Resumen
Objetivo
Las enfermedades valvulares cardíacas se producen por diversas etiologías evitables e inevitables. La valvulopatía reumática es una de las causas prevenibles y ha desaparecido casi por completo en los países desarrollados. En la literatura reciente existen pocas evidencias de baja calidad sobre la eficacia terapéutica de la penicilina para mantener y mejorar la función miocárdica en pacientes con enfermedad cardíaca reumática. En el presente estudio, nuestro objetivo fue investigar la importancia de la penicilina en el mantenimiento de los índices de función miocárdica dentro del rango normal.
Métodos
En este estudio retrospectivo descriptivo-analítico, se incluyeron 682 pacientes consecutivos con enfermedad cardíaca reumática. Se recopiló información sobre el historial de tratamiento con penicilina y sus detalles asociados, junto con la fracción de eyección del ventrículo izquierdo y la función sistólica del ventrículo derecho, mediante un cuestionario. Finalmente, todos los datos fueron analizados utilizando el software SPSS versión 26.
Resultados
La población del estudio consistió en 471 mujeres (69,1%) y 211 hombres (30,9%), con una edad media de 51,17 ± 12,80 años, en un rango de entre 17 y 87 años. Se encontró una asociación estadísticamente significativa entre el historial de tratamiento con penicilina (valor P=0,036) y la fracción de eyección del ventrículo izquierdo. La función sistólica del ventrículo derecho se vio influenciada tanto por el historial de tratamiento con penicilina (valor P=0,040) como por la duración del tratamiento (valor P=0,002).
Conclusión
Además de los efectos profilácticos ya comprobados de la penicilina, concluimos que la penicilina también es altamente eficaz como agente terapéutico para mantener la fracción de eyección del ventrículo izquierdo y la función sistólica del ventrículo derecho dentro del rango normal en pacientes con enfermedad cardíaca reumática.
Palabras clave: carditis, fiebre reumática, penicilinas, cardiopatía reumática
Abstract
Objective
Valvular heart diseases occur following different evitable and inevitable etiologies. Rheumatic valvular heart disease is among preventable etiologies and is almost disappeared in developed nations. In recent literature there are few low-quality evidences available about therapeutic efficacy of penicillin in maintaining and enhancing myocardial function in patients with rheumatic heart disease. In present study we aimed to investigate importance of penicillin in maintaining myocardial function indices within normal range.
Methods
In this retrospective descriptive-analytic study we enrolled a number of 682 consecutive patients with rheumatic heart disease. Information about history of treatment with penicillin and associated details along with left ventricular ejection fraction and right ventricular systolic function were collected in a questionnaire. Finally, all data were analyzed using SPSS ver.26 software.
Results
The study population consist of 471 (69.1%) women and 211 (30.9%) men with mean age of 51.17±12.80 years, ranged between 17 and 87. We found that there is a statistically significant association between history of penicillin treatment (P-value=0.036) and left ventricular ejection fraction. Right ventricular systolic function was affected by history of penicillin treatment (P-value=0.040) and duration of treatment (P-value=0.002).
Conclusion
Rather than approved prophylactic effects of penicillin; we conclude that penicillin is also highly effective as a therapeutic agent in maintaining left ventricular ejection fraction and right ventricular systolic function within normal range in patients with rheumatic heart disease.
Keywords: carditis, rheumatic fever, penicillins, rheumatic heart disease
Resumo
Objetivo
As doenças valvulares cardíacas ocorrem devido a diferentes etiologias evitáveis e inevitáveis. A valvulopatia reumática está entre as etiologias preveníveis e praticamente desapareceu em países desenvolvidos. Na literatura recente, há poucas evidências de baixa qualidade sobre a eficácia terapêutica da penicilina na manutenção e melhora da função miocárdica em pacientes com cardiopatia reumática. No presente estudo, nosso objetivo foi investigar a importância da penicilina na manutenção dos índices de função miocárdica dentro da faixa normal.
Métodos
Neste estudo retrospectivo descritivo-analítico, foram incluídos 682 pacientes consecutivos com cardiopatia reumática. Informações sobre o histórico de tratamento com penicilina e detalhes associados, juntamente com a fração de ejeção do ventrículo esquerdo e a função sistólica do ventrículo direito, foram coletadas por meio de um questionário. Todos os dados foram analisados utilizando o software SPSS versão 26.
Resultados
A população do estudo consistiu de 471 mulheres (69,1%) e 211 homens (30,9%), com idade média de 51,17 ± 12,80 anos, variando entre 17 e 87 anos. Encontrou-se uma associação estatisticamente significativa entre o histórico de tratamento com penicilina (valor de P = 0,036) e a fração de ejeção do ventrículo esquerdo. A função sistólica do ventrículo direito foi afetada pelo histórico de tratamento com penicilina (valor de P=0,040) e pela duração do tratamento (valor de P=0,002).
Conclusão
Além dos efeitos profiláticos comprovados da penicilina, concluímos que a penicilina também é altamente eficaz como agente terapêutico na manutenção da fração de ejeção do ventrículo esquerdo e da função sistólica do ventrículo direito dentro da faixa normal em pacientes com cardiopatia reumática.
Palavras-chave: carditis, febre reumática, penicilinas, cardiopatia reumática
KEY CONCEPTS
What is currently known about the subject?
Rheumatic heart disease (RHD) remains a significant public health issue, particularly in low- and middle-income countries, despite being largely controlled in developed nations. It is a major complication of acute rheumatic fever, which typically follows infection with group A β-hemolytic streptococcus. RHD primarily affects the heart valves and can lead to chronic cardiac dysfunction, disability, and early death. Prophylactic treatment with penicillin is widely accepted for primary prevention of rheumatic fever, but there is still considerable debate regarding the efficacy and optimal regimen for secondary prevention. Most previous research has focused on valvular damage, with limited evidence about the impact of penicillin treatment on myocardial function.
What does this work contribute?
This study provides new evidence on the potential protective effect of penicillin treatment on myocardial function in patients with rheumatic heart disease (RHD), beyond its well-established role in preventing valvular damage. By analyzing left ventricular ejection fraction (LVEF) and right ventricular (RV) systolic function in a large population of RHD patients, the study suggests that a history of penicillin treatment is associated with better myocardial function. It also highlights that even delayed or unsynchronized treatment may offer benefits. This is one of the first studies to focus specifically on ventricular function in relation to penicillin therapy in RHD, filling an important gap in the literature and encouraging further research in this area.
Divulgación
In this study, we looked at over 680 people in Iran with rheumatic heart disease, a condition that can seriously damage the heart if not treated properly. While penicillin is known to help prevent rheumatic fever, we wanted to see if it also helps protect the heart muscle itself, not just the valves. We found that patients who received penicillin had better heart function, even if treatment didn’t start immediately. This suggests penicillin might have broader benefits than previously thought. Our findings also highlight that many patients still lack proper treatment, especially in resource-limited areas. We hope this study encourages new ways to improve care for people with this disease.
Introducction
Cardiovascular diseases are the leading causes of death around the world and are followed by a higher chance of mortality and morbidity and cause serious lifelong complications or even early death. When talking about cardiovascular diseases, a wide spectrum of diseases come to mind such as ischemic heart diseases, congestive heart diseases, coronary artery diseases and valvular heart diseases(1).
Valvular heart diseases may appear followed by different etiologies which some are inevitable or hardly evitable such as congenital heart malformations and some are easily preventable. Among preventable etiologies of valvular heart diseases, rheumatic heart diseases are notable( 2). Rheumatic heart diseases have almost been controlled in developed countries but unfortunately, they are still a prominent clinical challenge for physicians in developing countries(3).
Rheumatic heart disease (RHD) and valvular involvement is the most important complication of rheumatic fever in which irreversible sequela may remain forever and cause disability for involved individuals and heavy economic burden for healthcare and medical insurance systems(4).
Acute rheumatic fever is followed by group A β-hemolytic streptococcus (GABHS) pharyngitis and may present with different systemic symptoms such as joint swelling, fever, chorea, skin lesions and etc. Since decades, clinicians are using Dr. Jones criteria (published in 1944) for diagnosis of acute rheumatic fever, which is based on five major diagnostic criteria: arthritis, chorea, erythema marginatum, subcutaneous nodules and carditis(5).
Rheumatic fever can be followed by different complications such as endocarditis, carditis, valvular involvement, heart failure and even death(6). In literature it is estimated that there are over 15 million cases of rheumatic heart disease worldwide with incidence of 282 000 new cases annually and mostly in developing regions and young generation( 7).
In recent literature there is an agreement on prophylaxis of rheumatic fever and primary prevention with penicillin, but there is a great controversy on efficacy of secondary prevention via penicillin and there is no definite agreement or even enough evidences on details such as duration, dosage, or efficacy of treatment(8).
Considering importance of rheumatic valvular disease and its complications specially in young generation, along with high prevalence and incidence in developing countries and shortage of reliable papers in this case, in this study we aimed to perform a comprehensive research specially focused on myocardial function indices in patients with rheumatic heart disease and its association with penicillin treatment in Iran.
Materials and Methods
This is a retrospective descriptive analytic study about rheumatic heart disease carried out in Yazd, Iran. In this study we enrolled a number of 682 consecutive Iranian patients with rheumatic heart disease during a period of 5 to 6 years. This study was designed and conducted based on latest declaration of Helsinki and is registered in committee of research ethics with IR.SSU.REC.1398.168 approval code.
Considering lack of an appropriate registry system in Iran for rheumatic heart diseases, in this investigation we tried to collect an accurate and reliable database for further data analysis. This database is collected within a long duration of 5 to 6 years by an expert cardiology fellowship in field of echocardiography in different outpatient clinics and hospitals in Yazd, Iran.
Yazd city is located in Yazd state in central zone of Iran which is recently known as a reference treatment city for its well accessibility, well known physicians and short distance from lower income cities in south and southeast regions of Iran and covers patients across borders of only Yazd state.
We included all patients from any hospital or outpatient clinic with evidences of rheumatic heart disease and history of rheumatic fever diagnosed based on echocardiography findings in accordance with latest World Heart Federation criteria(9) by an echocardiography fellowship trained physician. Patients with evidences of any other etiology for valvular diseases, history of myocardial infarction, percutaneous coronary intervention, endocarditis, coronary artery bypass grafting were excluded. An accurate history was obtained from all patients and was registered in a questionnaire by an expert echocardiography fellow in terms of demographic and background information and details about how they used penicillin.
After obtaining an informed consent, all patients’ information along with history of penicillin treatment and associated details such as age of initial penicillin injection, duration of treatment with penicillin and synchrony between penicillin prescription and symptoms were registered. Patients’ echocardiography findings such as RV systolic function and LVEF were registered in the questionnaire as well.
Patients were divided into 4 groups based on RV systolic function as normal, mild RV systolic dysfunction, moderate RV systolic dysfunction and severe RV systolic dysfunction. Based on LVEF, patients were categorized as normal and abnormal LVEF with a cutoff of 50%.
All echocardiographies were performed by the same experienced echocardiography fellowship trained cardiologist. For assessing LVEF the standard 2D visual estimation method was applied and Simpson’s method was used for susceptible patients in terms of intra observer variability. Fractional area change index was used for 2D eyeball evaluation of RV chamber systolic function(10).
Results of this study are completely focused on effect of penicillin in myocardial function indices including LVEF and RV systolic function. Other results associated with valvular involvement, associated medical conditions and other descriptive information are reported as a separate paper since we did not want to enlarge this paper and loose our focus over myocardial function indices as the main objective of this paper(11).
Statistical analysis
SPSS ver.26 software was applied for all statistical analyses. Frequency and descriptive tests were used for describing study population and the results are reported in form of mean±SD, minimum, maximum, frequency and percentage.
We used the Kolmogorov-Smirnov and Shapiro-Wilk tests to assess normality. Since both dependent variables (LVEF and RV systolic function) were not normally distributed, we applied non-parametric tests for all subsequent analyses.
Analyses associated with history of penicillin treatment were performed on the whole study population but other analyses performed of details about penicillin treatment (synchrony of treatment with symptoms, age of initial treatment and duration of penicillin treatment) were only performed on patients with positive history of penicillin treatment.
The Chi-square test was used to assess associations between nominal variables. For comparing continuous variables across three or more independent groups, the Kruskal-Wallis test was applied, while the Mann-Whitney U test was used for comparisons between two groups. Spearman’s correlation test was employed to evaluate relationships between two quantitative variables. A two-tailed P-value<0.05 was considered statistically significant in all analyses.
Results
Based on our database, mean patients’ age was 51.17±12.80 years ranged between 17 and 87 years. Among enrolled patients 140 (20.5%) of them aged below 40 years. There were 471 (69.1%) women and 211 (30.9%) men among study sample. Considering importance of family population in RHD we report that 437 (64.1%) of patients were from a family with ≥5 siblings and only 50 (7.3%) patients had a positive family history for RHD.
In the studied population, only 292 (42.8%) patients were treated with penicillin regardless of duration of treatment or any other variable such as dosage. Among 292 patients who had history of penicillin treatment, only 80 (27.4%) of them started penicillin simultaneous with their symptoms.
In this population, 139 (20.4%) patients had hypertension (HTN), 82 (12%) patients had diabetes mellitus (DM) and 95 (13.9%) patients had dyslipidemia. Among studied patients, 91, 94, 43 and 45 cases of severe mitral stenosis (MS), mitral regurgitation (MR), aortic stenosis (AS) and aortic insufficiency (AI) were observed respectively.
Effect on LVEF
In this study mean patients’ LVEF was 48.85±8.61. As seen in figure No.1, LVEF was not normally distributed and thus non-parametric tests were used in all analyses with LVEF as dependent variable (Kolmogorov- Smirnov P-value<0.001, Shapiro-Wilk P-value<0.001).
Figure 1. As seen in this histogram, LVEF is not normally distributed in our study sample size (Kolmogorov-Smirnov P-value<0.001, Shapiro-Wilk P-value<0.001).
To compare LVEF between patients with and without a history of penicillin treatment, we used the Mann- Whitney U test. The results indicated that LVEF was significantly higher in patients who had received penicillin (U=62,131, P-value=0.036).
However, there was no statistically significant difference in LVEF between patients who received penicillin treatment simultaneously with symptom onset and those who did not (U=7,261, P-value=0.051).
Additionally, no significant correlations were found between LVEF and either the age at first penicillin injection (Spearman’s r=0.110, P-value=0.060) or the duration of penicillin treatment (Spearman’s r=-0.088, P-value=0.131).
Figure No. 2 is presented to better demonstrate the association between history of treatment with penicillin and LVEF. Abnormal LVEF is defined as LVEF<50%.
Figure 2. There is a statistically significant association between LVEF and history of penicillin treatment (P-value=0.036).
Effect on RV systolic function
In this study, RV systolic function was not normally distributed among patients and thus non-parametric tests were used in all analyses with RV function as the dependent variable (Kolmogorov-Smirnov P- value<0.001, Shapiro-Wilk P-value<0.001).
Our results demonstrated a statistically significant association between a history of penicillin treatment and RV systolic function, as determined by the Chi-square test (P-value=0.040). In this analysis, patients were categorized into four groups based on RV systolic function: normal, mild dysfunction, moderate dysfunction, and severe dysfunction.
Table No. 1 presents the cross-tabulation of these RV function categories by penicillin treatment history. The distribution across categories suggests that patients with a history of penicillin treatment were more likely to exhibit better RV systolic function. This association indicates a potential protective effect of penicillin therapy on right ventricular function.
Table I. Association between history of penicillin treatment and RV systolic function.
|
RV systolic dysfunction |
History of penicillin treatment |
|||
|---|---|---|---|---|
|
Yes |
No |
|||
|
Normal |
190 (65.1%) |
236 (60.5%) |
||
|
RV dysfunction |
102 (34.9%) |
Mild: 69 |
154(39.5%) |
Mild: 114 |
|
Moderate: 20 |
Moderate: 34 |
|||
|
Severe: 13 |
Severe: 6 |
|||
|
Total |
292 (100%) |
390 (100%) |
||
Table 1 There is a statistically significant association between RV systolic function and history of treatment with penicillin (P-value=0.04). Results are reported as frequency (percentage%).
RV: right ventricle.
The Kruskal-Wallis test, a non-parametric alternative to one-way ANOVA, was used to compare the duration of penicillin treatment across groups based on RV systolic function. Results showed a significant difference among the groups (H(3)=15.018, P-value=0.002). Pairwise comparisons with Bonferroni correction revealed a significant difference between patients with normal and severe RV dysfunction (adjusted P-value=0.010).
Figure 3. There is a significant difference in duration of treatment with penicillin across different groups of patients based on RV systolic function (P-value=0.002).
In this study, no statistically significant association was found between RV systolic function and the age at first penicillin injection (H(3)=7.556, P-value=0.056) or the synchrony between penicillin injection and symptom onset (Chi-square P-value=0.120).
Table No. 2 presents the cross-tabulation of RV systolic function categories against the timing of penicillin treatment relative to symptom onset, which was analyzed using the Chi-square test to assess potential associations.
Table II. association between RV systolic function and synchrony of treatment with symptoms.
|
RV systolic function |
Synchrony of treatment with symptoms |
Total |
|
|
Simultaneous |
Not simultaneous |
||
|
Normal |
53 (27.9%) |
137 (72.1%) |
190 (100%) |
|
Mild RV dysfunction |
22 (31.9%) |
47 (68.1%) |
69 (100%) |
|
Moderate RV dysfunction |
1 (5%) |
19 (95%) |
20 (100%) |
|
Severe RV dysfunction |
4 (30.8%) |
9 (69.2%) |
13 (100%) |
|
Total |
80 (27.4%) |
212 (72.6%) |
292 (100%) |
Table 2 There is no significant association between synchrony of penicillin treatment with symptoms and RV systolic function (P-value=0.120).
In figure No.4, the association between severity of RV systolic dysfunction and history of treatment with penicillin is shown.
Figure 4. There is a statistically significant association between history of treatment with penicillin and RV systolic function (P-value=0.04).
Discussion
In this study, the focus was on LVEF and RV systolic function as the most important indices associated with myocardial function in patients with RHD. We defined clinically challenging and controversial variables from up-to-date guidelines and literature associated with penicillin treatment including: 1) history of penicillin treatment, 2) synchrony or asynchrony of penicillin prescription with symptoms, 3) duration of penicillin treatment and 4) age of first penicillin injection.
Based on our knowledge and comprehensive database search, we believe that there is no similar study performed in field of RHD up to now. There are different studies performed on efficacy of penicillin treatment but valvular outcomes are mainly focused in those studies. No paper is published about importance of treatment with penicillin in maintaining myocardial function indices. Details on how to prescribe penicillin for patients -which is really questionable in daily practice and is controversial in guidelines- are not discussed in recent publications(12). Although there have been few studies performed on other cardiac complications of RHD such as carditis, still none of them have directly investigated ventricular volumes and the most important cardiac function indices meaning LVEF and RV systolic function(13).
RHD cases are mostly seen in low income and developing countries and considering lack of a good registry in such countries along with low quality researches, previous reviews concluded that high quality researches are needed to achieve a conclusion in field of RHD. Our paper is actually only a part of a large ongoing registry we have started. We are proud to emphasize on reliability and accuracy of our data.
In this population of 682 cases less than half of cases mention history of treatment with penicillin which indicates poor management of patients for any reason. Poor management of such patients was also previously reported in different studies such as Karthikeyan G’s et al(14).
In previous studies it was reported that penicillin can significantly enhance long term outcomes in patients with acute rheumatic fever and penicillin injection was strongly suggested in them [4], but unfortunately, in our population, among those few patients with history of penicillin treatment, only 27.4% of them used penicillin with symptoms of the disease.
In this study we discovered a significant difference in mean LVEF based of history of penicillin treatment which means patients with history of penicillin treatment had a significantly higher mean LVEF compared those without history of penicillin treatment. We believe that this is the eminent finding of this paper. Our statistical analysis results indicate that this difference is same significant in patients above 30 compared to younger patients. This means that patients benefit penicillin prescription regardless of their age of diagnosis.
In this study we did not observe any statistically significant association between LVEF and synchrony of treatment with symptoms, duration of treatment with penicillin or age of initiation of treatment.
Considering significant association between LVEF and history of penicillin treatment we conclude that penicillin treatment is critical in safeguarding LVEF regardless of synchrony of symptoms, duration of treatment or age of first injection and almost all patients will benefit from treatment with penicillin.
In this study we also performed analysis on our data related to severity of RV systolic dysfunction. We report that penicillin injection can possibly avoid RV systolic dysfunction and, in this case, duration of penicillin treatment is also important.
Considering importance of clinical significance along with statistical significance, we don’t want to be dragged into a game of numbers and close our eyes on importance of synchrony of penicillin injection with symptoms in maintaining LVEF only because SPSS gives us a P-value of 0.051 or completely ignore importance of age of first penicillin injection in enhancing RV systolic function because of a P-value=0.056.
In an interesting cost effectiveness study about treatment with penicillin which was performed by Manji RA et al, researchers concluded that penicillin injection is worthy in comparison to morbidities that may happen in patients(15).
There were different studies performed on prevalence of RHD in endemic regions and they all indicated high burden of this disease and associated morbidities on their society and no good news is yet coming out of those regions(16-21).
Different studies were designed and performed to evaluate the role and importance of echocardiographic screening of young patients in different countries. Almost all of them have reported that prevalence and dimensions of the disaster is far beyond expectations and what statistics show( 20, 22-24).
Considering high prevalence of the disease and high number of not diagnosed cases, we strongly suggest that at least we must do something for those diagnosed cases and minimum we can do for them is to write “penicillin”.
Limitations
Despite very large study population of such rare cases, this study has several limitations. The main methodological limitation is related to retrospective and descriptive nature of this project. Another error which arises from retrospective method of the paper is the recall bias since we had to ask some included patients to remember their treatment history, therefore, it was not possible to collect data associated with accurate dosage and route of penicillin treatment. It is also mentionable that in present manuscript, the higher LVEF cutoff (60%) in cases with mitral regurgitation was ignored.
We do not claim that with this single study, it is possible to judge efficacy of penicillin, but due to very accurate echocardiographies, large study population and presentability of the data, we believe that this descriptive study can be a start point for further investigations.
Future researchers are advised to perform cohort studies in this field and in order to facilitate obtaining even a higher study population and multidisciplinary information from different countries, we warmly welcome authors to join us for data sharing.
Conclusion
As we know, previous studies were all focused on valvular complications of RHD and they all reported importance of penicillin without mentioning detailed information about treatment strategy.
In this study we worked on a population of 682 patients with RHD and concluded that penicillin is still the best choice to safeguard ventricular volumes and myocardial function indices in patients with rheumatic heart disease.
Notas
Limitaciones de responsabilidad
La responsabilidad de esta publicación es de los autores.
Conflicto de interés:
Ninguno.
Fuentes de apoyo
No posee.
Originalidad
Este artículo es original y no ha sido enviado para su publicación a otro medio de difusión científica en forma completa ni parcialmente.
Cesión de derechos
Quienes participaron en la elaboración de este artículo, ceden los derechos de autor a la Universidad Nacional de Córdoba para publicar en la Revista de la Facultad de Ciencias Médicas de Córdoba y realizar las traducciones necesarias al idioma inglés.
Contribución de los autores
Quienes participaron en la elaboración de este artículo, han trabajado en la concepción del diseño, recolección de la información y elaboración del manuscrito, haciéndose públicamente responsables de su contenido y aprobando su versión final.
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