Abstract 250: Haploinsufficiency of Muscle-Enriched A-Type Lamin Interacting Protein (MLIP) Manifests as Enlarged Dilated Hearts

Approximately 116 unique mutations in the lamin A/C gene have been described to date that are associated with dilated cardiomyopathy. We recently reported the discovery of MLIP through its interaction with lamin A/C. MLIP is expressed ubiquitously and most abundantly in heart, skeletal and smooth muscle of amniotes (mammals, reptiles and birds) and has no paralogous homologue suggesting no functional redundancy. The MLIP gene encodes at least seven, alternatively spliced, LMNA-interacting factors that possess several structural motifs not found in any other protein. The MLIP isoforms pattern of expression differs between each of the tissues with heart being the most heterogeneous. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mis-localization of MLIP. In addition to interacting and co-localizing with lamin A/C we also demonstrated that MLIP localizes to micro-domains in the nucleus with promyelocytic leukemia protein (PML) in close proximity to chromatin. MLIP's biological function still remains elusive. Eight week old hemizygous MLIP null mice develop enlarged hearts with a significant increase in heart to body weights (MLIP+/+ 5.62mg/g vs MLIP+/- 10.73mg/g, p<0.0001 n=7) with an overall 30% increase in the anterior-posterior ventricle length of MLIP hearts while maintaining a normal body weight (Figure). Echocardiographic analysis of MLIP+/- mice revealed that their hearts as having a significant (p3.93mm with a significant (p=0.011, n=12) reduction of left ventricular fractional shorting (LVFS) 31% when compare to littermate controls. Histological analysis of the hearts showed no overt phenotype other than an overall increase in the size of the MLIP+/- hearts. The cellular source for the increase in heart size and mass remains to be determined if it is the product of an increase in the number of cardiomyocytes due to aberrant hyperplasia or an increase in cardiomyocyte size through cellular hypertrophy. In conclusion, MLIP is a newly discovered lamin interacting protein that may serve as a transcriptional regulator that impact genes involved in heart development, growth and function and provides a new signaling paradigm.

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Associations between life-course frailty and later-life heart size and function in the 1946 NSHD British birth cohort-an epidemiological study

European Heart Journal ◽

10.1093/ehjci/ehaa946.2835 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C.C Topriceanu ◽

J.C Moon ◽

R Hardy ◽

A.D Hughes ◽

N Chaturvedi ◽

...

Keyword(s):

Life Course ◽

Birth Cohort ◽

Frailty Index ◽

Later Life ◽

Left Ventricular ◽

Step Change ◽

Deficit Accumulation ◽

Heart Size ◽

And Function ◽

The Life Course

Abstract Background Cardiovascular diseases are an important component of the multi-morbidity syndrome which is associated with negative health outcomes resulting in a major societal economic burden. An objective way to assess multi-morbidity is to calculate a frailty index based on medical deficit accumulation. Late-life frailty has been validated to predict mortality, but little is known about the association between life-course frailty and cardiovascular health in later-life. Purpose To study the association between life-course frailty and later-life heart size and function using data from the world's longest running birth cohort with continuous follow-up. Methods A 45-deficit frailty index (FI) was calculated at 4 age-intervals across the life-course (0 to 16 years old, 19 to 44 years old, 45 to 54 years old and 60 to 64 years old) in participants from the UK 1946 Medical Research Council (MRC) National Survey of Heath and Development (NSHD) birth cohort. The life-course frailty indices (FI0_16, FI19_44, FI45_54 and FI60_64) reflect the cumulative medical deficits at the corresponding age-intervals. They were used to derive FImean and FIsum reflecting overall-life frailty. The step change in deficit accumulation between age-intervals was also calculated (FI2-1, FI3-1, FI4-1, FI3-2, FI4-2, FI4-3). Echocardiographic data at 60–64 years provided: E/e' ratio, ejection fraction (EF), myocardial contraction fraction index (MCFi) and left ventricular mass index (LVmassi). Generalized linear mixed models with gamma distribution and log link assessed the association between FIs and echo parameters after adjustment for sex, socio-economic position and body mass index. Results 1.805 NSHD participants were included (834 male). Accumulation of a single deficit had a significant impact (p<0.0001 to p<0.049) on LVmassi and MCFi in all the life-course FIs and overall FIs. LVmassi increased by 0.89% to 1.42% for the life-course FIs and by 0.36%/1.82% for FIsum and FImean respectively. MCFi decreased by 0.62% to 1.02% for the life-course FIs and by 0.33%/ 1.04%. for FIsum and FImean respectively. One accumulated deficit translated into higher multiplicative odds (13.2 for FI60-64, 2.1 for FI4-1, 75.4 for FI4-2 and 78.5 for FI4-3) of elevated filling pressure (defined as E/e' ratio >13, p<0.0.005 to p<0.02).A unit increase in frailty decreased LV EF (%) by 11%/12% for FI45-54 and FI60-64 respectively, by 10% to 12% for FI2-1, FI3-1, FI4-1 and FI4-2, and 4%/15% for FIsum and FImean respectively (p<0.0014 to p<0.044). Conclusion Frailty during the life-course, overall life-frailty and the step change in deficit accumulation is associated with later-life cardiac dysfunction. Frailty strain appears to have its greatest impact on pathological myocardial hypertrophy (high LVmassi and low MCFi) potentially paving the way to later-life systolic or diastolic dysfunction in susceptible individuals. Funding Acknowledgement Type of funding source: None

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Life-course burden of health deficits associates with later-life heart size and function in the 1946 British birth cohort

10.1101/2020.08.13.20174599 ◽

2020 ◽

Author(s):

Constantin-Cristian Topriceanu ◽

James C Moon ◽

Rebecca Hardy ◽

Nishi Chaturvedi ◽

Alun Hughes ◽

...

Keyword(s):

Life Course ◽

Birth Cohort ◽

Later Life ◽

Myocardial Contraction ◽

Left Ventricular ◽

Heart Size ◽

Time Periods ◽

And Function ◽

The Life Course ◽

Myocardial Contraction Fraction

Aim: To study the association between the life course accumulation of health deficits and later life heart size and function using data from the 1946 National Survey of Heath and Development (NSHD) British birth cohort, the longest running birth cohort with continuous follow up in the world. Methods and Results: A multidimensional health deficit index (DI) looking at 45 health deficits was serially calculated at 4 time periods of the life course in NSHD participants (0 to 16, 19 to 44, 45 to 54 and 60 to 64 years), and from these the mean and total DI for the life course was derived (DImean, DIsum). The step change in deficit accumulation from one time period to another was also calculated. Echocardiographic data at 60-64 years provided: ejection fraction (EF), left ventricular mass indexed to body surface area (LVmassi, BSA), myocardial contraction fraction indexed to BSA (MCFi) and E/e. Generalized linear models assessed the association between DIs and echocardiographic parameters after adjustment for sex, socioeconomic position and body mass index. 1,375 NSHD participants were included (46.47% male). For each single new deficit accumulated at any one of the 4 time periods of the life course, LVmassi increased by 0.91 to 1.44% (p<0.013), while MCFi decreased by 0.6 to 1.02% (p<0.05 except at 45 to 54 years). One unit increase in DI at age 45 to 54 and 60 to 64 decreased LV EF by 11 to 12% (p<0.013). A single deficit step change occurring between 60-64 years and one of the earlier time periods, translated into significantly higher odds (2.1 to 78.5, p<0.020) of elevated LV filling pressure defined as E/e>13. Conclusion: The accumulation of health deficits at any time period of the life course associates with a maladaptive cardiac phenotype in older age, dominated by myocardial hypertrophy and poorer function. The burden of health deficits appears to strain the myocardium potentially leading to future cardiac dysfunction. Keywords: frailty; cardiovascular disease; ejection fraction; left ventricular mass index; myocardial contraction fraction; E/e.

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DIAGNOSTIC OF THE ATHLETE’S HEART AND FACTORS AFFECTING ITS DEVELOPING

Wiadomości Lekarskie ◽

10.36740/wlek202105121 ◽

2021 ◽

Vol 74 (5) ◽

pp. 1158-1163

Author(s):

Serhiy V. Popov ◽

Oleksandr I. Smiyan ◽

Andrii M. Loboda ◽

Viktoriia O. Petrashenko ◽

Olena K. Redko ◽

...

Keyword(s):

Left Ventricle ◽

Heart Development ◽

Ventricular Myocardium ◽

Left Ventricular ◽

Athlete’S Heart ◽

Left Ventricular Myocardium ◽

Factors Affecting ◽

Ultrasound Study ◽

And Function ◽

Athlete's Heart

The aim: Studying the features of the structure and function of the heart in athletes and identifying the factors that influence the development of these changes. Materials and methods: The study included 54 athletes, 29 men and 25 women. The ultrasound study was performed according to standard methods with determining the size of the main structures of the heart, indicators normalized to body surface area, height. Results: The heart of dilatation and hypertrophy of the left ventricular myocardium were found in 25.93% of the athletes. When comparing the diameter of the left ventricle of individual athletes with the average values of the norm, their excess was found in 94.44% of athletes. The Odds ratio (OR) of the relationship between left ventricle diameter (LVd) and time of the exercise less than 10 y was 16.13, time of the exercise less than 5 y – 0.17 (p <0.05). OR of increase LVd to age less than 20 years was 3.56 units (p <0.05). The ejection fraction was above the normative mean in 75.93%, as well as the ratio of the periods of filling of the ventricles. Conclusions: The most common sign of an athlete’s heart development was left ventricular dilatation, which occurred at a rate of 25 percent. Age less than 20 years and the duration of sports activities from 5 to 10 years is associated with a higher frequency of the athlete’s heart.

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Left Ventricular Size and Function and Heart Size in the Year Following Myocardial Infarction

Circulation ◽

10.1161/01.cir.50.2.331 ◽

1974 ◽

Vol 50 (2) ◽

pp. 331-339 ◽

Cited By ~ 29

Author(s):

BOLLING J. FEILD ◽

RICHARD O. RUSSELL ◽

ROGER E. MORASKI ◽

BENIGNO SOTO ◽

WILLIAM P. HOOD ◽

...

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

Ventricular Size ◽

Left Ventricular Size ◽

Heart Size ◽

And Function

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Effects of sympathectomy on heart size and function in aortic-constricted rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1987.252.2.h442 ◽

1987 ◽

Vol 252 (2) ◽

pp. H442-H447

Author(s):

F. M. Siri ◽

J. J. McNamara

Keyword(s):

Body Weight ◽

Diastolic Pressure ◽

Left Ventricular ◽

Stroke Work ◽

Lung Weight ◽

Norepinephrine Content ◽

Heart Size ◽

And Performance ◽

6 Hydroxydopamine ◽

And Function

Effects of chemical sympathectomy with 6-hydroxydopamine on left ventricular mass, norepinephrine content, and performance in aortic-constricted and sham-constricted rats were examined. Sympathectomy did not affect mean arterial pressure but it led to lower final body weights in aortic-constricted rats. Of the hypertensive aortic-constricted rats, those that had also been sympathectomized showed greater increases in left ventricular weight-to-body weight, right ventricular weight-to-body weight, and lung weight-to-body weight ratios. Left ventricular norepinephrine content was depressed by either sympathectomy or aortic constriction and was severely depleted by their combination. Sympathectomy had no effect on maximal cardiac output or left ventricular stroke work during rapid saline infusion. In aortic-constricted rats, however, it lowered heart rate during the infusion and increased left ventricular end-diastolic pressure at peak stroke work. This evidence suggests that elimination of the adrenergic nervous system's chronotropic influence promotes greater left ventricular filling, and the resultant increase in preload may importantly contribute to the stimulation of cardiac hypertrophy.

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Abstract 185: Muscle Enriched A-Type Lamin Interacting Protein (MLIP) mediates growth and function of the adult heart

Circulation Research ◽

10.1161/res.113.suppl_1.a185 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Marie-Elodie Cattin ◽

Stephanie L Thorn ◽

Jessica Wang ◽

Christoph Rau ◽

Esther W Mak ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Preliminary Data ◽

Histological Analysis ◽

Cell Cycle Control ◽

Interacting Protein ◽

Adult Heart ◽

Cellular Hypertrophy ◽

Cardiac Gene ◽

And Function

The newly discovered Muscle-enriched A-type lamin interacting protein (MLIP) is abundantly expressed in the heart. Its biological function remains elusive but it may be of high relevance for cardiac function as it has no paralogous homologue suggesting no functional redundancy. To elucidate MLIP’s function, we generated both hemizygous MLIP and homozygous MLIP null mice. At 8 weeks of age, they both develop dilated cardiomyopathy characterized by enlarged hearts (heart to body weights MLIP+/+ 5.62mg/g vs MLIP+/- 10.73mg/g & MLIP -/- 11.03mg/g) that are functionally dilated (LVDD : +/+ 2.89mm; +/- 3.93mm; -/- 4.11mm) with reduced function (LVFS : +/+ 47%; +/- 31%; -/- 29%). Histological analysis shows no overt abnormalities for both MLIP+/- and MLIP-/- hearts. Preliminary data indicate a preserved cardiomyocyte size in MLIP+/- and MLIP-/- mice, suggesting that the increase in heart size might be due to hyperplasia rather than cellular hypertrophy. Moreover, cardiac gene expression of 12 week-old MLIP+/- and MLIP-/- mice reveals an involvement in pathways associated with cell cycle control and growth. Specifically both gene expression and western analysis demonstrated that the mTORC1 pathway, that promotes protein synthesis and cell growth in response to mitogenic signal, was dysregulated in MLIP null mice. To further characterize these growth pathways the MLIP +/+ MLIP +/- and MLIP -/- mice (n = 3-5/group) were treated with 20 μg/g/day of isoproterenol through an abdominally implanted Alzet micropump for 3 weeks to induce heart failure. All mice went under echocardiographic analysis and were characterized by western, gene expression and histological analysis. Our preliminary data reveal that MLIP null mice are resistant to isoproterenol-induced heart failure as their hearts showed no increase in mass, unlike the significant (p<0.01) increase in heart mass observed in both the control mice (31%) or the MLIP hemizygous mice (19%). No cardiac remodeling was observed in either the MLIP hemizygous or null mice in response to the isoproterenol treatment. In conclusion, MLIP is a newly discovered protein that impacts key pathways involved in cardiac growth and function of an adult heart failure model.

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