from a littermate control mouse recorded at exactly the same time while the bottom trace is from a cardiomyocyte-specific CAP2- mouse at the time of its death. Note that at this time the initial p-wave to p-wave intervals (arrowheads) is longer in the CAP2- mouse, as is the QRS-complex to QRS-complex intervals (arrows). The rhythm then degenerates to high-grade AV block in the CAP2- mouse (several consecutive p-waves with no conducted QRS-complexes) while it remains normal in the control mouse. (d) Representative surface ECG and intracardiac tracings from CAP2- mice. Shown are surface ECGs leads (I through aVF), along with the intracardiac electrogram from the RA (RAE) and His bundle region (HBE) from an 81 week old female, cap2+/cap2+mouse (lefthand), a 19 week old male Myh6Cre-cap2loxp/cap2loxp mouse (middle), and an 81 week old female cap2−/cap2−mouse (righthand). Note the p-wave morphology (P), QRS-complex (QRS), PR-interval and T-wave morphology (T) are similar between the cap2+/cap2+ and Myh6Cre-cap2loxp/cap2loxp mice, but these are both significantly different from the ECG of the cap2−/cap2− mouse. In addition, the HV-interval is prolonged in both CAP2 mutant mice, compared to the control mouse, and these intervals are highlighted by the light blue vertical line at the bottom of each HBE.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4663486&req=5

f6: Cardiac conduction disease and sudden cardiac death by heart block in cardiomyocyte-specific knockouts.(a) survival of cardiomyocyte-specific knockout mice. (b) Left, plot of average heart rate in control littermate mice (top) cardiomyocyte-specific CAP2- (bottom) over the 12 days prior to sudden death of the CAP2- mice. Note that about 5 days prior to death, the average heart rate begins to drop in the CAP2- mice but remains stable in the control mice. (c) Loss of CAP2 leads to heart block and sudden death. Representative ECG recordings at the time of death from ambulatory mice using a telemetry recording system. The top trace is from a littermate control mouse recorded at exactly the same time while the bottom trace is from a cardiomyocyte-specific CAP2- mouse at the time of its death. Note that at this time the initial p-wave to p-wave intervals (arrowheads) is longer in the CAP2- mouse, as is the QRS-complex to QRS-complex intervals (arrows). The rhythm then degenerates to high-grade AV block in the CAP2- mouse (several consecutive p-waves with no conducted QRS-complexes) while it remains normal in the control mouse. (d) Representative surface ECG and intracardiac tracings from CAP2- mice. Shown are surface ECGs leads (I through aVF), along with the intracardiac electrogram from the RA (RAE) and His bundle region (HBE) from an 81 week old female, cap2+/cap2+mouse (lefthand), a 19 week old male Myh6Cre-cap2loxp/cap2loxp mouse (middle), and an 81 week old female cap2−/cap2−mouse (righthand). Note the p-wave morphology (P), QRS-complex (QRS), PR-interval and T-wave morphology (T) are similar between the cap2+/cap2+ and Myh6Cre-cap2loxp/cap2loxp mice, but these are both significantly different from the ECG of the cap2−/cap2− mouse. In addition, the HV-interval is prolonged in both CAP2 mutant mice, compared to the control mouse, and these intervals are highlighted by the light blue vertical line at the bottom of each HBE.
Mentions: Next, because histological analysis suggested the hearts of cap2−/cap2− mice were abnormal, we used transthoracic echocardiography to study heart function in mice as they age. In female cap2−/cap2− mice ranging from 9 to 109 weeks we found that left ventricular chamber size, function and wall thickness were unchanged compared to age-matched control mice (Supplementary Table S2). In male cap2−/cap2− mice, on the other hand, while at 10-weeks and 21-weeks of age, we did not observe changes in left ventricular chamber size, function and wall thickness (Supplementary Table S1), we did find changes in older males. At 55-weeks of age, the cap2−/cap2− males showed increased left ventricular diameter during systole (LVIDs/BW) and reduced LV ejection fraction (Supplementary Tables S1& S2). We also noted several anomalies on the surface ECGs including a prolonged QT interval and increased QRS duration in both male and female cap2−/cap2− mice as they aged. However, the rate corrected QT-intervals (QTm) were not significantly different for both male and female cap2−/cap2− mice compared to control mice (Supplementary Tables S3& S4; Fig. 6). Interestingly, all ECG parameters were normal in male and female cap2−/cap2− mice that were ~30-weeks old and younger. Taken together these data suggest that CAP2 mutant mice initially have normal cardiac function and conduction that degenerates later in life with ventricular conduction system disease and mild, dilated cardiomyopathy that is more pronounced in males versus females.

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus