Magnesium Deficiency in the Pathogenesis of Mitral Valve Prolapse
D. Galland, Sidney M. Baker, Robert K McLellan
Idiopathic mitral valve prolapse (MVP) is the commonest valvular disorder in industrialized nations. It is predominantly a familial condition, showing Mendelian dominance with delayed and variable penetrance. Although hyperkinesis and hypertrophy of the left ventricle have been described in MVP, its histopathology, somatic morphology and genetics support the leading theory that MVP results from a hereditary disorder of connective tissue. Latent tetany (LT) due to chronic Mg deficit (Mg-D) occurs in over 8 5 % of MVP cases; MVP complicates 26% of LT. Mg-D can explain many clinical features of the MVP syndrome which are not easily explained by its genetics. Mg-D hinders the mechanism by which fibroblasts degrade defective collagen, increases circulating catecholamines, predisposes to cardiac arrhythmias, thromboembolic phenomena and dysregulation of the immune and autonomic nervous systems. Mg therapy provides relief of MVP symptoms.
Mitral valve prolapse (MVP) is the commonest and most controversial vaivular abnormality presently encountered in industrialized nations. Variations in diagnostic criteria and subject selection have produced very different ideas on its general prevalence , but the present consensus suggests an overall prevalence of about 5% in the US. MVP may occur as a secondary event in several cardiac and connective tissue diseases, but the large majority of cases are idiopathic. Among these, familial occurrence has been demonstrated repeatedly . Three separate studies [21, 87, 95] have found evidence of autosomal dominant inheritance with about half the first-degree relatives of probands showing echocardiographic evidence of MVP. Gene penetrance is delayed and sex-linked, MVP frequency being reduced in children and in males.
An association between the FILA haplotype Bw35 and MVP has been described in two independent reports [10, 63], but not in two others [34, 61]. Durlach et al.  suggest that HLA-Bw35 may be associated with greater severity of MVP (i.e. enhanced gene penetrance).
Asthenic build and skeletal abnormalities such as arched palate, straight back and pectus excavaturn are common in idiopathic MVP [19, 22, 84]. Devereux et al. [22, 23] found lower body weight and blood pressure in individuals with MVP than in their relatives without MVP and in general population matched for sex and age. Women with clinical MVP demonstrate, in relationship to their height, a narrower anteroposterior chest diameter and a longer arm span than controls , a finding which led Schutte et al.  to label MVP as one component of a generalized syndrome of developmental dysgenesis. Consistent with this idea is the observation of Swartz et al.  that patients with MVP show dermatoglyphic abnormalities suggesting in utero interference with epidermal ridge patterns.
Anatomical features of MVP include redundant, scalloped and thickened leaflets, elongated chordae tendineae, mitral annular dilatation and myxomatous transformation of the valve substance with loss of fibrous tissue . Although the pathological description has been primarily derived from studies of patients with advanced disease and severe mitral regurgitation, the same changes have been found in individuals with isolated mid systolic nonejection clicks only [62, 95]. The essential histologic lesion is a loss of fibrous tissue in the central valve fibrosa with fragmentation and disruption of individual collagen bundles and increased acid mucopolysaccharide ('myxomatous' degeneration) [20, 62, 65, 81]. Similar changes are found in the tricuspid valve and aortic root. Periodicity of individual collagen fibrils is normal , although one report mentions large amounts of procollagen in the abnormal valves . While Pocock and Barlow  and others [20, 65] consider collagen dissolution to be the primary defect in MVP, the histologic lesions are nonspecific and may result from toxic damage or trauma . Surgical and necropsy specimens are greatly skewed toward those with severe disease or advanced age, so the pathology of early MVP remains uncertain.
The opinion most widely held in the US is that MVP is a hereditary disease of connective tissue affecting the mitral valve and the bony and cardiac skeleton.
The MVP Syndrome: Dysautonomia
Symptoms most commonly encountered in patients with MVP are chest pain, dyspnea, fatigue, dizziness, syncope, palpitations and anxiety [62, 96]. A cardiac origin for these symptoms has not been established and Wooley [96) and Boudoulas et al.  propose that they are neuroendocrine in origin. This group found higher urinary catecholaffiine excretion, higher blood glucose and shorter systolic time intervals in patients than in controls . Elevated plasma catecholamine levels were reported by a Canadian team . Gaffney et al.  measured cardiovascular responses to a series of maneuvers in 35 women and concluded that those with MVP had decreased parasympathetic, increased aadrenergic and normal P-adrenergic tone. On the other hand, orthostatic hypotension, a common finding among MVP patients with dizziness, appears to be due to excessive 0adrenergic tone . Resting bradycardia, a sign of parasympathetic overactivity. is common in MVP . even among patients with elevated catecholarnine levels . After analyzing cardiovascular and respiratory responses to postural change and Valsalva maneuver, Coghlan et al.  concluded that different patterns of dysautonomia may occur in MVP; cholinergic hyperactivity is as frequent as adrenergic, especially in patients with fatique and poor concentration.
MVP occurs in 15-50% of patients with panic disorder [51, 64, 76, 92], a condition of adrenergic hyperfunction [14, 77], and in 40% of patients with hyperthyroidism , another hyperadrenergic state associated with autoimmunity. The absence of MVP in juvenile hyperthyroidism  and the finding of MVP in 41 % of patients with autoimmune thyroiditis  suggest that adrenergic hyperactivity is not a cause of prolapse. It is more likely that dysautonomia, autoimmune phenomena and MVP are all manifestations of the same disturbance. Galland  found a 46% prevalence of MVP in patients being treated for chronic infection with Candida albicans,- these patients all had symptoms of hypersensitivity to Candida, as well as chronic infection. Recently, investigators at The Omega Institute in New Orleans, La., reported an unusually high frequency (96%) of MVP in women with infertility due to pelvic fibroadhesive disease . These observations indicate that the etiology of MVP is much broader than a simple Mendelian dyscollagenosis.
A role for magnesium-deficit (Mg-D) in the MVP syndrome is suggested by research from four different centers. Because symptoms of MVP are quite similar to those of latent tetany (LT) induced by Mg-D , Gatau-Pelanchon et al.  and Gerard et al.  sought evidence of LT in children and adults with symptomatic MVP, respectively. They reported data on 41 females and 34 males with idiopathic MVP. 8 5 % had EMGs which were positive for tetany and 73% showed Chvostek's sign. All had normal serum Ca and Mg; low serum phosphorus occurred in 6% and hypokalemia in 15%. Erythrocyte Mg, in contrast, was depressed in 7/13 females and 9/11 males. The authors found left ventricular hyperkinesis in all patients studied by cardiac cineangiography; they attributed valve prolapse to ventricular hyperkinesis and hyperkinesis to Mg-D. They also noted that the negative EMGs were confined to the older patients, a group known to manifest tetany with less frequency, presumably because of neurogenic changes. They reported improvement in symptoms during 1-month open and placebo-controlled trials of Mg supplementation, but no change in the frequency of cardiac arrhythmias [70-72]. Recently, a Portuguese group found EMG evidence of LT in 48 of 60 patients with MVP and physical signs of tetany in 59/60 . Hypomagnesemia occurred in over half. They initially treated 24 patients with 300 mg of Mg/day as Mg lactate for 16 weeks. There was a significant increase in mean serum Mg and marked improvement in palpitation, chest pain, fatigue, tremor, muscle cramps and dizziness. The next 24 patients received 8 weeks of placebo with no syptomatic improvement; they then received 8 weeks of Mg lactate and had improvement or disappearance of most symptoms, although the results were smaller than those seen after 16 weeks of treatment. The trial was double-blind, but treatment was not randomly assigned.
Durlach et al. [32, 33] examined the LT/MVP relationship from the opposite perspective, surveying patients with LT for the presence of MVP. In their initial study  they evaluated 136 patients referred with symptoms of anxiety. 80% of the patients were women; the mean age was 37.7 years. Among 111 patients with a positive EMG or Chvostek's sign, the frequency of MVP on M-mode echocardiography was 36%. Only 1 of the 25 nontetanic subjects showed evidence of MVP. There were no differences in plasma or erythrocyte Mg concentrations between the two groups, however. Their second study  was conducted on 170 patients and utilized physical examination, M-mode and 2D echocardiography done by 3 different blinded observers. None of the 27 patients without tetany showed MVP; 26% of the tetanic patients had MVP. Again there was no significant difference in plasma or erythrocyte Mg levels between the two groups, although the levels for all patients (LT and controls) were lower than standard reference ranges. These findings contrast with our observations of MVP among allergic patients . We compared the serum and erythrocyte Mg levels of patients with and without MVP who presented for evaluation and treatment of allergy. While there was no difference in serum Mg or Ca between the two groups, the MVP(+) group had a significantly lower erythrocyte Mg level than the MVP(-) group. We based the diagnosis of MVP on cardiac auscultation, not echocardiography, so that we may have been selecting a group with more severe prolapse. What is particularly noteworthy in the work just reviewed is the unique bidirectional association of MVP and LT. Not only is MVP common in patients with LT, but LT is almost universal in patients with prolapse. Considerable research by Durlach [27, 29, 30], Fehlinger , Fehlinger et al. [38, 39] and others [25, 26, 36, 43] has established Mg-D as a major determinant of the signs and symptoms of LT and LT as a useful functional test of Mg-D.
The Pathogenesis of MVP
Durlach et al.  considered all their patients to be Mg-deficient, based on blood Mg levels. They observed that the group who showed neuromuscular hyperexcitability as a manifestation of Mg-D was more susceptible to MVP than the group without tetany. They postulate a myocardial basis for prolapse, specifically a segmental papillary muscle hyperkinesis. They also suggest that complications of MVP such as cardiac arrhythmia, thromboembolism and neurasthenia may all have the same cause: Mg-D. The evidence in support of this hypothesis will now be examined.
The following features of the MVP syndrome have been reported in clinical or experimental Mg-D:
(1) Cardiac arrhythmia [35, 60]: Ventricular arrhythmia is characteristic of Mg-D. While premature ventricular contractions are the commonest arrhythmia in prolapse patients, atrial tachy- and bradyarrhythmias and conduction disturbances also occur , so that Mg-D alone cannot account for all the dysrhythmias of MVP. Prolongation of the Q-T interval has been described in some patients with MVP ; it can be caused by Mg-D .
(2) Increased urinary excretion of catecholamines [15, 52].
(3) Fatigue, depression, poor exercise tolerance , decreased resistance to psychological stress ('neuroticism') .
Irritable bowel syndrome, a condition associated with MVP  is one manifestation of LT  and can be a product of Mg-D . Experimental Mg-D in pregnant rodents produces skeletal dysgenesis in their offspring , but only with severe depletion. Mg-D increases hepatic fibrosis in response to toxic injury . Proliferation of fibroblasts also occurs in experimental Mg-D without toxic insult . These observations can explain the association between MVP and pelvic fibrosis.
HLA-Bw35, a factor favoring increased gene penetrance in MVP, is associated with abnormal Mg transport and a fall in erythrocyte Mg with age [19, 55]. Individuals bearing the Bw35 haplotype produce an abnormal response to influenza virus, characterized by impaired cytotoxicity and hence, elevated antibody levels [18, 56]. Antibody levels correlate inversely with erythrocyte Mg concentration . Furthermore, HLA-Bw16 is associated with high erythrocyte Mg and low antibody response , suggesting a role for Mg in immune regulation. The occurrence of a high frequency of C albicans infection and hypersensitivity in individuals with LT  and, conversely, of MVP in individuals with chronic candidiasis  may derive from immune dysregulation due to chronic Mg-D. Resistance to Candida infection depends on T cell cytotoxicity  and high antibody levels can be immunosuppressive . Other mechanisms by which Mg-D predisposes to candidiasis are impairment of the alternative complement pathway, which is an important part of the cytotoxic response to Candida, and elevation of circulating levels of histamine, which is immunosuppressive .
Some important aspects of the MVP syndrome cannot be explained by chronic Mg-D alone: its pathology, which suggests a dyscollagenosis, the association with autoimmune thyroid disorders and the complexity of dysautonomia. Mg-deficient animals show enhanced adrenergic responsiveness due to lack of induced down-regulation of P-receptors . MVP patients, on the other hand, are extremely sensitive to P-blockade , and may show excessive a-adrenergic and parasympathetic tone. Experimental Mg-D produces myocardial collagen deposition [52, 59] whereas MVP is associated with valvular collagen dissolution. These paradoxes might be explained by a failure of cAMP-dependent mechanisms.
Fibroblasts continually produce defective collagen and delete it by a process which is cAMP activated [3, 5]. Adenylate cyclase is Mg dependent  and Mg-D is associated with defective activity of some cAMP-dependent pathways . If MVP were indeed a genetic disorder of connective tissue, its penetrance would be enhanced by any condition which impairs the ability of fibroblasts to delete defective collagen.
Another means by which chronic Mg-D might affect cAMP activity is impairment of essential fatty acid (EFA) metabolism. Patients with normocalcernic LT show elevation of linoleic acid [18:2, n-6) in plasma phospholipids and decreased levels of its desaturation products . Dihomogammalinolenic acid (DGLA 20:3, n-6), the precursor of prostaglandin E, (PGEI), is significantly reduced. A similar desaturase block may occur in young rats and puppies rendered Mg deficient . This lesion is not easily reversed, at least in dogs [Rayssiguier, personal commun.]. The effects of this desaturation blockade would include a relative EFA deficiency and disordered PG synthesis. Physical examination of candidiasis patients reveals a significant association between MVP and dry skin/follicular keratoses , which are signs of EFA deficiency . Blocked EFA desaturation appears to play a key biochemical role in hereditary atopic diseases such as eczema  and seasonal allergic rhinitis . It is therefore likely that reduced levels of PG precursors impair the formation of immunoregulatory PGs such as PGEI . PGEI is an important determinant of cellular cAMP activity . It stimulates fibroblast collagen degradation  and enhances the maturation of cytotoxic/suppressor lymphocytes [2, 69]. PGEI protects against autoimmune phenomena (97, 98]; its deficiency may predispose to a autoirnmunity  and also to fibrosis .
PGEs are involved in the negative feedback regulation of noradrenaline secretion [54, 80]. PGE deficiency, like Mg-D, may thereby increase catecholamine secretion. On the other hand, depression of cellular cAMP/cGMP ratios, a feature of Mg  and PGE  deficiency, would augment cholinergic and a-adrenergic responsiveness and might create B-adrenergic subsensitivity . Impairment of cAMP formation impairs posttransmission synaptic hyperpolarization, an important regulatory mechanism in the central control of autonomic function . The combination of increased circulating catecholamines with distorted PG synthesis would allow all the varied forms of dysautonomia described in MVP. Further work on EFA metabolism, PG synthesis and autonomic regulation may yield new therapeutic approaches to this difficult and often refractory problem.
Most features of the MVP syndrome can be attributed to direct physiological effects of Mg-D or to secondary effects produced by blockade of EFA desaturation. These include valvular collagen dissolution, ventricular hyperkinesis, cardiac arrhythmias, occasional thromboembolic phenomena. autonomic dysregulation and association with LT, pelvic fibrosis, autoimmune disease, anxiety disorders, allergy and chronic candidiasis.
Hypornagnesemic LT is the commonest metabolic disturbance in patients with MVP. Identification and correction of pre- and postnatal Mg-D may delay or prevent the appearance of the MVP syndrome in genetically prone individuals.
The authors wish to thank Drs. J. Durlach, A. Reba, R. Lucchioni, M. Halpern, J. - G. Henrotte and Y. Rayssiguier for their comments and information, and Angelyn Singer for preparation of the manuscript.
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