Training-induced Increased Left Ventricular Trabeculation
Condition: Athletes Heart; Left Ventricular Hypertrabeculation
Study type: Observational

Summary: 
      This project will expand on research conducted by the investigators' group, where the
      investigators have demonstrated increased LV trabeculation, satisfying currently existing
      criteria for LV Non-Compaction Cardiomyopathy (LVNC), in groups exposed to high cardiac
      workloads. To the investigators' knowledge, this will be the first prospective study aiming
      to demonstrate a direct relationship between high levels of exercise and increased LV
      trabeculation. This study may add weight to the theory that this entity currently described
      as LVNC, is a morphological epiphenomenon common to many distinct myocardial remodeling
      processes associated with increased cardiac preload and afterload and may better define
      normal adaptive increases in LV trabeculation.
    

Detailed description: 
      Background of Left Ventricular Non-Compaction Cardiomyopathy Left Ventricular Non-Compaction
      Cardiomyopathy (LVNC) is a myocardial disorder defined by increased left ventricular (LV)
      trabeculation and intertrabecular recesses communicating with the LV cavity. The condition is
      associated with progressive heart failure, systemic thromboembolism and a predilection to
      fatal ventricular arrhythmia and sudden cardiac death. However, a large proportion of
      affected individuals may be asymptomatic. One cohort study demonstrated 28% of detected cases
      of LVNC were asymptomatic, with the majority being identified through family screening. It
      must be emphasized that currently there is no diagnostic tool, neither genetic nor imaging,
      that can categorically identify an individual as having LVNC or not. This lack of a 'gold
      standard' makes the description of increased left ventricular trabeculation difficult,
      creating a tendency to apply a diagnostic label of LVNC inappropriately.

      Traditional thought has been that LVNC results from arrest of the normal trabecular
      regression and myocardial compaction that occurs during embryological development. However,
      this concept is challenged by reported cases of 'acquired' LVNC, where serial echocardiograms
      have demonstrated a transition from a normal endocardial appearance to a hypertrabeculated
      LVNC phenotype. Whether this is a delayed presentation of a genetically heterogeneous
      cardiomyopathy or a morphological epiphenomenon shared by many phenotypically distinct
      cardiomyopathies, remains unknown. This irresolution is exemplified by international
      discordance, with the American Heart Association classifying LVNC as a genetic cardiomyopathy
      and the European Society of Cardiology and World Health Organisation taking the view that
      LVNC remains an 'unclassified cardiomyopathy'.

      In the absence of congenital heart disease, LVNC was thought to be an extremely rare
      condition with a prevalence between 0.05% and 0.24%. Technical advances in echocardiography,
      largely second harmonic imaging, have led to improvement in LV apex and lateral wall
      visualization, which has dramatically increased the frequency of detection in the last 20
      years.

      Limitations in current diagnostic criteria At present, various diagnostic criteria exist
      entirely based on morphological findings on echocardiography or magnetic resonance imaging
      (MRI). All of these criteria have limitations in that they are generated from small patient
      cohorts, have substantial inter-observer variability and poor correlation between them. This
      is perhaps not surprising as they all measure different parameters in different echo planes
      and during different phases of the cardiac cycle.

      In a study by Kohli et al, 24% of heart failure patients had at least one of three diagnostic
      echocardiography criteria for LVNC (Chin 19%, Jenni 15%, Stollberger 13%), as well as 8% of
      healthy controls, most of whom were of black ethnicity. Only 7% fulfilled all three criteria,
      indicating the relatively poor concordance between these criteria. These studies highlight
      the concern that echocardiographic criteria are too sensitive and lack specificity,
      particularly in black individuals, resulting in over-diagnosis of LVNC.

      Whilst MRI has advantages over echocardiography in tissue characterisation, superior
      contrast-to-noise and signal-to-noise ratio and greater ability to visualize the cardiac
      apex, CMR criteria for the identification of LVNC suffer the same limitations as for
      echocardiography. When applying CMR criteria from Petersen et al, a recent population-based
      prospective multi-ethnic cohort study identified 25.7% of a low-risk 'healthy' population
      meeting criteria for LVNC.

      Currently, application of imaging-based criteria for diagnosis to low risk populations
      creates a considerable burden of anxiety, potential loss of opportunity/earnings, unnecessary
      investigations and clinical follow-up, with their associated costs to the National Health
      Service. There is a considerable need in this area to evaluate what cardiac imaging criteria
      contribute to the diagnosis of LVNC. Indeed, some propose integration of clinical criteria
      including malignant arrhythmias, thromboembolic events, neuromuscular disorders and family
      history of LVNC into a diagnostic algorithm, though none currently exist.

      Influence of ethnicity in cardiac remodeling and pilot data Racial differences in cardiac
      remodeling have previously been described with respect to cardiac hypertrophy. Athletes
      develop physiological increases in LV wall thickness and cavity size in an adaptive response
      to high cardiac preload and afterload. This response is exaggerated in black athletes. For
      the purposes of this study, black ethnicity will be defined as a person of African or
      African-Caribbean origin. In a study comparing highly trained male athletes, 18% of black
      athletes exhibited left ventricular hypertrophy (LVH), as defined as an LV wall thickness of
      >12mm, compared with only 4% of white athletes (p<0.001)13.

      The investigators' group has shown that athletes also display a higher prevalence of
      increased LV trabeculation compared with controls (18.3% vs 7.0%; p < 0.0001) with 8.1% of
      athletes fulfilling conventional echocardiographic criteria for LVNC. As with LVH, this
      difference in LV hypertrabeculation appears to be exaggerated in black athletes as compared
      to white athletes (28.8% vs 16.3%; p = 0.002).

      The investigators' group has also investigated the presence of increased LV trabeculation in
      a population of sickle cell anaemia patients. Chronic anaemia of sickle cell disease is
      associated with an increased LV preload and high cardiac output. The investigators found
      increased LV trabeculation in 28% of sickle cell anaemia patients as compared with 12% of
      asymptomatic healthy black controls. 8% of sickle cell anaemia patients fulfilled both Chin
      and Jenni criteria for LVNC.

      These studies have limitations in their cross-sectional design and therefore a relationship
      of temporal causality between increased cardiac preload and the development of increased LV
      trabeculations could not be established.

      This led the investigators' group to conduct a longitudinal cohort study utilizing pregnancy
      as a model of increasing cardiac preload and observing the effects on LV trabeculation.
      During pregnancy, at 28-36 weeks gestation, in increase in LV trabeculation was seen in
      25.4%, having demonstrated normal myocardium at baseline. Moreover, 7.8% of women fulfilled
      Chin and Jenni criteria for LVNC. In addition, black women appeared to demonstrate a higher
      prevalence of increased LV trabeculation as compared with white women (46% vs. 13%; p =
      0.0003).

      With this proposed study the investigators aim to be the first to demonstrate that LV
      hypertrabeculation can be induced with athletic training in individuals with structurally
      normal hearts and that this will return to baseline after de-training. Although the
      population sampled will be a healthy cohort, the implications of the investigators' findings
      would resonate throughout the cardiac imaging community and fundamentally change perspective
      on the clinical detection of increased left ventricular trabeculation. The investigators aim
      to go further than before and compare echocardiographic and CMR measurements of left
      ventricular trabeculation and investigate whether a positive correlation exists between
      improvement in cardiopulmonary performance and extent of de novo LV hypertrabeculation. The
      project will also enable the assessment of the impact of gender on the development of LV
      trabeculation.

      Should the investigators' hypothesis prove correct, this would potentially avoid
      inappropriate diagnostic labelling, unnecessary anxiety, investigations, treatment, follow up
      and family screening. This study may strongly emphasize the need for more robust diagnostic
      criteria for the diagnosis of LVNC.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy participants running first marathon event in Virgin London Marathon 2016.
      
Biospecimen description: 
      Blood samples. Urine samples.
    
Keywords: exercise; cardiac remodelling; left ventricular non-compaction cardiomyopathy