Floppy Mitral Valve/Mitral Valve Prolapse and Manifestations Not Related to Mitral Regurgitation: Time to Search the Dark Side of the Moon.

BACKGROUND: Floppy mitral valve/mitral valve prolapse (FMV/MVP) is a complex entity in which several clinical manifestations are not directly related to the severity of mitral regurgitation (MR). SUMMARY: Patients with FMV/MVP and trivial to mild MR may have exercise intolerance, orthostatic phenomena, syncope/presyncope, chest pain, and ventricular arrhythmias, among others. Several anatomical and pathophysiologic consequences related to the abnormal mitral valve apparatus and to prolapse of the mitral leaflets into the left atrium provide some explanation for these symptoms. Further, it should be emphasized that MVP is a non-specific finding, while FMV (redundant mitral leaflets, elongated/rupture chordae tendineae, annular dilatation) is the central issue in the MVP story. KEY MESSAGE: The purpose of this review was to highlight the clinical manifestations of FMV/MVP not directly related to the severity of MR and to discuss the pathophysiologic mechanisms contributing to these manifestations.

Acute mitral regurgitation with and without acute heart failure.

Acute severe mitral regurgitation (MR) is rare, but often leads to cardiogenic shock, pulmonary edema, or both. Most common causes of acute severe MR are chordae tendineae (CT) rupture, papillary muscle (PM) rupture, and infective endocarditis (IE). Mild to moderate MR is often seen in patients with acute myocardial infarction (AMI). CT rupture in patients with floppy mitral valve/mitral valve prolapse is the most common etiology of acute severe MR today. In IE, native or prosthetic valve damage can occur (leaflet perforation, ring detachment, other), as well as CT or PM rupture. Since the introduction of percutaneous revascularization in AMI, the incidence of PM rupture has substantially declined. In acute severe MR, the hemodynamic effects of the large regurgitant volume into the left atrium (LA) during left ventricular (LV) systole, and in turn back into the LV during diastole, are profound as the LV and LA have not had time to adapt to this additional volume. A rapid, but comprehensive evaluation of the patient with acute severe MR is essential in order to define the underline cause and apply appropriate management. Echocardiography with Doppler provides vital information related to the underlying pathology. Coronary arteriography should be performed in patients with an AMI to define coronary anatomy and need for revascularization. In acute severe MR, medical therapy should be used to stabilize the patient before intervention (surgery, transcatheter); mechanical support is often required. Diagnostic and therapeutic steps should be individualized, and a multi-disciplinary team approach should be utilized.

Cardiovascular Disease, Cancer, and Multimorbidity Interactions: Clinical Implications.

BACKGROUND: With the aging population, the frequency of cardiovascular disease (CVD), cancer, and other morbid conditions is increasing dramatically. In addition, one disease may affect the other leading to a vicious cycle. SUMMARY: With aging, the function of organs and systems of the human body declines including the immune system resulting in a diminished response to various pathogens and a chronic inflammatory process; these changes, in addition to other risk factors, contribute to the development of multiple morbid conditions including CVD and cancer. Multimorbidity in the elderly has become the rule rather than the exception today. Further, this association between CVD and cancer, at least partially, is explained by both diseases sharing common risk factors and from accelerated vascular aging due to cancer and its associated therapies. Multiple studies have shown that the incidence of cancer is much higher in patients with CVD compared to the general population. These associations among CVD, cancer, and their connection to systems of the human body provide an opportunity for novel therapies. Development of new drugs should be addressed to focus on multiple systems and not just only to one disease. Further, collecting information from registries and processing large amounts of data using artificial intelligence may assist the clinician when treating an individual patient in the future. KEY MESSAGES: As the aging population increases, CVD, cancer, and multimorbidity will continue to constitute a major health problem in the years to come. The physician who is taking care of such a patient, in addition to knowledge, requires clinical wisdom, clinical experience, and common sense in order to apply the continuous evolving knowledge to the individual patient.

Renin-angiotensin-system inhibition in the context of corona virus disease-19: experimental evidence, observational studies, and clinical implications.

Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.

The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications.

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.

Matrix Metalloproteinase Polymorphisms in Patients with Floppy Mitral Valve/Mitral Valve Prolapse (FMV/MVP) and FMV/MVP Syndrome.

BACKGROUND: It has been suggested that collagen abnormalities of the mitral valve are present in patients with floppy mitral valve (FMV)/mitral valve prolapse (MVP). Genetic factors determining collagen synthesis and degradation have not been well defined in these patients. This study was undertaken to determine whether selective polymorphisms of matrix metalloproteinase-2 (MMP2) or transforming growth factor-ß (TGFß), with known or putative effects on collagen turnover, are more frequent in FMV/MVP. METHODS: Single nucleotide polymorphisms (SNPs) in select genes related to collagen turnover, including MMP2 rs2285053, MMP2 rs243865, TGFß1 rs1800469, and TGFß2 rs900, were determined in 98 patients with FMV/MVP who had severe mitral regurgitation and compared to 99 controls. RESULTS: MMP2 rs243865 was the only SNP significantly associated with FMV/MVP as compared to the control (odds ratio 2.07, 95% CI 1.23-3.50, p = 0.006). MMP2 rs228503 was the only SNP significantly associated with the FMV/MVP syndrome as compared to patients with FMV/MVP without the syndrome (odds ratio 2.41, 95% CI 1.08-5.40, p = 0.032). CONCLUSION: The frequency of certain MMP2 polymorphisms is higher in patients with the FMV/MVP syndrome and patients with FMV/MVP without the syndrome. The data suggest that a genetic predisposition that alters collagen turnover may play a role in the pathogenesis and development of FMV/MVP.

Heart Rate, Life Expectancy and the Cardiovascular System: Therapeutic Considerations.

It has long been known that life span is inversely related to resting heart rate in most organisms. This association between heart rate and survival has been attributed to the metabolic rate, which is greater in smaller animals and is directly associated with heart rate. Studies have shown that heart rate is related to survival in apparently healthy individuals and in patients with different underlying cardiovascular diseases. A decrease in heart rate due to therapeutic interventions may result in an increase in survival. However, there are many factors regulating heart rate, and it is quite plausible that these may independently affect life expectancy. Nonetheless, a fast heart rate itself affects the cardiovascular system in multiple ways (it increases ventricular work, myocardial oxygen consumption, endothelial stress, aortic/arterial stiffness, decreases myocardial oxygen supply, other) which, in turn, may affect survival. In this brief review, the effects of heart rate on the heart, arterial system and survival will be discussed.

The shortcomings of clinical practice guidelines.

Accumulation of medical knowledge related to diagnosis and management over the last 5-6 decades has altered the course of diseases, improved clinical outcomes and increased survival. Thus, it has become difficult for the practicing physician to evaluate the long-term effects of a particular therapy on survival of an individual patient. Further, the approach by each physician to an individual patient with the same disease is not always uniform. In an attempt to assist physicians in applying newly acquired knowledge to patients, clinical practice guidelines were introduced by various scientific societies. Guidelines assist in facilitating the translation of new research discoveries into clinical practice; however, despite the improvements over the years, there are still several issues related to guidelines that often appear 'lost in translation'. Guidelines are based on the results of randomized clinical trials, other nonrandomized studies, and expert opinion (i.e. the opinion of most members of the guideline committees). The merits and limitations of randomized clinical trials, guideline committees, and presentation of guidelines will be discussed. In addition, proposals to improve guidelines will be presented.

The left atrium: from the research laboratory to the clinic.

Studies of left atrial (LA) function, until the latter part of the 20th century, were mostly limited to experimental animal models and to studies related to clinical research in the cardiac catheterization laboratory. For this reason, LA function has received considerably less attention than left ventricular (LV) functions, even though evidence suggests that LA myopathy and failure may exist as an isolated entity, precede and/or coexist with LV myopathy. The introduction of echocardiography and Doppler echocardiography in clinical practice has contributed significantly to our understanding of LA function and its interrelationships with the LV, aorta, pulmonary artery and other parts of the cardiovascular system. In addition, LA with the secretion of atrial natriuretic peptides is playing an important role in cardiovascular and neurohumoral homeostasis. Today, it is well known that LA structural and functional abnormalities that are present in many diseases and disorders constitute a powerful prognostic indicator. As technology (echocardiography, magnetic resonance imaging, computed tomography and others) continues to evolve, it is expected that, in the near future, LA structure and function will be routinely used as LV function is used today.

Back to the basics: The need for an etiological classification of chronic heart failure.

The left ventricular (LV) ejection fraction (LVEF), despite its severe limitations, has had an epicentral role in heart failure (HF) classification, management, and risk stratification for decades. The major argument favoring the LVEF based HF classification has been that it defines groups of patients in which treatment is effective. However, this reasoning has recently collapsed, since medical treatment with neurohormonal inhibitors, has proved beneficial in most HF patients regardless of the LVEF. In addition, there has been compelling evidence, that the LVEF provides poor guidance for device treatment of chronic HF (implantation of cardioverter defibrillator, cardiac resynchronization therapy) since sudden cardiac death may occur and cardiac dyssynchronization may be disastrous in all HF patients. The same holds true for LV assist device implantation, in which the LVEF has been used as a surrogate for LV size. In this review article we update the evidence questioning the use of LVEF-based HF classification and argue that guidance of chronic HF treatment should transition to more contemporary concepts. Specifically, we propose an etiologic chronic HF classification predominantly based on epidemiological data, which will be foundational for further higher resolution phenotyping in the emerging era of precision medicine.

Floppy mitral valve (FMV)/mitral valve prolapse (MVP) and the FMV/MVP syndrome: pathophysiologic mechanisms and pathogenesis of symptoms.

Mitral valve prolapse (MVP) results from the systolic movement of a portion or segments of the mitral valve leaflets into the left atrium during left ventricular systole. It is well appreciated today that floppy mitral valve (FMV) is the central issue in the MVP and mitral valve regurgitation (MVR) story. The term FMV refers to the expansion of the area of the mitral valve leaflets with elongated chordae tendineae, chordae rupture and mitral annular dilation. FMV/MVP occurs in a heterogeneous group of patients with a wide spectrum of mitral valve involvement from mild to severe. Two types of symptoms can be defined in FMV/MVP patients. In one group of patients, symptoms are directly related to progressive MVR. In the other group, symptoms cannot be explained by the degree of MVR alone; activation of the autonomic nervous system has been implicated for the explanation of symptoms in this group of patients which is referred to as the FMV/MVP syndrome. In this brief review, the natural history, pathophysiologic mechanisms and management of patients with FMV/MVP/MVR and FMV/MVP syndrome are discussed.

Etiology of valvular heart disease in the 21st century.

A metamorphosis in the etiology of valvular heart disease (VHD) has occurred over the last 6 decades. In this review, the factors contributing to this metamorphosis, the common causes of VHD today, the relationship of valvular calcification to atherosclerosis and the interrelationship of VHD with other systems/organs are presented.